Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:31])[CH2:3][N:4]([C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:12]([O:14][CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[O:13])[S:5]([CH3:8])(=[O:7])=[O:6]>CO.[Pd]>[NH2:1][C:2](=[O:31])[CH2:3][N:4]([C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:12]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[S:5]([CH3:8])(=[O:6])=[O:7]
Reactant: COc1ccc(C(=O)OCC(=O)OCc2ccccc2)cc1N(CC(N)=O)S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C(=O)OCC(=O)O)cc1N(CC(N)=O)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
2-(benzyloxy)-2-oxoethyl 3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxybenzoate (180 mg, 0.400 mmol) was dissolved in MeOH (10 ml), then Pd/C 5% (85 mg, 0.040 mmol) was added. The solution was shaken under hydrogen atmosphere at 35 psi on a Parr apparatus for 30 minutes. The catalyst was filtered off, and the solvent removed under vacuum to give 2-(3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxybenzoyloxy)acetic acid (130 mg, 90% yield).
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[C:14]2[C:9]3=[C:10]([CH2:15][CH2:16][N:8]3[CH:7]=1)[CH:11]=[CH:12][CH:13]=2)=O.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:19]1.CC(C)([O-])C.[K+].Cl>O1CCCC1.C(OCC)(=O)C>[C:6]1([C:4]2[C:3](=[O:17])[NH:30][C:28](=[O:29])[C:27]=2[C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:18][CH:19]=2)[C:14]2[C:9]3=[C:10]([CH2:15][CH2:16][N:8]3[CH:7]=1)[CH:11]=[CH:12][CH:13]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC2
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CC3)=C1c1c[nH]c2ccccc12
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
To a solution of (4,5-dihydro-pyrrolo[3,2,1-hi]indol-1-yl)-oxo-acetic acid methyl ester (150 mg, 0.66 mmol) and 2-(1H-indol-3-yl)-acetamide (114 mg, 0.66 mmol) in anhydrous tetrahydrofuran (10 ml) at 0° C. was added potassium tert-butoxide (2.6 ml, 2.6 mmol; 1M solution in tetrahydrofuran). The mixture was stirred at room temperature for 1 hour before concentrated hydrochloric acid (3 ml) was added and the mixture stirred for an additional 20 minutes. The mixture was poured into ethyl acetate (200 ml) washed with water (700 ml) and brine (100 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by flash column chromatography (SiO2, 40% EtOAc in hexanes) to afford 3-(4,5-dihydro-pyrrolo[3,2,1-hi]indol-1-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione as a red solid (115 mg). 400 MHz 1H NMR (DMSO-d6) δ: 11.63 (s, 1H), 10.84 (s, 1H), 7.98 (s, 1H), 7.62 (d, J=2.8 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.05-7.01 (m, 2H), 6.78-6.74 (m, 2H), 6.53 (t, J=7.2 Hz, 1H), 6.08 (d, J=8.0 Hz, 1H), 4.58 (t, J=7.2 Hz, 2H), 3.71 (t, J=6.8 Hz, 2H); LCMS: 354 [M+H].
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[N:4]=1)=O.[CH:10]([C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[C:14]=1[NH2:15])([CH3:12])[CH3:11].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:9][C:5]1[NH:4][C:3](=[N:15][C:14]2[C:16]([CH:20]([CH3:21])[CH3:22])=[CH:17][CH:18]=[CH:19][C:13]=2[CH:10]([CH3:12])[CH3:11])[CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1N=c1cccc(Br)[nH]1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
Prepare a mixture of the 2-formyl-6-bromopyridine (72 g, 0.38 mol) of Step (a) and 2,6-diisopropylaniline (73 g, 0.38 mmol) in 500 mL of anhydrous toluene containing 0.3 nanometer (nm) pore size molecular sieves (6 g) and 80 mg of 4-methylbenzenesulfonic acid (p-TsOH) to give a mixture. Add the mixture to a dry, 500 mL 3-neck round bottom flask equipped with a condenser, an overhead mechanical stirrer, and a thermocouple well. Heat the mixture to 70° C. under a nitrogen gas atmosphere and stir for 12 hours. Cool the mixture to room temperature, filter it, and remove volatiles under reduced pressure until a constant weight to give the 6-bromo-2-(2,6-diisopropylphenyl)iminopyridine as a brown oil. Yield is 0.11 kg (82%). GC/MS 346 (M+), 331, 289, 189, 173, 159, 147, 131, 116, 103, 91, 78. Use the 6-bromo-2-(2,6-diisopropylphenyl)iminopyridine without further purification in step (c) below.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[C:5](Br)[CH:4]=1.Cl.[CH:17]1(C2C=CC(NN)=CC=2)[CH2:22][CH2:21]C[CH2:19][CH2:18]1>>[ClH:1].[CH:2]1([C:3]2[CH:14]=[C:13]3[C:6]([NH:7][CH:8]=[C:9]3[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=2)[CH2:21][CH2:22][CH2:17][CH2:18][CH2:19]1
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Reactant: NNc1ccc(C2CCCCC2)cc1
Agent: Cl
Product: NCCc1c[nH]c2ccc(C3CCCCC3)cc12

