Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].C([Li])CCC.[NH2:12][C:13]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:14]=1[C:15](OCC)=[O:16]>>[NH2:12][C:13]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:14]=1[C:15](=[O:16])[CH2:6][S:3](=[O:5])(=[O:4])[NH:2][CH3:1]
Reactant: CNS(C)(=O)=O
Reactant: CCOC(=O)c1cc(OC)ccc1N
Agent: [Li]CCCC
Product: CNS(=O)(=O)CC(=O)c1cc(OC)ccc1N

Procedure:
In a similar manner to that described in Example 12(a), N-methylmethanesulphonamide was reacted with n-butyl lithium and the product was reacted with ethyl 2-amino-5-methoxybenzoate to give the novel compound 1-(2-amino-5-methoxyphenyl)-2-(N-methylsulphamoyl)ethanone, m.p. 117°-118°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:17]([N+]([O-])=O)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=[CH:14][C:13]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[C:27]([N+]([O-])=O)[C:26]=1[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][C:38]=1[Cl:47].[SH-:48].[Na+].Cl.[SH2:51]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:17]([SH:48])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=[CH:14][C:13]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[C:27]([SH:51])[C:26]=1[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][C:38]=1[Cl:47]
Reactant: [SH-]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2-c2ccc(C(F)(F)F)cc2Cl)c(-c2ccc(C(F)(F)F)cc2Cl)c1[N+](=O)[O-]
Reactant: S
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])c(S)c2-c2ccc(C(F)(F)F)cc2Cl)c(-c2ccc(C(F)(F)F)cc2Cl)c1S
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
18 g of Compound 1 was dissolved in 100 ml of tetrahydrofuran. To this solution was dropped 200 ml of a sodium hydrosulfide solution* over 1 hourin a stream of nitrogen gas. After the dropping, the solution was agitated for further 4 hours at room temperature, to which was added dilute hydrochloric acid while ice-cooling unit it became slightly acidic. Nitrogen gas was violently injected into the solution to expel the liberated hydrogen sulfide, followed by extraction with benzene. The benzene extract was washed with water, dried and treated under reduced pressure to distill off the solvent. Then it was purified by a chromatography using a silica gel column (solvent: benzene/hexane=1/1) to obtain 15 g of Compound 12 (yield 87%).
Reaction SMILES: [CH:1]1([CH:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[CH:1]1([CH:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][C:9]([Cl:21])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CC(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CC(C1CCCCC1)C1CCCCC1
Reaction time: 1 h
Yield: 98 %

Procedure:
A stirred solution of 3,3-dicyclohexylpropionic acid (15.2 g, 0.064 mol) in 225 ml of dichloromethane was cooled to 5° C. and treated with 6.8 ml (0.078 mol) of oxalyl chloride, followed by 10 drops of dimethylformamide. The cooling bath was removed and stirring was continued at room temperature. Gas evolution, which was vigorous initially, essentially ceased after 1 hour. After 3 hours, dichloromethane and excess oxalyl chloride were removed on a rotary evaporator. The residue was taken up in dichloromethane and the evaporation was repeated to give 16.1 g of a pale yellow oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:19]=[CH:18][NH:17][C:16](=O)[CH:15]=1.CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>ClCCl.O1CCOCC1>[Cl:29][C:16]1[CH:15]=[C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[N:19]=[CH:18][N:17]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1cc(-c2ccccc2OCC2CCCO2)nc[nH]1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1cc(-c2ccccc2OCC2CCCO2)ncn1
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a stirred suspension of 6-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-3H-pyrimidin-4-one (0.375 g, 1.37 mmol) in dichloromethane (5 mL) and dioxane (5 mL) was added DMF (0.05 mL) followed by a solution of oxalyl chloride (0.5 mL, 4 mmol). After stirring for 1 h, the mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to give 0.4 g (99%) 4-chloro-6-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-pyrimidine as colorless oil.
