Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18](Br)[CH:19]=[CH2:20].O>C1COCC1>[CH2:20]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[N:4][CH:5]=1)[CH:19]=[CH2:18]
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc(C#N)nc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
4 mmol of 6-Cyanonicotinic acid were dissolved in THF. 1.5 eq. of Cs2CO3 were added he reaction stirred for 10 min. 1.5 eq allylbromide and a catalytic amount of KI were added he reaction heated to 100° C. for 4 h. The product was isolated via extraction from cetate/water.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]3[N:19]=[CH:20][N:21]([CH3:22])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:23]([F:26])([F:25])[F:24].C(Br)(Br)(Br)[Br:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:28][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]3[N:19]=[CH:20][N:21]([CH3:22])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:23]([F:26])([F:25])[F:24]
Reactant: BrC(Br)(Br)Br
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(CCCO)c(C(F)(F)F)c3)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cnc2c(C#N)nc(-c3ccc(CCCBr)c(C(F)(F)F)c3)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
6-[4-(3-Hydroxypropyl)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.3 g) was gently heated in THF (36 ml) until all dissolved and then cooled to 0° C. in an ice bath. Carbon tetrabromide (2.4 g) was added followed by triphenylphosphine (1.9 g). The mixture was stirred at 0° C. for 15 minutes and then at room temperature for 20 minutes until the cloudy suspension became a clear solution. The reaction mixture was diluted with DCM (100 ml) and washed with water (100 ml×2). Organic layer was dried over sodium sulphate and solvent was evaporated under reduced pressure. The residue was then columned (100 g SiO2 column, 1:1 EtOAc/Heptane to EtOAc gradient) to afford 6-(4-(3-bromopropyl)-3-(trifluoromethyl)-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.2 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[CH:26][C:25]([CH2:30][CH2:31][NH:32][CH3:33])=[CH:24][C:23]=1[Cl:34]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:32]([CH3:33])[CH2:31][CH2:30][C:25]3[CH:26]=[C:27]([C:28]#[N:29])[C:22]([NH2:21])=[C:23]([Cl:34])[CH:24]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNCCc1cc(Cl)c(N)c(C#N)c1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(C#N)c1)CC2

Procedure:
This compound was prepared analogous to Example 5(b) from 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloro-propane and 2-(4-amino-3-chloro-5-cyano-phenyl)-N-methyl-ethylamine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.C([O-])([O-])=O.[Cs+].[Cs+].[F:27][C:28]([F:47])([F:46])[C:29]1[CH:30]=[C:31]([C:39]2[O:43][N:42]=[C:41]([CH2:44]Cl)[N:40]=2)[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1.CC#N>CCOC(C)=O>[F:47][C:28]([F:27])([F:46])[C:29]1[CH:30]=[C:31]([C:39]2[O:43][N:42]=[C:41]([CH2:44][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:3][C:2]([F:1])([F:19])[F:20])[N:40]=2)[CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Reactant: N#Cc1ccc2[nH]c(CC(F)(F)F)cc2c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(cc(CC(F)(F)F)n2Cc2noc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 50 °C
Reaction time: 24 h
Yield: 18.3 %