Procedure:
5-Cyclohexyltryptamine hydrochloride was prepared (1.29 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 4-cyclohexylphenylhydrazine hydrochloride as starting material. ##STR45##
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([OH:14])[CH:10]=[CH:11][C:12]#[CH:13]>C(NC(C)C)(C)C.[Cu]I.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>[OH:14][CH2:9]/[CH:10]=[CH:11]/[C:12]#[C:13][C:2]1[CH:7]=[CH:6][C:5]([C:13]#[C:12]/[CH:11]=[CH:10]/[CH2:9][OH:14])=[CH:4][CH:3]=1
Reactant: C#CC=CCO
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: OC/C=C/C#Cc1ccc(C#C/C=C/CO)cc1
Reaction time: 1 h
Yield: 54.6 %

Procedure:
To a solution of 1,4-diiodobenzene (1.32 g, 4.0 mmol) in diisopropylamine (12 mL) under a nitrogen atmosphere were added copper(I) iodide (60 mg, 0.3 mmol) and tetrakis(triphenylphosphine)palladium (80 mg, 0.07 mmol). After the mixture stirred for 1 h, a solution of 2-penten-4-yn-1-ol (1.0 g, 12.0 mmol) in diisopropylamine (7 mL) was added. After stirring under a nitrogen at 60° C. for 8 h, the reaction mixture was filtered and the filtrate evaporated to dryness. The product was purified by flash chromatography using toluene/ethyl acetate (2:1) graduated to ethyl acetate as eluent to give 520 mg (55%) of (E)(E) 5-[4-(5-hydroxy-pent-3-en-1-ynyl)-phenyl]-pent-2-en-4-yn-1-ol.
Reaction SMILES: Cl[CH:2]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]2)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:25][OH:26]>>[CH3:25][O:26][CH:2]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]2)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CO
Reactant: COC(=O)c1ccc2cc(C(Cl)c3cccnc3)ccc2c1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccc2cc(C(OC)c3cccnc3)ccc2c1
Yield: 94 %