Reaction SMILES: Cl[C:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[CH:3]Cl.C(OCC)C.CN(CCN(C)C)C.C([Li])CCC>CCCCC.C(O)C>[C:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)#[CH:3]
Reactant: ClC=C(Cl)Oc1ccc(-c2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: CCO
Solvent: CCOCC
Product: C#COc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56.9 %

Procedure:
To a two-necked, round-bottomed flask (100 mL) equipped with a nitrogen inlet adapter and rubber septum was added the vinyl ether 2 (2.0 g, 7.6 mmol, 1 eq), anhydrous diethyl ether (30 mL), and TMEDA (23 mmol, 3.3 mL, 3 eq), and then cooled at −78° C. 2.5 M n-Butyllithium (9.0 mL, 23 mmol, 3 eq) was then added drop-wise to the reaction mixture for over 5 min. The reaction mixture was then maintained at −78 C for 1 h and at −40° C. for 40 min, and then cooled to −78° C. while 10% ethanol in pentane (10 mL) was added drop-wise. After 10 min, the reaction mixture was then diluted with n-pentane (20 mL) and the washed with saturated solution of ammonium chloride (25 mL). The organic phase was later washed twice with water (20 mL) and then finally with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give brown oil. The oil was purified by column chromatography with hexane as the eluent to yield 3 as dark brown oil (0.84 g, 70%) that later crystallized out as brown amorphous solid: mp 48-49° C. The compound was placed in a round bottom flask and was flushed with nitrogen and kept at −78° C. to avoid the decomposition if it was not to be used immediately. 1H NMR (300 MHz, CDCl3): 7.64-7.52 (m, 4H, HAr), 7.48-7.41 (m, 2H, HAr), 7.40-7.34 (m, 3H, HAr), 2.13 (s, 1H, ≡—H) ppm; 13C NMR (75 MHz, CDCl3): 155.0, 140.1, 138.0, 128.9, 128.4, 127.4, 127.0, 115.4, 84.5, 33.5 ppm; IR (cm−1): 3317 (≡C—H), 3029, 2927, 2174 (C≡C), 1606, 1512, 1484, 1208, 1166, 1062, 1008, 941, 838, 641, 548, 450; HRMS (ESI) Calculated for C14H10 [M−H]− 193.0654. Found 193.0651; Elemental analysis Calculated. for C14H10O.0.13H2O: C, 85.54; H, 5.26. found: C, 85.54; H, 5.38.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[CH:4]([NH2:7])[CH2:5][OH:6].N1C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[S:24][C:25]=1[Cl:26]>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([S:27]([NH:7][CH:4]([CH2:5][OH:6])[CH:3]([C:8]([F:9])([F:10])[F:11])[C:2]([F:12])([F:13])[F:1])(=[O:29])=[O:28])[S:24][C:25]=1[Cl:26]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Reactant: NC(CO)C(C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1cc(Cl)c(Cl)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9 %

Procedure:
A solution of 3,3,3-trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propylamine (0.192 g, 0.9 mmol) in THF (1 mL) was stirred under nitrogen at 25° C. Pyridine (0.147 mL, 1.82 mmol) was added followed by 4,5-dichlorothiophene-2-sulfonyl chloride (0.226 g, 0.391 mmol) in THF (1 mL), and the resulting solution stirred for 18 h at 25° C. After concentration, the residue was taken up in EtOAc (15 mL) and washed with 1 N aq. HCl (10 mL), brine (10 mL), and then dried (Na2SO4). After concentration, the crude product was purified by preparatory TLC, eluent: 30:70 EtOAc:hexanes, to provide 4,5-dichloro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white solid (0.037 g, 9% yield, racemic mixture). Mass Spectrum (−ESI): 423.9 (M−H)−.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25]O)(C)([CH3:23])[CH3:22].[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1>[Mo](=O)(=O)=O>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][CH:35]2[C:36]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:32]([O:18][N:13]3[C:14]([CH3:16])([CH3:15])[CH2:23][CH:21]([O:25][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:22][C:12]3([CH3:19])[CH3:11])[CH2:33][CH2:34]2)[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: c1ccc2c(c1)CCCC2
Reactant: CC(C)(C)OO
Agent: O=[Mo](=O)=O
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCC(ON2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)c2ccccc21

Procedure:
A mixture of 80 mmol of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 300 mmol of 90% tert-butyl hydroperoxide, 5 mmol of molybdenum trioxide and 80 ml of 1,2,3,4-tetrahydronaphthalene (tetralin) is heated at 135° C. in a Fischer-Porter pressure bottle till the red color of the N-oxyl starting material is no longer visible. Purification of the crude reaction mixture by flash chromatography affords the title compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][C:17]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=1)=[O:4].C([O-])([O-])=O.[K+].[K+]>>[F:1][C:2]([F:25])([F:26])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][C:17]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=1)=[O:4]
Reactant: O=C(NCCCc1cccc(C#CC2(O)CCCCCC2)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NCCCc1cccc(CCC2(O)CCCCCC2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Deprotection of 2,2,2-trifluoro-N-(3-(3-((1-hydroxycycloheptyl)ethynyl)phenyl)propyl)acetamide was conducted following the method used to prepare Example 2 except that 5 equivalents of K2CO3 were used and the reaction was stirred at room temperature overnight. Purification by flash chromatography (10% 7M NH3 in MeOH/CH2Cl2) gave 2,2,2-trifluoro-N-(3-(3-(2-(1-hydroxycycloheptyl)ethyl)phenyl)propyl)acetamide as a clear oil. Yield (0.635 g, 86%): 1H NMR (400 MHz, DMSO-d6) δ 7.16-7.32 (m, 4H), 5.13 (s, 1H), 4.65 (t, J=6.0 Hz, 1H), 2.56-2.64 (m, 2H), 1.44-1.63 (m, 12H), 0.90 (t, J=7.6 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[Cl:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[ClH:27].[ClH:27].[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:28](=[O:29])[O:30][CH2:31][CH3:32])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: CCOC(=O)Nc1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Product: Cl
Yield: 79 %

Procedure:
The title compound was prepared in 79% yield according to the general procedure for the preparation of carbamates (Method D) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and ethyl chloroformate.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: COc1ccccc1B(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: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2OC)c(C)c1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A suspension of methyl 4-bromo-3-methylbenzoate (4.9 g; 21.4 mmol; 1 eq.), 2-methoxyphenylboronic acid (Aldrich 44, 523-1; 3.6 g; 23.5 mmol; 1.1 eq.), potassium carbonate (14.8 g; 107 mmol; 5 eq.) and Pd(PPh3)4 (2.47 g; 2.14 mmol; 0.1 eq.) in toluene (24.5 mL) and water (24.5 mL) was refluxed for 6 hours. The reaction mixture was cooled down to room temperature and filtered through a pad of CELITE which was further washed with toluene (500 mL). The filtrate was concentrated in vacuo and the residue taken up in ethyl acetate (500 mL). The organic layer was washed with sat. aq. NaHCO3 (200 mL), water (200 mL) and brine (200 mL) then dried over magnesium sulfate and concentrated in vacuo. The crude was purified by column chromatography (c-hexane/ethyl acetate, 90/10) to afford the title compound (4.38 g, 80%) as a colorless oil. HPLC (Method A): Rt 4.85 min (purity 98.9%). LC/MS: 257.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[S:3]1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:8]=2)[S:3]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2S1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)ccc2S1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A solution of 600 mg (2.11 mmol) of 2,2,4,4-tetramethyl-6-bromothiochroman (Compound 33) in 1.5 ml of triethylamine was placed in a heavy-walled tube and degassed and then treated under argon with 1.4 g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. The reaction mixture was degassed again, then placed under argon and the tube was sealed. The mixture was heated at 100 degrees C. for 24 h, allowed to cool to room temperature and then treated with a further 1.4 g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was then degassed, placed under argon and then heated in the sealed tube at 100 degrees C. for 96 h. The mixture was cooled to room temperature and extracted with 3×10 ml of ether. The organic extracts were combined, washed successively with 25 ml of water and 25 ml of saturated sodium chloride solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; hexanes followed by 3% ethyl acetate in hexanes) to give the title compound as a yellow, crystalline solid. PMR (CDCl3): & 0.23 (9H, s), 1.36 (6H, s), 1.39 (6H, s), 1.94 (2H, s), 7.17 (1H, dd, J~8.2 Hz, 1.8 Hz), 7.25 (1H, d, J~1.8 Hz), 7.30 (1H, d, J~8.2 Hz). MS exact mass, m/1 302.1519 (calcd. for C18H26S Si, 382.1524).
