Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([Cl:31])[C:25]=1[S:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)(=[O:24])=[O:23]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3c(Cl)cccc3Cl)CC2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)c2c(Cl)cccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a solution of {4-[1-(2,6-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (96 mg, 0.183 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (87.6 mg, 2.1 mmol) in water (2 mL). The reaction mixture was stirred at room temperature overnight under nitrogen. After this time, the reaction mixture was diluted with water (˜20 mL) and then acidified with 1.0 N aqueous HCl (3.66 mL). The resulting mixture was extracted with ethyl acetate (2×25 mL), then the combined extracts were washed with brine (30 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated to provide {4-[1-(2,6-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (63 mg, 67%) as a yellow solid. MS cald. for C24H23Cl2FNO4S [(M+H)+]: 510, obsd. 510.1.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[NH:9]1[CH:13]=[N:12][C:11]([S:14]([CH2:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)(=[O:16])=[O:15])=[N:10]1.Cl>N1C=CC=CC=1>[CH:18]1([CH2:17][S:14]([C:11]2[N:12]=[CH:13][N:9]([C:4]([N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:5])[N:10]=2)(=[O:16])=[O:15])[CH2:19][CH2:20][CH2:21]1
Reactant: O=S(=O)(CC1CCC1)c1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(S(=O)(=O)CC2CCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
Diethylcarbamoyl chloride (1.49 ml; 11.3 mmol) was added to cyclobutylmethyl 1,2,4-triazol-3-yl sulfone (2.06 g; 10.2 mmol) in dry pyridine (10 ml) under dry nitrogen, and the solution stirred at room temperature overnight. The reaction mixture was poured into cold 2M hydrochloric acid (60 ml) and the cloudy solution extracted with two portions of ethyl acetate (120 ml and 50 ml). The extracts were combined, washed with saturated brine (50 ml), dried (Na2SO4), filtered and the volume of solution reduced by evaporation until a white solid precipitates. Hexane was added to the mixture which was then cooled and the solid filtered off to afford 3-(cyclobutylmethylsulfonyl)-N,N-diethyl-1,2,4-triazole-1-carboxamide (2.40 g; 78%) as white crystals, m.p. 113°-116° C., (Found, C: 47.96; H: 6.56; N: 18.51; S: 10.85. C12H20N4O3S requires C: 47.98; H: 6.71; N: 18.65; S: 10.67%). NMR - d(CDCl3 ; 60 MHz) 1.3 (6H, t, J=7 Hz), 1.5-2.4 (6H, m), 2.4-3.2 (1H, m), 3.4-3.8 (6H, m) and 8.9 (1H, s). IR vmax (CHCl3) 3000, 1710, 1440, 1340, 1270, 1180, 1145, 1030 and 870 cm-1.
Reaction SMILES: [OH:1][CH:2]1[C:13]2[C:14](=[O:15])[C:9]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])([CH2:10][CH2:11][CH:12]=2)[C:8]#[C:7][CH:6]=[CH:5][C:4]#[C:3]1.FC(F)(F)S(O)(=O)=O.[C:32]([O:35][CH2:36]C)(=[O:34])[CH3:33]>CCOCC>[CH3:36][O:35][C:32]([CH2:33][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][O:1][CH:2]2[C:13]3[C:14](=[O:15])[C:9]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])([CH2:10][CH2:11][CH:12]=3)[C:8]#[C:7][CH:6]=[CH:5][C:4]#[C:3]2)=[CH:10][CH:11]=1)=[O:34]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OC12C#CC=CC#CC(O)C(=CCC1)C2=O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)Cc1ccc(COC2C#CC=CC#CC3(O[Si](C)(C)C(C)(C)C)CCC=C2C3=O)cc1
Yield: 59 %

Procedure:
To a solution of the alcohol 6 (208 mg., 0.63 mmol) and imidate 7 (300 mg, 0.92 mmol) in 5 mL of anhydrous ether was added trifluoromethanesulfonic acid (25 μL, 0.28 mmol). The solution was diluted with ethyl acetate and washed with saturated bicarbonate. The organic fraction was dried over MgSO4, concentrated and the residue chromatographed over silica gel (5:1 hexane/ethyl acetate) to give compound 8a (184 mg, 59%) and 77 mg of recovered alcohol 1 (37%).
Reaction SMILES: [CH2:1](OC(C1C(=O)N(CC2C=CC=CC=2)C2SC=C(C)C=2C=1O)=O)C.[CH2:25]([N:32]1[C:37](=[O:38])[C:36]([C:39]#[N:40])=[C:35]([Cl:41])[C:34]2[CH:42]=[CH:43][S:44][C:33]1=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:37](=[O:38])[C:36]([C:39]#[N:40])=[C:35]([Cl:41])[C:34]2[C:42]([CH3:1])=[CH:43][S:44][C:33]1=2)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1c(O)c2c(C)csc2n(Cc2ccccc2)c1=O
Reactant: N#Cc1c(Cl)c2ccsc2n(Cc2ccccc2)c1=O
Product: Cc1csc2c1c(Cl)c(C#N)c(=O)n2Cc1ccccc1
Yield: 87 %