Procedure:
52 mg (0.17 mmol) of methyl 6-[1-chloro-1-(3-pyridyl) methyl]-2-naphthoate and 8 mg (0.18 mmol) of sodium hydride dispersion (55%) in 4 ml of absolute methanol are heated under reflux for 6 hours. After the reaction mixture has been evaporated, the residue is taken up in sodium bicarbonate solution, which is extracted with ethyl acetate. After the ethyl acetate phase has been dried and evaporated in vacuo, the residue is chromatographed on silica gel using ethyl acetate. 48.2 mg (94%) of methyl 6-[1-methoxy-1-(3-pyridyl)methyl]-2-naphthoate are obtained. RF (ethyl acetate/cyclohexane 1:1): 0.17.
Reaction SMILES: [CH:1]1([CH2:5][N:6]([CH2:20][CH2:21][CH3:22])[CH:7]2[CH2:19][CH2:18][C:10]3[C:11]4[CH:12]=[CH:13][NH:14][C:15]=4[CH:16]=[CH:17][C:9]=3[CH2:8]2)[CH2:4][CH2:3][CH2:2]1.[Cl:23]N1C(=O)CCC1=O>O1CCCC1>[Cl:23][C:12]1[C:11]2[C:10]3[CH2:18][CH2:19][CH:7]([N:6]([CH2:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)[CH2:20][CH2:21][CH3:22])[CH2:8][C:9]=3[CH:17]=[CH:16][C:15]=2[NH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCN(CC1CCC1)C1CCc2c(ccc3[nH]ccc23)C1
Solvent: C1CCOC1
Product: CCCN(CC1CCC1)C1CCc2c(ccc3[nH]cc(Cl)c23)C1
Yield: 81.2 %

Procedure:
A solution of cyclobutylmethyl-propyl-(6,7,8,9-tetrahydro-3H-benzo[e]indol-7-yl)amine 48 mg, 0.16 mmol) and N-chlorosuccinimide (35 mg, 0.26 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature for 1 day. After pouring the reaction mixture into water, extraction (diethyl ether), drying (magnesium sulfate), filtering, and evaporation yielded 43 mg (80%) of the desired compound.:
Reaction SMILES: CO[C:3](=O)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1OC1C=CC=CC=1)=O.[CH3:20][NH:21][C:22](=[O:40])[C:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1OC1C=CC=CC=1)=[N:24][O:25][CH3:26]>>[CH3:20][NH:21][C:22](=[O:40])/[C:23](/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:3][CH2:4][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N:24]/[O:25][CH3:26]
Reactant: CNC(=O)C(=NOC)c1ccccc1Oc1ccccc1
Reactant: COC(=O)C(=O)c1ccccc1Oc1ccccc1
Product: CNC(=O)/C(=N/OC)c1ccccc1CCc1ccccc1

Procedure:
Some examples for production of methyl-2-(2-phenoxyphenyl)-2-oxo-acetate, which is the intermediate compound for methyl-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide, are as follows:
Reaction SMILES: [S:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=[O:4])(=[O:3])[NH2:2].Cl[C:19]1[CH:24]=[C:23]([O:25][C@@H:26]([C@@H:28]2[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]2)[CH3:27])[N:22]=[C:21]([S:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:38]=2[F:44])[N:20]=1>>[F:44][C:38]1[C:39]([F:43])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][S:35][C:21]1[N:20]=[C:19]([NH:2][S:1]([N:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)(=[O:3])=[O:4])[CH:24]=[C:23]([O:25][C@@H:26]([C@@H:28]2[CH2:32][O:31][C:30]([CH3:33])([CH3:34])[O:29]2)[CH3:27])[N:22]=1
Reactant: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCN(S(N)(=O)=O)CC1
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1

Procedure:
The subtitle compound was prepared from 1,1-dimethylethyl 4-sulfamoylpiperazine-1-carboxylate (the product of example 15, step i), 0.26 g) and 4-chloro-2-[(2,3-difluorobenzyl)thio]-6-{(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy}pyrimidine (the product of Example 47, step i) (0.21 g) according to the procedure outlined in Example 1, step iv). Yield: 0.28 g
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[Cl:13])[CH:2]1[O:4][CH2:3]1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[NH:22][CH2:23][CH2:24][NH2:25]>>[Cl:13][C:7]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=1[O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:25][CH2:24][CH2:23][NH:22][C:16]1[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:14]
Reactant: Clc1ccc(Cl)c(OCC2CO2)c1
Reactant: Cc1cccc(C)c1NCCN
Product: Cc1cccc(C)c1NCCNCC(O)COc1cc(Cl)ccc1Cl