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[C:11]([C@H:19]([CH3:23])[C:20](Cl)=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C=CC=CC=1>[C:11]([C@H:19]([CH3:23])[C:20]([N:9]1[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]1=[O:10])=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H](C(=O)Cl)C(=O)c1ccccc1
Reactant: C=CC1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@@H](C)C(=O)c1ccccc1
Temperature: 25 °C
Yield: 45 %

Procedure:
To 60% sodium hydride (336 mg, 10.0 mmol) in toluene (20 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (1.0 mg, 9.0 mmol) in toluene (10 mL) over a 10 min period. The cooling bath was removed and the solution was allowed to warm to 25° C. to ensure complete generation of the anion. To the anion at 25° C. was added dropwise a solution of (2S)-2-benzoylpropanoyl chloride (21, 2.7 g, 12.6 mmol) in toluene (10 mL) over a 10 min period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and t-butyl methyl ether, 1:1). Water (50 mL) as added to the reaction mixture and the phases were separated. The aqueous phase was extracted with diethyl ether (2×40 mL). The combined organic phases were washed with a saturated aqeous sodium bicarbonate solution (1×100 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 6.5 cm diameter×20 cm length) using hexane and t-butyl methyl ether (10:1) afforded 1.1 g (42%) of (5S)-N-((2S)-2-benzoylpropanoyl)-5-ethenylpyrrolidin-2-one (24a) as a thick oil: 1H NMR (CDCl3) δ1.44-1.46 (d, J=6.5 Hz ,3 H), 1.64-1.80 (m, 1 H), 2.12-2.20 (m, 1 H), 2.42-2.84 (m, 2 H), 4.12-4.21 (q, J=6.4 Hz, 1 H), 4.38-4.47 (m, 1 H), 4.58-4.67 (m, 1 H), 4.89-4.91 (m, 1 H), 5.06-5.19 (m, 2 H), 5.77-5.85 (m, 1 H), 7.28-7.40 (m, 5 H); 13C NMR (CDCl3) δ174.8, 173.5, 137.7, 135.3, 128.0, 127.7, 127.4, 115.1, 74.6, 71.6, 31.3, 24.0, 18.1; IR (neat) 3066 (w), 3033 (w), 2939 (w), 1740 (vs), 1708 (vs), 1455 (s), 1370 (s), 1277 (s), 1148 (s), 1113 (s), 739 (s) cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]([OH:20])=O)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.[CH3:21][C:22]1[C:27]([CH3:28])=[C:26]([NH2:29])[CH:25]=[CH:24][N:23]=1.O.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C.CN(C)C1C=CN=CC=1.CS(C)=O.O>[CH3:21][C:22]1[C:27]([CH3:28])=[C:26]([NH:29][C:18]([C:17]2[CH:16]=[N:15][N:5]3[CH:6]=[C:7]([C:9]4[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=4)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=23)=[O:20])[CH:25]=[CH:24][N:23]=1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C(=O)O)c12
Reactant: Cc1nccc(N)c1C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C(=O)Nc3ccnc(C)c3C)c12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (30.0 mg, 0.110 mmol), 2,3-dimethyl-pyridin-4-ylamine (26.9 mg, 0.220 mmol), N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (31.7 mg, 0.165 mmol), and 1H-1,2,3-benzotriazol-1-ol hydrate (16.9 mg, 0.110 mmol) were suspended in DMF (1 ml). Diispropylethylamine (0.058 ml, 0.331 mmol) was added and the reaction mixture was allowed to stir. After 2 h, N,N-dimethylpyridin-4-amine (13.5 mg, 0.110 mmol) was added and the mixture was stirred overnight. After 16 h, the reaction mixture was heated to 60° C. for 4 h, after which additional 2,3-dimethyl-pyridin-4-ylamine (26.9 mg, 0.220 mmol) was added and the mixture was heated to 70° C. overnight. The reaction mixture was diluted in DMSO/water and filter through a 45 μm filter. The filtrate was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA to give a solid that was contaminated with trace impurities. Additional purification by column chromatography on silica gel (methanol/ethyl acetate gradient) afforded (N-(2,3-dimethylpyridin-4-yl)-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide. 1H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H); 8.83 (s, 1H); 8.41 (s, 1H); 8.37 (s, 1H); 8.19 (d, 1H); 8.10 (s, 1H); 7.82 (d, 1H); 7.28 (s, 1H); 4.13 (s, 3H); 3.88 (s, 3H); 2.47 (s, 3H); 2.24 (s, 3H). LRMS (ESI) calculated for C20H21N6O2 [M+H]+, 377.2; found 377.2.