Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1
Reactant: CC(C)Cn1cnc2c(N)nc3cccnc3c21
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1cnc2c(N)nc3c(c21)NCCC3

Procedure:
A catalytic amount of platinum oxide was added to a solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (0.46 g) in trifluoroacetic acid (10 mL). The reaction mixture was reduced on a Parr apparatus under 45 psi (3.15 Kg/cm2) hydrogen pressure for 4 hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum. The residue was combined with aqueous sodium bicarbonate then a small amount of 10% sodium hydroxide was added. The resulting precipitate was extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate then concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with 5% methanol in dichloromethane containing 0.5% ammonium hydroxide). The eluant was concentrated under vacuum. The residue was recrystallized from ethyl acetate to provide 6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a solid, m.p. 222-226° C. Analysis: Calculated for C13H19N5: %C, 63.65; %H, 7.81; %N, 28.55; Found: %C, 63.07; %H, 7.51; %N, 28.00.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[C:19]([C:27]([OH:29])=[O:28])=[N:20][N:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=2)(C(=O)N)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30](=[O:33])(O)[O-].[Na+].FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I=O)C=CC=1)=O.Cl.C(#[N:60])C>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:17][C:18]2[C:19]([C:27]([OH:29])=[O:28])=[N:20][N:21]([C:23]([CH3:25])([CH3:26])[CH3:24])[CH:22]=2)([N:60]=[C:30]=[O:33])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cn(C(C)(C)C)nc2C(=O)O)(C(N)=O)CC1
Agent: Cl
Agent: O=Ic1cccc(OC(=O)C(F)(F)F)c1OC(=O)C(F)(F)F
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cn(C(C)(C)C)nc2C(=O)O)(N=C=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 4-((1-(tert-butoxycarbonyl)-4-carbamoylpiperidin-4-yl)methyl)-1-tert-butyl-1H-pyrazole-3-carboxylic acid (388 mg, 0.95 mmol) in acetonitrile (20 mL) was added sodium bicarbonate (319 mg, 3.80 mmol) and bis(trifluoroacetoxy) iodosobenzene (632 mg, 1.42 mmol). The mixture was stirred 90 minutes at room temperature, diluted with 50 mL water, acidified with 1 N aqueous hydrochloric acid, and then extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (1-10% methanol/dichloromethane, 25 g silica gel) to yield 4-((1-(tert-butoxycarbonyl)-4-isocyanatopiperidin-4-yl)methyl)-1-tert-butyl-1H-pyrazole-3-carboxylic acid (172 mg) as a colorless solid. −APCI (M−H) 405.4; 1H NMR (400 MHz, DMSO-d6, δ): 12.52 (br. s., 1H), 7.82 (s, 1H), 3.83 (br. s., 2H), 3.03 (s, 2H), 2.82 (br. s., 2H), 1.49 (m, 13H), 1.36 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].[OH-].[K+].[CH3:18]I>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:15])[CH3:14])[S:11][CH3:18]
Reactant: CI
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSC(=NC(C)=O)Nc1c(Cl)cccc1Cl

Procedure:
26.3 g (0.1 M) of N-(2,6-dichlorophenyl)-N'-acetylthiourea, 8.1 g (0.12 M as 100%) of potassium hydroxide, 7.7 ml (0.12 M) of methyliodide and 250 ml of ethanol are mixed and are heated in a water bath at 50°-60° for 5 hours. The ethanol is distilled off. The residue in the flask is washed with water and filtered. After recrystallization from isopropanol 14.0 g (50.5 % of the theoretical yield) of N-(2,6 -dichlorophenyl)-N'-acetyl-S-methylisothiourea are isolated.
Reaction SMILES: [I-:1].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:13])=[CH:5][CH:4]=1.[CH3:14][N:15]1[C:27]2[CH:26]=[CH:25][C:24]([CH:28]=O)=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2.N1CCCCC1>C(O)C>[I-:1].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](/[CH:13]=[CH:28]/[C:24]2[CH:25]=[CH:26][C:27]3[N:15]([CH3:14])[C:16]4[C:21]([C:22]=3[CH:23]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:5][CH:4]=1
Reactant: Cn1c2ccccc2c2cc(C=O)ccc21
Reactant: Cc1cc[n+](C)c2ccccc12
Agent: [I-]
Solvent: CCO
Solvent: C1CCNCC1
Product: Cn1c2ccccc2c2cc(/C=C/c3cc[n+](C)c4ccccc34)ccc21
Temperature: 25 °C
Yield: 58.8 %