Procedure:
This compound is obtained, in a manner analogous to that described in Example 17, from 2,5-dichlorophenyl glycidyl ether and N-(2,6-dimethylphenyl)-ethylenediamine, the base obtained crystallizing. The desired product is obtained in a yield of 4.2 g. (55% of theory) in the form of colorless crystals which, after recrystallization from diethyl ether-ligroin, melt at 66°-68° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37](C(OC(C)(C)C)=O)[CH:38]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[NH:36]1[CH:35]=[C:34]([C:2]2[CH:7]=[N:6][N:5]3[C:8]([C:11]4[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH:38]=[N:37]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)cnn23)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cn[nH]c4)cnn23)c1
Temperature: 100 °C

Procedure:
A mixture of N-[3-(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (0.30 g, 0.81 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.29 g, 0.97 mmol), tetrakis(triphenylphosphine)palladium(0) (46.9 mg, 0.0406 mmol) and K3PO4 (0.43 g, 2.0 mmol) in 1,4-dioxane (4.0 mL) and water (2 mL) was heated at 100° C. under an atmosphere of nitrogen for 3 h. After cooling, the reaction mixture was extracted with ethyl acetate (3×30 mL), and washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-15%) to afford the desired product. LCMS (M+H)+: m/z=402.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH:14]=[O:15])[N:11]([CH3:16])[N:10]=2)=[CH:5][CH:4]=1.[CH3:17][C:18]1[C:22](B(O)O)=[C:21]([CH3:26])[O:20][N:19]=1.C([O-])([O-])=O.[K+].[K+]>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.COCCOC.O>[CH3:17][C:18]1[C:22]([C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[N:10][N:11]([CH3:16])[C:12]=2[CH:14]=[O:15])=[C:21]([CH3:26])[O:20][N:19]=1
Reactant: COc1ccc(-c2cc(C=O)n(C)n2)cc1
Reactant: Cc1noc(C)c1B(O)O
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: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2nn(C)c(C=O)c2-c2c(C)noc2C)cc1
Yield: 32 %

Procedure:
A mixture of 4-bromo-3-(4-methoxyphenyl-1-methyl-1H-pyrazole-5-carbaldehyde (74.5 mg, 0.25 mmol), 3,5-dimethylisoxazol-4-ylboronic acid (53.4 mg, 0.38 mmol), K2CO3 (140 mg, 1.01 mmol) and Pd(PPh3)4 (14.6 mg, 0.01 mmol) in 1 DME/water (1 mL/1 mL) was flushed with argon and irradiated in the microwave at 140° C. for 30 min, extracted with EtOAc (3×4 mL) after 3 mL water were added. The mixture was concentrated and purified on silica gel to give 4-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde (25.6 mg, 0.08 mmol, 33%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10](Cl)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:13]([OH:16])[C:14]#[CH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:7]([O:6][P:4]([CH2:9][C:10]([O:16][CH2:13][C:14]#[CH:15])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Reactant: C#CCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C#CCOC(=O)CP(=O)(OCC)OCC
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
The above 2-(diethoxyphosphoryl)acetic acid chloride and 31.4 g (0.56 mol) of propargyl alcohol were dissolved in 100 mL of toluene and cooled to 5° C. 67.1 g (0.66 mol) of triethylamine was dropwise added to the solution at 15° C. or lower, then stirred at room temperature for 90 minutes, and disappearance of the starting materials was confirmed through gas chromatography. The formed salt was filtered and washed with 30 ml of a saturated saline solution. The organic layer was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (ethyl acetate/hexane=1/1 for elution) to give 111.9 g (yield 93%) of the intended 2-propynyl 2-(diethoxyphosphoryl)acetate. The obtained 2-propynyl 2-(diethoxyphosphoryl)acetate was analyzed through 1H-NMR to confirm the structure thereof. The results are shown below.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[N:7]3[CH2:15][CH2:14][NH:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Br[CH:18]([CH2:20][CH3:21])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[N:7]3[CH2:15][CH2:14][N:13]([CH:18]([CH2:20][CH3:21])[CH3:19])[CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Br)cc2nc2n1CCNC2
Reactant: CCC(C)Br
Solvent: CN(C)C=O
Product: CCC(C)N1CCn2c(nc3cc(Br)ccc3c2=O)C1

