Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:24](COCC[Si](C)(C)C)[C:16]2[N:17]=[CH:18][C:19]3[N:20]([CH:21]=[N:22][CH:23]=3)[C:15]=2[CH:14]=1.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:24][C:16]2[N:17]=[CH:18][C:19]3[N:20]([CH:21]=[N:22][CH:23]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cncn43)n1COCC[Si](C)(C)C)cn2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cncn43)[nH]1)cn2C
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
7-(5-Methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.048 g, 0.11 mmol) in DMF (4 mL) was treated with ethylenediamine (0.22 mL, 3.3 mmol) and heated to about 85° C. for about 5 min. The solution was cooled and TBAF (1 M in THF, 0.11 mL, 0.11 mmol) was added. The solution was re-heated to about 85° C. for about 30 min. The mixture was cooled to ambient temperature and another portion of the TBAF (1 M in THF, 0.054 mL, 0.054 mmol) was added and heating was continued for about 1.5 h. The solution was cooled and the material was purified by preparative RP-HPLC (Table 2, Method 1). The product-containing fractions were concentrated to remove MeCN then basified with saturated aqueous NaHCO3 and extracted with EtOAc (2×10 mL). The combined organic solutions were dried over anhydrous MgSO4, filtered, and concentrated. Trituration of the solid with heptane (5 mL) then collection by filtration gave 7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.028 g, 8%): LC/MS (Table 2, Method a) Rt=1.91 min; MS m/z: 318.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6 δ12.18 (s, 1H), 8.77 (s, 1H), 8.59 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.43 (d, J=8.9 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 6.92 (dd, J=8.90, 2.36 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[N:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][CH:26]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:31][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:21]3[S:20][CH:24]=[CH:23][N:22]=3)[N:30]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2nccs2)n1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2nccs2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 6-(thiazol-2-yl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 409.94 g/mol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:15]([CH3:14])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.8 %

Procedure:
N-tert-Butoxycarbonylpiperazine (2.94 g, 16.0 mmol) was dissolved in pyridine (8 mL) under nitrogen and the solution cooled to 0° C. Methanesulfonyl chloride (1.5 mL, 19.3 mmol) was added. After 5 minutes, more pyridine was added (5 mL) and the reaction mixture was allowed to warm to ambient temperature. After 40 minutes, the pyridine was removed in vacuo. The residue was dissolved in ethyl acetate (250 mL), washed with 0.1M citric acid (3×125 mL), dried over magnesium sulfate, concentrated in vacuo, and dried under vacuum to give 3.84 g (92%) of N-tert-butoxycarbonyl-N′-methylsulfonylpiperazine.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][C@H:45]1[CH2:47][O:46]1.CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:29][CH2:30][N:31]([CH2:44][C@@H:45]([OH:46])[CH3:47])[CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:35])=[O:36])[CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: C[C@H]1CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 62.1 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-benzyl-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (175 mg. 0.249 mmol) was alkylated using (S)-2-methyloxirane (27 mg, 0.498 mmol), DIPEA (129 mg, 0.996 mmol) and ethanol (5 mL) to get 100 mg (62.1% yield) of the titled compound. MS: m/z=647.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:21]([NH2:22])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:23]([NH:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)(=[O:25])[CH3:24].C1C(Cl)=CC=C(Cl)C=1>N1C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:21]([NH:22][S:33]([C:29]3[CH:28]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[CH:32]=[CH:31][CH:30]=3)(=[O:35])=[O:34])=[N:20][C:19]3[C:14]([N:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CC(=O)Nc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1cc(Nc2nc3ccccc3nc2N)cc(OC)c1
Solvent: c1ccncc1
Solvent: Clc1ccc(Cl)cc1
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(NC(C)=O)c2)cc(OC)c1
Temperature: 25 °C
Yield: 24 %