Procedure:
A mixture of the indole (0.040 g, 0.14 mmol) from step A, Cs2CO3 (0.054 g, 0.16 mmol), 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole (0.091 g, 0.27 mmol) and CH3CN (4 mL) was stirred at 50° C. for 24 h. The mixture was diluted with EtOAc (25 mL) and washed with water (15 mL) and brine (15 mL). Drying (MgSO4), filtration, and concentration was followed by purification (SiO2, 0-30% EtOAc in hexanes) to afford the title compound (0.015 g, 19%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 2H), 8.10 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 6.96 (s, 1H), 5.58 (s, 2H), 3.94 (q, 2H); MS m/z 585 (M−H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:6](=[O:7])[CH:5]=[CH:4]1.CC1(C)O[C@@H]([C@@H](O)[C@H](O)[C@@H]2OC(C)(C)OC2)CO1.N1C=CN=C1.[C:32]([Si:36](Cl)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C>[Si:36]([O:1][CH2:2][C@H:3]1[O:8][C:6](=[O:7])[CH:5]=[CH:4]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C1C=C[C@@H](CO)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CC1(C)OC[C@H]([C@@H](O)[C@H](O)[C@H]2COC(C)(C)O2)O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@@H]1C=CC(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of (S)-5-hydroxy-2-penten-4-olide [3.2 g, 28.07 mmol; prepared from 1,2:5,6-di-O-isopropylidene-D-mannitol (Aldrich) in a 3-step sequence described by Hafele and Jager in Liebigs Ann. Chem. 1987, 85-87], in dry DMF (50 ml), at 0° C., was added imidazole (2.95 g, 42.1 mmol), followed by tert-butylchlorodiphenylsilane (7.95 ml, 30.9 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for a period of 1 h. Then, the solvent was evaporated and the residue was purified on a silica gel column using hexane/EtOAc (7:3 v/v) as the eluent. The appropriate fractions were evaporated and gave 9.0 g (91%) of MSC-006. 13C-NMR (CDCl3)δ: 19.40, 26.88, 63.53, 83.40, 122.89, 128.05, 130.20, 132.68, 132.95, 135.71, 135.76, 154.20. (The carbonyl carbon was not detected).
Reaction SMILES: [CH2:1]([C:5]1([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[O:10][C:9](=[O:11])[CH:8]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:19])[CH2:6]1)[CH2:2][C:3]#[CH:4].Br[C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1.CC(O)=O>CC#N>[CH:20]1([C:5]2([CH2:1][CH2:2][C:3]#[C:4][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=3)[O:10][C:9](=[O:11])[CH:8]([S:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7](=[O:19])[CH2:6]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C#CCCC1(C2CCCC2)CC(=O)C(Sc2ccccc2)C(=O)O1
Reactant: Oc1cccc(Br)c1
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C1CC(CCC#Cc2cccc(O)c2)(C2CCCC2)OC(=O)C1Sc1ccccc1

Procedure:
The title compound was prepared analogously to Example 6 using 6-but-3-ynyl-6-cyclopentyl-3-phenylsulfanyl-dihydro-pyran-2,4-dione (described in Example 16) in place of 6-but-3-ynyl-6-dihydro-pyran-2,4-dione and 3-bromophenol in place of iodobenzene. 1H NMR (CDCl3): δ1.40-1.82 (m, 8H); δ2.14 (t, 1H, J=7.58 Hz); δ2.21-2.33 (m, 2H); δ0.40-2.56 (m, 2H); δ0.92 (dd, J1=17.94 Hz, J2=22.99 Hz, 2H); δ0.06-7.56 (m, 9H). Anal. Calcd. for C26H26O4S.0.2 AcOH. 1 MeCN: C, 69.95; H, 6.16; S, 6.85. Found C, 70.23; H, 6.58; S, 6.09. ESIMS (M+Na+): 457.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17]([F:20])([F:19])[F:18])=[C:6]([NH:21][C:22](=O)[CH2:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH:5]=1.Cl.O>O1CCOCC1>[S:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[CH2:23][C:22]1[N:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17]([F:19])([F:18])[F:20])[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:30])=[CH:5][C:6]=2[N:21]=1
Reactant: COC(=O)c1ccc(NC2CCCCC2C(F)(F)F)c(NC(=O)Cc2cccs2)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)nc(Cc1cccs1)n2C1CCCCC1C(F)(F)F
Yield: 107.8 %