Procedure:
A solution of 9-bromo-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one (30 mg, 0.11 mmol) and excess 2-bromobutane in DMF (5 mL) was stirred at 140° C. for 6 h. Then the reaction mixture was concentrated and purified by column chromatography to give the desired product. MS (ESI): 336, 338 (MH+).
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=1)([F:4])[F:3].[Cl:17][CH:18](Cl)[C:19](=O)[CH3:20]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:16]=[C:14]([CH:13]=[CH:12][C:9]2[CH:8]=[CH:7][C:6]([S:5][C:2]([F:4])([F:3])[F:1])=[CH:11][CH:10]=2)[O:15][CH:20]=1
Reactant: NC(=O)C=Cc1ccc(SC(F)(F)F)cc1
Reactant: CC(=O)C(Cl)Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)co2)cc1

Procedure:
4.45 g (18.0 mmol) 3-(4-Trifluoromethylsulfanyl-phenyl)-acrylamide, 2.79 g (22.0 mmol) dichloro acetone and 50.0 ml toluene were kept at reflux temperature for 30 h with continuous removal of water by use of a Dean-Stark trap. The reaction mixture was cooled for 30 min. in an ice bath and the precipitated amide (1.2 g) was removed by filtration and discarded. After removal of solvents in vacuo, the residue (5.92 g) was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 1:1). All fractions containing the product were concentrated to a volume of 10 ml, n-heptane added and the crystallized material isolated by filtration, washed with cold heptane and dried. 2.02 g (35%) 4-Chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-oxazole.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4](OC)=[O:5].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][C:4](=[O:5])[C:3]([CH3:9])([CH3:8])[CH2:2][OH:1]
Reactant: COC(=O)C(C)(C)CO
Reactant: NCc1ccccc1Cl
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(CO)C(=O)NCc1ccccc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of methyl 3-hydroxy-2,2-dimethylpropanoate (1 g, 7.31 mmol) and 2-chlorobenzylamine (1 mL, 8.75 mmol, 1.2 equiv.) in toluene (7 mL) was added trimethylaluminum (2 M in hexane, 5.4 mL, 10.8 mmol, 1.5 equiv.). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was quenched with saturated NaHCO3. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give N-(2-chlorobenzyl)-3-hydroxy-2,2-dimethylpropanamide (1.5 g, 85%), which was used without further purification. LRMS (M+H+) m/z 242.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)N.C(ON=O)CC(C)C.[S:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: c1ccsc1
Agent: CC(C)CCON=O
Solvent: CCOCC
Product: Brc1cccc(-c2cccs2)c1
Temperature: 25 °C
Yield: 34 %

Procedure:
To a stirred solution of m-bromoaniline (34.4 g; 0.2M) in thiophene (200 mL) was added isoamylnitrite (46.86 g; 0.4M) dropwise over a period of 30 mins. at 0° C. The resulting mixture was cautiously warmed to R.T. and heated to reflux for 16 hours. The reaction mixture was cooled, diluted with 400 mL of ether, washed with 3×100 mL of satd sodium chloride solution, and dried over anhydrous magnesium sulfate. Solvent and excess thiophene were removed. A solution of the residue in 200 mL of ether was filtered through 50 G silica gel bed. Solvent was removed, and the residue was distilled to give 34% of 2-(3'-bromophenyl) thiophene as a yellow liquid boiling at 130°-2°/~0.2 m. This liquid solidified on standing in the refrigerator.
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:19]2[C:23]([CH3:24])=[CH:22][N:21]=[CH:20]2)=[C:16]([F:18])[CH:17]=1)=O)C1C=CC=CC=1.C([Li])CCC.[CH2:30]([O:34][C:35](=[O:39])CCC)[C@@H:31]1[O:33]C1.C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[F:18][C:16]1[CH:17]=[C:12]([N:11]2[CH2:9][C@H:30]([CH2:31][OH:33])[O:34][C:35]2=[O:39])[CH:13]=[CH:14][C:15]=1[N:19]1[C:23]([CH3:24])=[CH:22][N:21]=[CH:20]1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: Cc1cncn1-c1ccc(NC(=O)OCc2ccccc2)cc1F
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cncn1-c1ccc(N2C[C@H](CO)OC2=O)cc1F
Reaction time: 0.33 h
Yield: 30 %