Procedure:
This compound was prepared from 7-benzyl-4-hydroxy-3-methyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyrdine-5-carboxylic acid ethyl ester (61) by applying a similar procedure as described for the preparation of 7-benzyl-4-chloro-6,7-dihydro-6-oxo-thieno[2,3-b]pyrdine-5-carbonitrile (64). Yield 87%. 1H-NMR (DMSO-d6): δ 2.48 (s, 3H), 5.36 (s, 2H), 7.14 (s, 1H), 7.32 (m, 5H) ppm; EIMS m/z 315 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]([OH:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C@H:21]([C:23]([NH:25][C@H:26]([CH:39]=[O:40])[CH2:27][C:28](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:24])[CH3:22].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]([NH:20][C@H:21]([C:23]([NH:25][C@H:26]([CH:39]=[O:40])[CH2:27][C:28](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:24])[CH3:22])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cc2ccccc2n1Cc1ccccc1)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Yield: 56.1 %

Procedure:
1-Benzylindole-2-carboxylic acid (477 mg, 1.9 mmol) and 3(S)-(alaninyl)amino-4-oxobutanoic acid, t-butyl ester semicarbazone (581 mg, 1.9 mmol) were dissolved in methylene chloride (8 mL) and both DMAP (232 mg, 1.9 mmol) and EDAC (498 mg, 2.6 mmol) were added to the solution under a nitrogen atmosphere at 0° C. The resultant solution was stirred for 1 hour at 0° C. and an additional 2 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated to give a yellow foam. Flash column chromatographic purification of the foam (silica gel, methanol/methylene chloride 2-5%) afforded the title product as a white powder (570 mg, 56%). TLC: (methanol/methylene chloride: 1/9, silica gel): Rf0.38; 1H NMR (CDCl3): δ8.60 (bs, 1H), 7.67 (dd, J=8.0, 1.1, 1H), 7.50 (d, J=8.0, 1H), 7.33-7.01 (m, 8H), 6.79 (d, J=7.4, 1H), 5.78 (s, 2H), 4.87-4.83 (m, 1H), 4.67-4.62 (m, 1H), 2.73-2.43 (m, 2H), 1.46 (d, J=7.1, 3H), 1.39 (s, 9H).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.C(OCC)(=O)C>[Cl:1][C:2]([C:3]([C:15]1([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]=[CH:17][CH:18]=[CH:19]1)=[O:4])([Cl:7])[Cl:6]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Clc1ccc(-c2ccc[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(C(Cl)(Cl)Cl)C1(c2ccc(Cl)cc2)C=CC=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
A solution of trichloroacetyl chloride (11.26 g, 0.0619 mol) in ether is treated with a solution of 2-(p-chlorophenyl)pyrrole (10.0 g, 0.0503 mol) in ether, stirred for four hours at room temperature, treated with saturated potassium carbonate solution and diluted with ethyl acetate. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow solid. The solid is recrystallized from 2-propanol to give the title product as a yellow solid (12.63 g, mp 166°-168° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N[S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26])(=[O:15])=[O:14])CC>>[CH2:1]([NH:8][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26])(=[O:14])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reactant: NCc1ccccc1
Product: O=C1Nc2ccc(S(=O)(=O)NCc3ccccc3)cc2C1=O

Procedure:
The title compound was prepared from benzyl amine following the procedure for 2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonic acid propylamide.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:15][NH2:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[C:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24](O)=[O:25])(=[O:19])[CH3:18]>>[C:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24]([NH:16][CH2:15][C:5]1[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([Br:2])[CH:4]=1)=[O:25])(=[O:19])[CH3:18]
Reactant: NCc1cnc(OCC(F)(F)F)c(Br)c1
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Agent: Cl
Product: CC(=O)Nc1cc(C(=O)NCc2cnc(OCC(F)(F)F)c(Br)c2)ccn1
Yield: 61 %