Procedure:
0.75 g 3-(2-Thiophen-2-yl-acetylamino)-4-(2-trifluoromethyl-cyclohexylamino)-benzoic acid methyl ester with 10 ml of 4M hydrochloric acid in dioxane were heated in a microwave reactor to 110° C. for 5 h. 3 ml water was added to the reaction mixture, which was reacted again to 110° C. for 2 h. The mixture was then concentrated in vacuo, the residue taken up in ethyl acetate and water, and the pH of the aqueous phase was brought to 4. The phases were separated, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, concentrated and 0.75 g (100%) of 2-Thiophen-2-ylmethyl-1-(2-trifluoromethyl-cyclohexyl)-1H-benzoimidazole-5-carboxylic acid were obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH:13]([CH2:14][OH:15])[CH2:12][C:11]2=[CH:16][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[S:2]([OH:4])(=[O:7])(=[O:3])[CH3:1].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH:13]([CH2:14][OH:15])[CH2:12][C:11]2=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)Cl
Agent: COc1ccc2c(c1)C(CO)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methane sulphonyl chloride (13.4 ml) is added dropwise to a stirred solution of 5-methoxy-1-hydroxymethyl benzocyclobutene (26 g) and triethylamine (26.5 ml) in methylene chloride (670 ml) cooled to 0° C. under nitrogen. The reaction mixture is allowed to warm to RT, stirred for 2 hours at RT, washed with water and saturated salt, dried over Na2SO4, and filtered. The filtrate is concentrated in vacuo yielding the desired product as a liquid.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:4]([C:6]2[N:7]=[C:8]([C:15]3[C:16]([O:23][CH3:24])=[CH:17][CH:18]=[CH:19][C:20]=3[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1nc(-c2c(OC)cccc2OC)n(C)c(=O)c1O
Reactant: NCc1ccc(F)cc1
Product: COc1cccc(OC)c1-c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (50 mg, 0.15 mmol) and 4-fluorobenzylamine (125 mg, 1.0 mmol). The title product was obtained as a pink solid (48.7 mg, 79% yield). 1HNMR (500 MHz, CDCl3) δ: 12.10 (1H, s), 7.92 (1H, t, J=5.50 Hz), 7.39 (1H, t, J=8.54 Hz), 7.30 (1H, d, J=5.19 Hz), 7.28 (1H, d, J=5.19 Hz), 7.00 (2H, t, J=8.54 Hz), 6.62 (2H, d, J=8.24 Hz), 4.52 (2H, d, J=6.40 Hz), +3.75 (6H, s), 3.28 (3H, s). HRMS (ESI) calcd for C21H21FN3O5 (M+H): 414.1465; found: 414.1454.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH2:16]Br>>[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH2:16][N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: O=C1CNc2ncc(I)cc2N1
Product: O=C1CNc2ncc(I)cc2N1Cc1cc(F)ccc1F
Yield: 70 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (525 mg) was reacted with 2,5-difluorobenzyl bromide as in General Procedure 1 to give 1-(2,5-Difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one as a tan solid (70% yield). This amide was then reduced as in General Procedure 3 to give the title compound as a white solid (42% yield). M.p. 175° C., LCMS: m/z=388.10 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.26-3.30 (m, 2H), 3.36-3.42 (m, 2H), 4.44 (s, 2H), 6.63 (bs, 1H), 6.77 (s, 1H), 7.05-7.10 (m, 1H), 7.15-7.19 (m, 1H), 7.20-7.27 (m, 1H), 7.41 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[CH:11]=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:6])=[O:5].I[CH3:23]>CN(C=O)C>[CH3:23][N:7]([C:8]1[CH:9]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[CH:11]=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])[S:4]([CH3:3])(=[O:6])=[O:5]
Reactant: CI
Reactant: COC(=O)c1cc(NS(C)(=O)=O)cc(C(=O)OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)c1
Reaction time: 5 h

Procedure:
To a stirred suspension of NaH (0.24 g, 10 mmol, 60% in oil dispersion) in 10 mL of DMF was added dimethyl 5-(methylsulfonamido)isophthalate (1.435 g, 5 mmol) followed by iodomethane (0.62 mL, 10 mmol) at room temperature. After 5 h, the reaction was quenched by H2O (25 mL). Then the reaction mixture was extracted with EtOAc, further washed with H2O to remove excess of DMF, dried over anhydrous Na2SO4 and concentrated. The crude product thus obtained was washed with hexanes to give dimethyl 5-(N-methylmethylsulfonamido)isophthalate as a white solid in 91% (1.37 g) yield.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O.CNN>CO>[NH2:3][O:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CON1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCCC1CON
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a mixture of tert-butyl 2-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}piperidine-1-carboxylate 104 (1.50 g, 4.16 mmol) in a solution of methanol (20 mL) was added methylhydrazine hydrate (4.16 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 105 (0.50 g, 53%) as a white solid.
Reaction SMILES: [C@@H:1]12[CH2:7][C:6](=[CH:8][C:9]([OH:11])=[O:10])[C@@H:5]1[CH2:4][CH:3]=[CH:2]2.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[C@@H:1]12[CH2:7][C:6](=[CH:8][C:9]([O:11][CH2:17][CH3:18])=[O:10])[C@@H:5]1[CH2:4][CH:3]=[CH:2]2
Reactant: O=C(O)C=C1C[C@H]2C=CC[C@@H]12
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=C1C[C@H]2C=CC[C@@H]12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
The compound of Example 2 was dissolved in ethanol (20 ml) and concentrated sulfuric acid was added. The reaction was heated to 80° C. and stirred for 18 hours. The solvent was removed in vacuo to yield the title compound as an oil.
Reaction SMILES: C([O-])(=O)C.[K+].[CH3:6][S:7]([NH:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]([CH2:17][C:18]([O:20]CC)=[O:19])=O)=[CH:13][CH:12]=1)(=[O:9])=[O:8].Cl.[NH2:26]O.CO>O>[CH3:6][S:7]([NH:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]2[CH2:17][C:18](=[O:19])[O:20][N:26]=2)=[CH:13][CH:12]=1)(=[O:9])=[O:8]
Reactant: CCOC(=O)CC(=O)c1ccc(NS(C)(=O)=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C2=NOC(=O)C2)cc1
Yield: 55.1 %