Procedure:
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine (50 mg, 0.168 mmol), 3-Acetylamino benzene sulfonylchloride (59 mg, 0.5 mmol, commercially available from INTERCHIM) are dissolved in a 1 to 2 mixture of pyridine: dichlorobenzene (0.3 ml) and the reaction mixture is heated to 150° C. overnight in an orbital shaker. When TLC confirms the total consumption of the starting material, the reaction mixture is cooled down to rt. The precipitate formed is filtered and purified by column chromatography, using Pet.Ether: EtOAc as eluent, to afford 20 mg (24%) of the title compound as a yellow solid. HPLC (max plot) 89%, rt. 4.08 min. LC/MS: (ES+): 494.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[OH:15])[C:11](O)=[O:12])=[CH:4][C:3]=2[O:2]1.Cl.[NH2:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[CH3:38][O:37][C:35](=[O:36])[C@H:24]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[NH:23][C:11](=[O:12])[CH:10]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[CH:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[OH:15]
Reactant: O=C(O)C(c1ccc2c(c1)OCO2)C(O)C1CCCCC1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(c1ccc2c(c1)OCO2)C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a solution of (2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionic acid (100 mg), HCl.H-L-Trp-OMe (136 mg) and HOBT (55 mg) in dimethylformamide (6 ml) was added WSCD (64 mg) under ice-bath cooling. After being stirred overnight at room temperature, the mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml). The organic layer was washed with 5% hydrochloric acid solution, 1M aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo to afford N-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophane methyl ester (165 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]([CH3:7])=[CH:5][CH2:4][C@@H:3]1[CH:8]([OH:10])[CH3:9].Br[CH2:13]Br>C(Br)(=O)C.C(OCC)C.[Zn]>[CH3:7][C:6]12[CH2:13][CH:5]1[CH2:4][C@H:3]([CH:8]([OH:10])[CH3:9])[C:2]2([CH3:1])[CH3:11]
Reactant: CC1=CC[C@H](C(C)O)C1(C)C
Reactant: BrCBr
Agent: CC(=O)Br
Agent: [Zn]
Solvent: CCOCC
Product: CC(O)[C@H]1CC2CC2(C)C1(C)C
Reaction time: 0.17 h
Yield: 4.2 %

Procedure:
A drop of acetyl bromide (1 drop) was added to a mixture of activated (with 1N HCl) zinc (19.6 g, 0.3 mol), cuprous bromide (1.5 g, 0.01 mol) and 1-((1S)-2,2,3-trimethylcyclopent-3-enyl)ethanol (ca. 20% ee, 15.4 g, 0.3 mol) in diethyl ether (50 ml). After 10 minutes stirring, dibromomethane (52.0 g, 0.3 mol) was added and stirring at reflux continued for 6 h. The solid was filtered off and washed with MTBE. The combined organic phases were washed with water and diluted citric acid solution, dried (MgSO4), concentrated in vacuo and distilled using a 5 cm Widmer-column to give 1-((3S)-1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)ethanol (2.1 g, 12.5% yield, colourless liquid; GC/MS: 3 main diastereomeric pairs of enantiomers 33+30.5+20%). Analytical samples of the three main pairs of enantiomers were obtained by flash chromatography (MTBE/hexane 1:3)
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[N+:17]([O-])=O)[CH3:6])(=[O:3])[CH3:2].[H][H]>[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-].CO>[NH2:17][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:7]=1[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:6])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc([C@@H](C)NC(C)=O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc([C@@H](C)NC(C)=O)c(N)c1
Yield: 100.3 %