Procedure:
The title compound is prepared in 61% yield (380 mg, a white solid) from (5-bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (450 mg, 1.4 mmol, Amine-67) and 2-acetamidoisonicotinic acid (250 mg, 1.4 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[F:46][C:47]1[CH:62]=[CH:61][C:50]([CH2:51][CH:52]2[CH2:57][CH2:56][N:55]([CH2:58][CH2:59][NH2:60])[CH2:54][CH2:53]2)=[CH:49][CH:48]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6](/[CH:8]=[CH:9]/[C:10]([NH:60][CH2:59][CH2:58][N:55]2[CH2:56][CH2:57][CH:52]([CH2:51][C:50]3[CH:49]=[CH:48][C:47]([F:46])=[CH:62][CH:61]=3)[CH2:53][CH2:54]2)=[O:12])[CH:7]=1
Reactant: COc1ccc(Br)cc1/C=C/C(=O)O
Reactant: NCCN1CCC(Cc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Br)cc1/C=C/C(=O)NCCN1CCC(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (E)-3-(5-bromo-2-methoxy-phenyl)-acrylic acid (0.072 g, 0.28 mmol) in DMF (10 ml) is treated with 2-(1H benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate (0.09 g, 0.28 mmol) and diisopropylethylamine (0.058 ml, 0.33 mmol). The resultant solution is added to 2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethylamine and the mixture stirred at RT for 18 hours. The solvents are evaporated and the crude residue purified by preparative HPLC to afford (E)-3-(5-bromo-2-methoxy-phenyl)-N-{2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethyl}-acrylamide [MH]+ 475.2
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:18]2[CH:17]=[C:16]3[C:8]([C:9]4[CH:10]=[C:11]5[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19]([CH3:26])([CH3:25])[C:12]5=[CH:13][C:14]=4[CH2:15]3)=[CH:7][C:6]=2[C:5]([CH3:28])([CH3:27])[CH2:4][CH2:3]1.CCCCCC.C([Li])CCC.[C:41]([C:45]1[CH:46]=[CH:47][C:48](=[C:50]([CH3:52])[CH3:51])[CH:49]=1)([CH3:44])([CH3:43])[CH3:42]>C1COCC1.O>[C:41]([C:45]1[CH:46]=[CH:47][CH:48]([C:50]([CH:20]2[CH2:21][C:22]([CH3:24])([CH3:23])[C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][C:12]=3[C:19]2([CH3:26])[CH3:25])[CH2:15][C:16]2[CH:17]=[C:18]3[C:2]([CH3:29])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:28])([CH3:27])[C:6]3=[CH:7][C:8]4=2)([CH3:52])[CH3:51])[CH:49]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)=C1C=CC(C(C)(C)C)=C1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)C1=CC(C(C)(C)C2CC(C)(C)c3cc4c(cc3C2(C)C)Cc2cc3c(cc2-4)C(C)(C)CCC3(C)C)C=C1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
To a solution of 1.55 g (4.0 mmol) of 1,1,4,4,7,7,10,10-octamethyl-1,2,3,4,7,8,9,10-octahydrodibenzo(b,h)-fluorene in 50 ml of THF, 2.6 ml (4.2 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. To the resulting red solution, a solution of 0.97 g (6.0 mmol) of 3-tert-butyl-6,6-dimethylfulvene in 25 ml of THF was further dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. Then, 60 ml of water was added. The organic phase extracted with ether and separated was dried over magnesium sulfate and then filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a solid. The solid was purified by column chromatography (silica gel, developing solvent: hexane) to obtain 0.95 g of a light yellow solid (yield: 43%). The analyzed values are given below.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].Cl.[CH2:6]([C:13]1([OH:42])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=2)[CH2:22][NH:23][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[ClH:4].[CH2:6]([C:13]1([O:42][C:1](=[O:3])[CH3:2])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=2)[CH2:22][NH:23][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(NCC(CCN1CCC(O)(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1Cl
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1(Cc2ccccc2)CCN(CCC(CNC(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
0.12 g of acetyl chloride is added to 0.4 g of N-[4-(4-benzyl-4-hydroxypiperidyl) -2-(3,4-dichlorophenyl)butyl]-2,4-dichlorobenzamide hydrochloride (Compound 7), obtained according to Example 1, dissolved in 10 ml of dichloromethane in the presence of two equivalents of triethylamine.
Reaction SMILES: [Na].[F:2][C:3]([F:18])([F:17])[S:4]([NH:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([F:16])[N:9]=1)(=[O:6])=[O:5].[F:19]F>C(#N)C>[F:18][C:3]([F:17])([F:2])[S:4]([N:7]([F:19])[C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([F:16])[N:9]=1)(=[O:6])=[O:5]
Reactant: FF
Reactant: O=S(=O)(Nc1nc(F)nc(F)c1F)C(F)(F)F
Agent: [Na]
Solvent: CC#N
Product: O=S(=O)(N(F)c1nc(F)nc(F)c1F)C(F)(F)F
Reaction time: 3 h