Procedure:
Potassium acetate (8.2 g) was added to a mixture of ethyl 4-methanesulfonamidobenzoylacetate (23.0 g), hydroxylamine hydrochloride (5.8 g) and methanol (35 ml), and the mixture was heated for refluxing for 30 minutes. The reaction mixture was poured into water (210 ml) to filter off the deposited crystals and dry them, whereby 3-(4-methanesulfonamidophenyl)isoxazoline-5-one (11.3 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:13]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.[CH2:34]([N:36]([CH2:41][CH3:42])[CH2:37][CH2:38]CCl)[CH3:35]>>[CH2:34]([N:36]([CH2:41][CH3:42])[CH2:37][CH2:38][CH2:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:13]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1)[CH3:35]
Reactant: COc1ccc(S(=O)(=O)c2c(-c3ccccc3)sc3ccccc23)cc1
Reactant: CCN(CC)CCCCl
Agent: Cl
Solvent: c1ccncc1
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(-c3ccccc3)sc3ccccc23)cc1

Procedure:
3-(4-Methoxyphenylsulfonyl)-2-phenylbenzothiophene is demethylated with pyridine hydrochloride as described above and the resulting product is reacted with 3-diethylaminopropyl chloride, also as described above, to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16]1([N:22]=[C:23]=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[C:16]1([NH:22][C:23](=[S:24])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=C=Nc1ccccc1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Solvent: CN(C)C=O
Product: CC1NC(=O)NN=C1c1ccc(NC(=S)Nc2ccccc2)cc1

Procedure:
A solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (3 g) and phenyl isothiocyanate (1.8 ml) in dimethylformamide (30 ml) was stirred at room temperature for 6 hours and then concentrated under reduced pressure. To the residue was added water and the thus-produced crystals were recovered by filtration, washed with water and dried to give 6-[4-(3-phenyl-thioureido)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (5.32 g).
Reaction SMILES: [CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=O)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=1.C(Cl)(Cl)Cl>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]#[N:17])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(=O)n3cc(C#N)ccc3nc2s1

Procedure:
2-Methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyridimine-7-carboxamide (Example 21), 2.6 g (0.010 mol), in 30 ml of phosphorus oxychloride and 30 ml of chloroform is refluxed on a steam bath for three hours. The chloroform and excess phosphorus oxychloride are evaporated in vacuo and the residue is treated with 200 ml of ice water. The resulting precipitate is filtered to give 2.1 g of 2-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile; mp 256°-258° C. after recrystallization from glacial acetic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:9][C:10]=2I)[CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[NH:35][CH:34]=[CH:33]3)O1>C1(P([Pd-4](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)C=CC=CC=1>[CH:12]1([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[NH:35][CH:34]=[CH:33]4)[N:9]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4[nH]ccc4c3)c12
Temperature: 80 °C