Procedure:
Methyl (R)-4-(1-acetamidoethyl)-3-nitrobenzoate (1 g) was stirred in a stream of hydrogen at room temperature for 3 hours using 10% palladium hydroxide carbon (0.3 g) in a methanol (20 ml) solution. After the reaction, the catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to give 0.89 g of methyl (R)-3-amino-4-(1-acetamidoethyl)benzoate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)([CH3:25])=[O:24].Cl.C(=O)(O)[O-].[Na+]>COCCO.CCO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([P:23]([CH3:25])([CH3:22])=[O:24])=[CH:32][CH:31]=2)=[N:3][CH:4]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CP(C)(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(P(C)(C)=O)cc2)ncc1Cl
Temperature: 140 °C
Yield: 149.1 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (prepared as in Example 17: 50 mg, 0.14 mmol) in 1 mL of 2-methoxyethanol was added 4-(dimethylphosphoryl)-aniline (0.025 g, 0.14 mmol) and 0.12 ml of 2.5M HCl in EtOH. The mixture was heated in a sealed tube at 140° C. for 1 h. The mixture was basified with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was purified by prep-HPLC to give the final product (0.100 g, 15% yield). MS/ES+: m/z=478.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][C:17]([O:23][CH3:24])([C:20]([OH:22])=O)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2].Cl.[CH3:26][C:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][O:23][C:17]1([C:20](=[O:22])[NH:31][C:27]2([CH3:26])[CH2:30][CH2:29][CH2:28]2)[CH2:16][CH2:15][N:14]([CH:9]2[CH2:8][CH:7]3[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH2:19][CH2:18]1
Reactant: CC1(N)CCC1
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC(OC)(C(=O)O)CC1)C2
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: CN(C)C=O
Product: CCOC(=O)N1C2CCC1CC(N1CCC(OC)(C(=O)NC3(C)CCC3)CC1)C2
Temperature: 25 °C
Reaction time: 60 h
Yield: 25.4 %

Procedure:
1-[8-(Ethoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-4-methoxypiperidine-4-carboxylic acid (0.093 g, assumed 0.27 mmol) was dissolved in DMF (5 mL) and (1-methylcyclobutyl)amine hydrochloride (0.05 g, 0.411 mmol), HATU (0.156 g, 0.41 mmol) and DIPEA (0.177 g, 0.24 mL, 1.37 mmol) were added. The reaction mixture was stirred at rt for 60 h and the solvents were removed in vacuo. The residue was partitioned between DCM and sat. NaHCO3 sol., the organic layer was washed with sat. NaCl sol. and dried (MgSO4). The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 A, 25 mL per min, gradient 0% to 10% MeOH in DCM]) to give ethyl 3-{4-methoxy-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate isomer 1 (0.028 g, 25%) as a pale yellow gum.
Reaction SMILES: O.O.[Na+].[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:14][OH:15])[C:11]([O-:13])=[O:12])[N:9]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:14][O:15][C:16](=[O:18])[CH3:17])[C:11]([OH:13])=[O:12])[N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(C(=NO)C(=O)[O-])cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)ON=C(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate sodium dihydrate (syn-isomer) (24.6 g) was added to water (160 ml) and stirred at 20 to 30° C. Acetic anhydride (28.7 g) was added dropwise thereto for 60 minutes. During the dropwise addition, the pH of the mixture was controlled to 6.0±0.2 by using 20% aqueous sodium carbonate. After the dropwise addition, the mixture was stirred for 30 minutes, and the pH of the mixture was adjusted to 2.5 by using 6N hydrochloric acid. After the reaction liquid was cooled to 5° C., the precipitated crystal was filtered and washed with isopropanol and acetone successively. The obtained wet crystal was dried under reduced pressure to obtain 2-(2-aminothiazole-4-yl)-2-acetoxyiminoacetic acid (syn-isomer) (23.9 g) including two molecules of crystal water.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:13].[CH2:14](O)[CH3:15]>[Pd]>[ClH:13].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:14][CH3:15])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCO
Reactant: N#Cc1cccc(CC(=O)O)c1
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)Cc1cccc(CN)c1