Procedure:
A cold (-35° C.), efficiently stirred solution of the sodium salt of perfluoro-[N-(4-pyrimidinyl)methanesulphonamide] (1.22 g) in dry acetonitrile (200 cm3) was treated with neat fluorine at 10-15 mmHg (1.3 to 2.0 kPa) pressure until uptake of the halogen appeared to cease (this took nearly 3 hours). The product solution was filtered (to remove sodium fluoride) and the filtrate evaporated, leaving a colourless oily sample (about 1 g) of perfluoro-[N-fluoro-N-(4-pyrimidinyl)methanesulphonamide], shown by 19F n.m.r. spectroscopy to be contaminated with perfluoro-[N-(4-pyrimidinyl)methanesulphonamide] and its sodium salt. This impure product showed NF absorption at 47.5 p.p.m. in its 19F n.m.r. spectrum [solution in CH3CN; external CF3CO2H reference (computed chemical shift relative to CFCl3 =-29.05 p.p.m.)], and rapidly liberated iodine from aqueous potassium iodide solution. Examination of the filtered iodimetric test solution by 19F n.m.r. spectroscopy revealed only absorptions assignable to perfluoro-[N-(4-pyrimidinyl)methanesulphonamide] [δF 30.1 (m; 2-F), 2.0 (s; CF3SO2), -0.8 (m; 6-F), and -88.2 (m; 5-F) p.p.m. (CF3CO2H ext. ref)]. Examination by 19F n.m.r. spectroscopy of the solution prepared by addition of an excess of heat anisole to the impure perfluoro-[N-fluoro-N-(4-pyrimidinyl)methanesulphonamide] revealed the rapid formation at room temperature of an about 1:1 mixture of o- and p-fluoroanisole, accompanied by complete consumption of the N-fluoro-compound.
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1)[CH:2]([CH3:4])[CH3:3].CC([O-])(C)C.[K+].[CH3:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Cl>CN(C=O)C>[CH2:1]([S:5][C:6]1[CH:11]=[CH:10][N:9]([CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:20]=2[CH3:19])[C:8](=[O:12])[CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Reactant: CC(C)CSc1cc[nH]c(=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cn2ccc(SCC(C)C)cc2=O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
A mixture of 100 mg of 4-(isobutylthio)pyridine-2(1H)-one, 2 ml of DMF, 65 mg of t-BuOK was stirred at room temperature and 105 mg of 2-methyl-3-nitrobenzyl chloride was added. After 3 hour, the resulting solution was evaporated, extracted with dichloromethane and subjected to silica gel column chromatography (hexane/ethyl acetate) to obtain the compound (90 mg).
Reaction SMILES: [CH:1]([C:4]1[C:12]([CH:13](O)[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>C1C=CC=CC=1>[CH:1]([C:4]1[C:12]([CH:13]=[C:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nn2ccccc2c1C(O)C(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C)=Cc1c(C(C)C)nn2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.3 %

Procedure:
To a solution of 9.2 g of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in 25 ml of MeOH was added 1.5 g of NaBH4. The solution was stirred at RT overnight. 10.25 g of oily 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-ol was obtained after workup. 1.05 g of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-ol in 10 ml of benzene was treated with 0.92 g of PCl5 and 1 ml of pyridine with stirring for 3 hours at RT. The crude 2-isopropyl-3-(2-methylprop-1-enyl)pyrazolo[1,5-a]pyridine obtained was purified on an Al2O3 column to furnish 255 mg of pure compound. Compound 1049.
Reaction SMILES: O.NN.[OH-].[K+].C([C:9]1[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)(=O)C.Cl.[CH2:18](O)[CH2:19]OCCO>O>[CH2:18]([C:11]1[CH:10]=[CH:9][S:13][C:12]=1[C:14]([OH:16])=[O:15])[CH3:19]
Reactant: OCCOCCO
Reactant: CC(=O)c1ccc(C(=O)O)s1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Product: CCc1ccsc1C(=O)O
Temperature: 110 °C
Reaction time: 16 h