Procedure:
A dry mixture of 8-amino-3-cyclobutyl-1-iodoimidazo[3,4-a]pyrazine (30 mg, 0.096 mmol), cesium carbonate (38 mg, 0.117 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (26 mg, 0.107 mmol) was purged with Argon 3 times prior to the addition of tetrakistriphenylphosphino palladium (0) (6 mg, 0.005 mmol). The mixture was purged twice more and then treated with a degassed mixture of DME:water (5:1, 2 mL). The resulting solution was degassed twice more and then heated at 80° C. overnight. The resulting reaction mixture was concentrated in vacua, the residue dissolved in 1:1 MeCN:MeOH (1.5 mL) and purified by mass directed preparative HPLC to afford 3-cyclobutyl-1-(1H-indol-5-yl)imidazo[1,5-a]pyrazin-8-amine. 1 H NMR (400 MHz, DAZO-d6) δ ppm 1.82-1.92 (1 H, m) 1.95 2.08 (1 H, m) 2.32-2.41 (4 H, m) 3.82-3.93 (1 H, m) 5.91 (2 H, br. s.) 6.45 (1 H, d, J=3.03 Hz) 6.90 (1 H, d, J=5.05 Hz) 7.26 (1 H, dd J=8.34 1.52 Hz) 7.34 (1 H, d, J=5.05 Hz) 7.35-7.39 (1 H, m) 7.45 (1 H, d, J=8.34 Hz) 7.64-7.68 (1 H, m) 11.20 (1 H, br. s.); MS (ES+): m/z 304.15 [MH+]. HPLC: tr 6.18 min (XTerra C18 5 uM, 4.6×15 mm, A: MeCN & B:10 mmol NH4OAc in 0.05% HOAc/aq., method Polar15).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][CH:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)[OH:6].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>COC(C)(C)C>[F:1][C:2]([F:18])([F:19])[CH2:3][CH2:4][CH:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)[O:6][S:28]([CH3:27])(=[O:30])=[O:29]
Reactant: CCOC(=O)c1ccc(C(O)CCC(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CCOC(=O)c1ccc(C(CCC(F)(F)F)OS(C)(=O)=O)cc1
Reaction time: 1 h

Procedure:
To a solution of ethyl (+/−)-4-(4,4,4-trifluoro-1-hydroxybutyl)benzoate (264 mg, 0.956 mmol) in tert-butyl methyl ether (4.8 mL) was added triethylamine (0.201 mL, 1.43 mmol), followed by methanesulfonyl chloride (0.091 mL, 1.15 mmol). The resulting mixture was stirred for 1 hour. Then, the reaction mixture was diluted with tert-butyl methyl ether (25 mL) and washed with water (15 mL), sat. aq sodium bicarbonate (15 mL), then sat. aq sodium chloride (15 mL). The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to give ethyl (+/−)-4-(4,4,4-trifluoro-1-((methylsulfonyl)oxy)butyl)benzoate. This material was used without further purification. 1HNMR (400 MHz, CDCl3) δ 8.12 (d, J=8.4 Hz, 2 H), 7.48 (d, J=8.2 Hz, 2 H), 5.63 (dd, J=7.9, 4.8 Hz, 1 H), 4.41 (q, J=7.0 Hz, 2 H), 2.77 (s, 3 H), 2.39-2.08 (m, 4 H), 1.41 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])[C:4](O)=[O:5].C(=O)=O.[NH2:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1>O1CCCC1>[C:24]1([C:22]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:4](=[O:5])[C:3]([OH:7])([C:8]([F:11])([F:10])[F:9])[C:2]([F:13])([F:12])[F:1])=[CH:31][CH:30]=2)=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
Tetrahydrofuran (35 ml,dry) was added to a mixture of 2,2-bis-trifluoromethyl 2-hydroxyacetic acid (1.08 g,5.1 mmol) and 1', 1'-carbonyldiimidazole (0.83 g, 5.1 mmol), while under a nitrogen atmosphere. There was an immediate evolution of carbon dioxide. The reaction was refluxed for 0.5 hrs and cooled to 23° C. The reaction was treated with 4-aminobenzophenone (1.01 g, 5.1 mmol), stirred at 23° C. for 1.5 hrs, and then at reflux 18 hrs. The reaction was evaporated to a yellow oil-solid mixture. The mixture was dissolved in ethyl ether, treated with hydrogen chloride in ethyl ether, and filtered. The filtrate was evaporated to a yellow oil-solid mixture. Chromatography of this mixture on silica gel, eluting with 5% ethylether in methylenechloride provided the title compound as an off-white solid; mp=143°-146° C. 1H-NMR (250 MHz, d6 -DMSO): 7.67(m, 2H, ArH), 7.83(m, 5H, ArH),7.96(d, J=8.8, 2H, ArH), 9.82(s, 1H, OH), 10.82(s, 1H, NH). MS(CI,CH4): 392 (M+1).