Procedure:
A mixture of (3-cyanophenyl)acetic acid (3 g, 18.6 mmol), 10% palladium on charcoal (300 mgs) and conc. hydrochloric acid (3 eqs, 4.6 mls, 55.8 mmol) in ethanol (100 mls) was subject to an atmosphere of hydrogenation overnight. The resulting mixture was filtered through hyflo and the catalyst washed thoroughly with ethanol. The solvent was then evaporated in vacuo to give a crunchy white solid. This was triturated with ether, filtered off and dried to afford a white solid (2.76 g). 1H-NMR (400 MHz, d4-MeOH) δ 1.24 (3H,t, J 8.0), 3.69 (2H,s), 4.11 (2H,s), 4.15 (2H,q, J 13.2 6.0), 7.17-7.20 (1H, m), 7.34-7.44 (4H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@H:14]([OH:18])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CN(C1C=CN=CC=1)C>[C:25]([O:18][C@@H:14]([CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:15]([OH:17])=[O:16])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NCC[C@H](O)C(=O)O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(NCC[C@H](OC(=O)c1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 51 %

Procedure:
To a stirring solution of (S)-4-(benzyloxycarbonylamino)-2-hydroxybutanoic acid (1, 612 g, 2.41 mol) in THF (6 L) at 0° C. was added DMAP (2.4 g) and pyridine (196 mL, 2.41 mol). After stirring for 20 minutes, benzoyl chloride (280 mL) was added slowly and the reaction was allowed to stir overnight at room temperature. The resulting precipitate was filtered and the filtrate was acidified with 1 M citric acid (1 L). The organic solvent was removed by rotary evaporation and the desired product was extracted with EtOAc (2×2 L). The combined organic layers were washed with 1 M citric acid (1 L), brine (1 L) and then dried over MgSO4. Solvent removal under vacuum resulted in a viscous oil, which was purified on a 6-inch reverse-phase HPLC column to yield (S)-2-(benzoyloxy)-4-(benzyloxycarbonylamino)butanoic acid (2) as a non-flowing viscous oil (439 g, 51% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:17])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[C:32]([C:36](Cl)=[O:37])=[CH:31][CH:30]=[CH:29]3)[CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:36]([C:32]2[C:33]3[C:28](=[CH:27][C:26]([O:25][C:21]4[CH:20]=[C:19]([Cl:18])[N:24]=[CH:23][N:22]=4)=[CH:35][CH:34]=3)[CH:29]=[CH:30][CH:31]=2)=[O:37])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(F)cc2)n1
Reactant: O=C(Cl)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)c2cccc3cc(Oc4cc(Cl)ncn4)ccc23)n(-c2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
560 mg (2.4 mMol) 5-tert-butyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-ylamine and 763 mg (2.4 mMol) 6-(6-chloropyrimidin-4-yloxy)-naphthalene-1-carbonyl chloride (see Step 19.3) are dissolved in 5 ml CH2Cl2 and cooled to 0° C. 193 μl (2.4 mMol) Pyridine are added dropwise and after complete addition the reaction is allowed to warm to rt. It is stirred for 2 h at ambient temperature. The reaction is concentrated under reduced pressure and the remaining crude product is purified by flash chromatography (combi-flash, 40 g column; CH2Cl2/MeOH; gradient 0-5% MeOH) to give the title compound as a yellow foam: MS: [M+1]+=517.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][NH:10][C:11]([O:13][CH2:14][CH2:15][Cl:16])=[O:12].[CH3:17][O:18][CH2:19][C:20](Cl)=[O:21].COCC(O)=O.S(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[CH3:17][O:18][CH2:19][C:20]([N:9]([C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[NH:10][C:11]([O:13][CH2:14][CH2:15][Cl:16])=[O:12])=[O:21]
Reactant: COCC(=O)Cl
Reactant: Cc1cccc(C)c1NNC(=O)OCCCl
Agent: COCC(=O)O
Solvent: Cc1ccccc1C
Solvent: O=S(Cl)Cl
Product: COCC(=O)N(NC(=O)OCCCl)c1c(C)cccc1C