Procedure:
5-Benzyloxycarbonylamino-2-(5-methyl-imidazol-1-yl)fluorobenzene (3.2 g, 9.85 mmol) was dissolved in dry tetrahydrofuran (40 ml) under nitrogen, cooled to −70°, and treated with a solution of n-butyllithium (1.6 M in isohexane, 6.81 ml). After stirring for 20 minutes at −70°, (R)-glycidylbutyrate (1.57 g, 10.09 mmol) was added at −70°. Stirring was continued for 16 hours allowing the temperature to rise to ambient. The mixture was treated MeOH (10 ml), stirred 15 minutes, then poured into aqueous sodium bicarbonate (5%, 100 ml) and extracted with EtOAc (3×40 ml). The combined extracts were washed with brine (20 ml), dried (magnesium sulfate) and evaporated. and the residue purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 5 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated, to give the desired product (0.86 g). MS (ESP): 292 (MH+) for C14H14FN3O3.
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7](=[O:22])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[N:10][CH:9]=1>C(OCC)(=O)C.[Cl-].[NH4+]>[C:16]1([C:15]#[C:14][C:12]2[CH:13]=[C:8]([C:7](=[O:22])[CH3:1])[CH:9]=[N:10][CH:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CON(C)C(=O)c1cncc(C#Cc2ccccc2)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CC(=O)c1cncc(C#Cc2ccccc2)c1
Reaction time: 8 h
Yield: 84 %

Procedure:
Add methylmagnesium bromide (1.25 mL, 3.7 mmol) dropwise at 0° C. to a solution of N-methoxy-N-methyl-5-phenylethynylnicotinamide, (prepared essentially as described in PREPARATION 2), (1.0 g, 3.76 mmol). Allow the mixture to warn to room temperature overnight. Dilute with ethyl acetate and saturated ammonium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 to 30:70 tetrahydrofuran:hexanes) to give title compound as a white solid (0.70 g, 84%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[N:29]=[C:28]([C:30](O)=[O:31])[O:27][N:26]=2)[CH:20]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:28]3[O:27][N:26]=[C:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[N:29]=3)=[O:31])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1nc(-c2cccnc2)no1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1nc(-c2cccnc2)no1
Yield: 11.9 %

Procedure:
Following the method of Example 34(d), the title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.27 g, 1.05 mmol), 3-(pyridin-3-yl)-1,2,4-oxadiazole-5-carboxylic acid (0.2 g, 1.05 mmol), HOBt (0.21 g, 1.57 mmol), DIPEA (0.55 mL, 3.14 mmol) and EDCI (0.3 g, 1.57 mmol) using DMF as solvent to afford 54 mg of the title product. 1H NMR (400 MHz; d6-DMSO): δ 1.23 (d, 3H), 4.37 (m, 2H), 4.50 (m, 1H), 6.96 (d, 1H), 7.65 (m, 1H), 7.88 (d, 1H), 7.92 (m, 2H), 8.04 (m, 1H), 8.38 (m, 1H), 8.83 (dd, 1H), 9.19 (dd, 1H), 9.50 (m, 1H).