Procedure:
Hydrazine monohydrate (0.97 mL, 1.019 mol) and potassium hydroxide (1.12 g, 20 mmol) were added to a solution of 5-acetyl-thiophene-2-carboxylic acid (1.70 g, 10 mmol) in diethylene glycol (20 mL) and water (1 mL). The reaction mixture was stirred in an oil bath at 110° C. for 16 hrs, cooled to rt, acidified with 2N HCl and then extracted with methylene chloride (4×50 mL). Organic layers were combined, dried, concentrated and subjected to chromatography separation on silica gel (eluted with 10% methanol/methylene chloride) to produce 3-ethylthiophene-2-carboxylic acid Compound 3A as a pale yellow solid (1.161 g, 74%). 1H NMR (300 MHz, CD3OD) δ 7.59 (d, J 3.7, 1H), 6.87 (d, J 3.7, 1H), 2.88 (q, J 7.5, 1H), 1.32 (t, J 7.5, 3H); MS (ESI) m/z: 155 (M−H+). Using the procedure of Example 1, Compound 1E was acylated with Compound 3A mediated by DIC/HOBt in anhydrous DMF to produce Compound 32 (59% yield). 1H NMR (300 MHz, (CD3)2CO) δ 8.90 (s, br, 1H), 8.25 (d, 1H), 7.88 (q, 4H), 7.45 (s, br, 2H), 7.10 (d, 1H) 6.45 (s, br, 2H), 3.05 (q, 2H), 1.42 (t, 3H); MS (ESI) m/z: 393 (M+H+), 415 (M+Na+).
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[CH3:17].CN([CH:21]=[O:22])C.C([O-])(O)=O.[Na+]>C1COCC1.Cl>[CH3:17][C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:7]=1[CH:21]=[O:22])=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: Cc1ncc2ccccc2c1Br
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncc2ccccc2c1C=O
Reaction time: 0.17 h
Yield: 42.6 %

Procedure:
To a solution of n-BuLi (2.5M, 0.869 ml, 2.17 mmol)) in 10 ml anhydrous THF at −50° C., 4-bromo-3-methylisoquinoline (0.460 q, 2.07 mmol) was added. After 10 minutes of stirring, DMF (0.32 g, 4.14 mmol) was added to the solution. The reaction mixture was allowed to stir at −50° C. for 20 minutes and then at room temperature for 15 minutes. 5 ml of in HCl was added and the solution was stirred for another 5 minuses. The reaction mixture was neutralized with saturated solution of NaHCO3 (25 ml) and partitioned between ethylacetate (2×20 ml) and water (10 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and column purified (hexane:EtOAc; 3:2) to give 0.151 g (43%) of the product as a syrup.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[CH3:18][O:17][C:15]1[C:14]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1
Reactant: COc1cc2c(cc1-c1cccs1)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1-c1cccs1)C(C)CNCC2
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methyl-8-(2-thienyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (28 mg, 0.076 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred 0.5 hours at 50 C. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 18 mg of a yellow oil. 1H NMR (400 MHz, CDCl3) d 7.45 (d, J=4 Hz, 1 H), 7.39 (s, 1 H), 7.27 (d, J=6 Hz, 1 H), 7.07 (dd, J=4, 6 Hz, 1 H), 6.71 (s, 1 H), 3.90 (s, 3 H), 3.1-2.9 (m, 6 H), 2.80 (m, 1 H), 2.22 (bs, 1 H), 1.38 (d, J=7 Hz, 3 H). MS calculated for C16H19NOS+H: 274, observed: 274.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[C:20]([O:19][CH3:18])[CH:21]=[CH:22][C:23]=3[O:26][CH3:27])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14]
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: CCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCNC(=O)c1nnc2c(-c3cc(OC)ccc3OC)cccc2c1N
Yield: 53.9 %

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-ethyl-cinnoline-3-carboxamide (100.0 mg, 0.339 mmol) and 2,5-dimethoxyphenyl boronic acid (123.3 mg, 0.678 mmol) according to Method A. The solid obtained after chromatography was washed with diethyl ether and dried overnight at 40° C. to afford the title compound as a fluffy white solid (64.4 mg, 54% yield). 1H NMR (300.132 MHz, CDCl3) δ 8.51 (bt, J=5.2 Hz, 1H), 7.86 (dd, J=7.5, 2.1 Hz, 1H), 7.76-7.68 (m, 2H), 6.97-6.91 (m, 3H), 3.79 (s, 3H), 3.64 (s, 3H), 3.52 (dq, J=5.7, 7.3 Hz, 2H), 1.26 (t, J=7.3 Hz, 3H). MS APCI, m/z=353 (M+H). HPLC 2.41 min.