Procedure:
200 g (0.825 mol) 2-Chloroethyl 2-(2,6-dimethylphenyl)-hydrazinecarboxylate in 500 ml xylene are warmed to 80°, and added to a warm (80°) solution of 2-methoxyacetylchloride in 250 ml xylene, prepared in situ by treating 73.5 g (0.826 mol) 2-methoxyacetic acid in 250 ml xylene with 107.1 g (0.9 mol) thionyl chloride at 80° for 2 hours. The mixture is heated for 30 minutes at 80°, then worked up as described in Example 1a.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].CCN(CC)CC.[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([Si:16]([CH3:18])([CH3:17])[O:4][CH2:1][C:2]#[CH:3])([CH3:15])([CH3:14])[CH3:12]
Reactant: C#CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of prop-2-yn-1-ol (168 g, 3 mol), Et3N (412 g, 4.08 mol) in CH2Cl2 (3500 mL) was added a solution of TBSCl (543 g, 3.45 mol) in CH2Cl2 (500 mL) at 0° C. Then the reaction mixture was warmed up to room temperature and stirred overnight. The mixture was washed by water (3000 mL), dried over Na2SO4, and concentrated to give crude product, which was purified by flash chromatography (petroleum ether) and distillation to give compound S-1 as a yellow liquid. (110 g, 43%)
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[N:7](=[C:9]1[CH:13]([CH3:14])[O:12][CH2:11][S:10]1)[OH:8]>CCOCC.C(N(CC)CC)C>[CH2:1]([NH:4][C:5]([O:8][N:7]=[C:9]1[CH:13]([CH3:14])[O:12][CH2:11][S:10]1)=[O:6])[CH:2]=[CH2:3]
Reactant: CC1OCSC1=NO
Reactant: C=CCN=C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CCNC(=O)ON=C1SCOC1C

Procedure:
A quantity of 3 ml of allyl isocyanate was caused to react with 3 grams of 4-oximino-5-methyl-1,3-oxathiolane dissolved in 50 ml of ether containing 2 drops of triethylamine over a period of 20 hours at room temperature. Conventional workup and recrystallization from isopropyl ether afforded 3 grams of product, mp 66.0°-67.5°, structure confirmed by spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[CH:22]([OH:27])[C:23]([O:25][CH3:26])=[O:24].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(O)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To a mixture of methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (2.5 g, 6.48 mmol) in CH2Cl2 (70 mL) was added Dess-Martin periodinane (3.02 g, 7.13 mmol) and stirred at room temp for 1 h. Then diluted with ethyl acetate (500 mL) and washed with sat. NaHCO3 solution (100 mL), dried (Na2SO4), filtered and concentrated and the residue was purified by silica gel chromatography (5-30% EtOAc/hexane) to afford desired methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (1.1 g, 2.87 mmol, 44.2% yield) as off-white solid. 44% yield based on 2 steps. 1H NMR (500 MHz, CDCl3) δ 7.77-7.71 (m, 2H), 7.20 (d, J=7.6 Hz, 1H), 7.00 (s, 1H), 4.02 (s, 3H), 2.89-2.83 (m, 4H), 2.64 (s, 3H), 1.86 (dt, J=6.5, 3.3 Hz, 4H). LCMS (M+H)=384.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: O=C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(S(=O)(=O)c2cccs2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a mixture of 2-piperazinone (0.98 g, 9.79 mmol, Sigma-Aldrich, St. Louis, Mo.) and triethylamine (Aldrich, 2.0 mL, 14.35 mmol) in CH2Cl2 (20 mL) at 0° C. was added a solution of 2-thiophenesulfonyl chloride (1.79 g, 9.79 mmol, Sigma-Aldrich, St. Louis, Mo.) in CH2Cl2 (10 mL). After 30 min, the mixture was diluted with saturated aqueous NaHCO3 (10 mL) and stirred at room temperature for 3 d. The slurry was filtered and washed with water (3×5 mL) to give 4-(2-thiophenylsulfonyl)-2-piperazinone as a white powder (2.1 g).