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:41][CH:42]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]2[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[CH:51][CH:50]=2)[CH2:44][CH2:43]1>O>[Br:1][C:2]1[S:3][C:4]([C:7]([NH:41][CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][C:49]3[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[CH:51][CH:50]=3)[CH2:44][CH2:43]2)=[O:9])=[CH:5][N:6]=1
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Reactant: O=C(O)c1cnc(Br)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCC(NC(=O)c3cnc(Br)s3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred mixture of 2-bromothiazole-5-carboxylic acid (500 mg, 2.4 mmol) in anhydrous N,N-dimethylormamide (5 mL) was added triethylamine (1.1 mL, 7.92 mmol), HATU (1 g, 2.64 mmol), and 4-((4-aminopiperidin-1-yl)methyl)benzonitrile (762 mg, 2.64 mmol). The mixture was stirred at room temperature overnight and then poured into water. The resulting solids were collected by filtration and purified by column chromatography to yield 972 mg (100%) of 2-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)thiazole-5-carboxamide as a yellow solid. LCMS (m/z): 406 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:7]([CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[Br:16]Br.O>ClCCl>[Br:16][C:9]1[C:2]([CH3:1])=[C:3]([CH:6]=[C:7]([CH3:11])[C:8]=1[CH3:10])[CH:4]=[O:5]
Reactant: Cc1cc(C)c(C=O)cc1C
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C=O)c(C)c(Br)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
To a solution of 2,4,5-trimethylbenzaldehyde (21.3 g, 144 mmol) in dichloromethane (200 mL) was added aluminum chloride (48.0 g, 360 mmol) with ice-cooling, and the mixture was warmed to room temperature. Bromine (7.80 mL, 151 mmol) was added dropwised to the reaction solution at room temperature, the mixture was stirred for 4 hours, water was added to the reaction solution, and dichloromethane was distilled off under reduced pressure. The residue was extracted with ethyl acetate and the organic layer was washed with water, a saturated sodium hydrogen carbonate solution, 5% sodium sulfite aqueous solution, water and a saturated brine. The organic layer was dried over anhydrous sodium sulfate and then was concentrated under reduced pressure to obtain 32.5 g (yield 100%) of the title compound. Melting point: 108-110° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:36])[CH2:26][C:27]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](C3N(C)C=CN=3)[S:17][C:10]=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C([C:54]3[N:55]([CH3:59])[CH:56]=[CH:57][N:58]=3)SC=12.CCCCCCCCCCCCN>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:36])[CH2:26][C:27]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:56]3[N:55]([CH3:59])[CH:54]=[N:58][CH:57]=3)[S:17][C:10]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4cccnc4)cc3F)c2s1
Agent: CCCCCCCCCCCCN
Product: Cn1cncc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4cccnc4)cc3F)c2s1
Yield: 33 %

Procedure:
Following the procedure described above for the compound 40 (example 17, step 2, scheme 14) but substituting the amine 9 for the amine 12, title compound 41 was obtained in 33% yield (scheme 14) 1H NMR (DMSO-d6) δ (ppm): 10.58 (s, 1H), 10.44 (s, 1H), 8.74 (d, 1H), 8.49 (d, 1H), 8.27 (dd, 1H), 8.05 (m, 1H), 7.86 (m, 2H), 7.77 (s, 1H), 7.48 (t, 1H), 7.42 (m, 2H), 7.35 (q, 1H), 6.63 (d, 1H), 3.88 (s, 3H), 3.54 (s, 2H). MS (m/z): 502.7 (M+H).