Procedure:
A solution mixture of 1,4-dimethylquinolinium iodide (0.14 g, 0.5 mmol), 3b (0.13 g, 0.6 mmol) and piperidine (0.1 mL) in ethanol (40 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed. The residue was purified by precipitation from methanol and ethyl acetate to afford Me-SLM (0.14 g) in 62% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J=6.4 Hz, 1H), 9.12 (d, J=8.4 Hz, 1H), 8.86 (s, 1H), 8.49 (d, J=6.4 Hz, 1H), 8.45-8.23 (m, 5H), 8.15 (d, J=8.8 Hz, 1H), 8.06 (t, J=7.6 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 4.51 (s, 3H), 3.95 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 152.9, 147.3, 144.8, 142.2, 141.2, 138.7, 134.8, 128.8, 127.4, 126.6, 126.4, 126.3, 126.0, 122.6, 122.0, 121.8, 120.4, 119.7, 119.1, 116.0, 115.0, 109.8, 109.7, 44.3, 29.3. HRMS (MALDI-TOF) m/z Calcd for C25H21N2 349.1699. Found 349.1694 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.I[C:36]1[C:46]([CH3:47])=[CH:45][C:39]([C:40]([N:42]([CH3:44])[CH3:43])=[O:41])=[CH:38][C:37]=1[CH3:48].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1>[CH3:43][N:42]([CH3:44])[C:40]([C:39]1[CH:38]=[C:37]([CH3:48])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:46]([CH3:47])[CH:45]=1)=[O:41]
Reactant: Cc1cc(C(=O)N(C)C)cc(C)c1I
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C(=O)N(C)C)cc5C)ccc(F)c43)ccc21
Temperature: 120 °C
Reaction time: 5 h

Procedure:
In a microwave vial, methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (75 mg), 4-iodo-N,N,3,5-tetramethylbenzamide (97 mg), K3PO4 (102 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (7 mg) are suspended in toluene (2 mL) and water (0.2 mL) and purged for 10 minutes with argon. Palladium-(II)-acetate (4 mg) are added, the vial is sealed and the mixture is stirred at 120° C. for 5 hours. After cooling to ambient temperature the mixture is partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→80:20) to give the title compound. Yield: 70 mg; LC (method 25): tR=1.41 min; Mass spectrum (ESI+): m/z=518 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([Cl:9])[CH:3]=1.N1C=CC=CC=1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][Cl:16])=[C:4]([Cl:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: O=C(Cl)CCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCCl)Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
To a solution of 4-bromo-2-chloro-phenylamine (32 g, 0.15 mol) and pyridine (13.45 g, 0.17 mol) in DCM (200 mL) was added 3-chloropropionyl chloride (21.65 g, 0.17 mol) dropwise at 15° C. After stirring at room temperature for 1 hour, the mixture was washed with water and then hydrochloric acid (2 N, aqueous). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford title compound (10.9 g, yield: 90%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21]O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:25]([NH:27][CH2:28][CH2:29][OH:30])[CH3:26]>>[CH2:25]([N:27]([CH2:21][CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:24])([F:1])[F:23])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:28][CH2:29][OH:30])[CH3:26]
Reactant: CCNCCO
Reactant: OCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CCN(CCO)CCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 19.1, 4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol and 2-Ethylaminoethanol were converted to yield 2-(Ethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amino)-ethanol as light yellow oil, MS: 419 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16](C)([O-])[CH3:17].[K+].C(I)(C)C>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH:16]([CH3:17])[CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [K+]
Solvent: CC(C)I
Solvent: C1CCOC1
Product: CC(C)C1CN(Cc2ccccc2)CCC1=O
Reaction time: 0.25 h

Procedure:
1-benzylpiperidin-4-one (10 g, 53.0 mmole) was added to the stirred suspension of potassium tert. butoxide (6.0 g, 54.0 mmole) in tetrahydrofuran (50 ml) at 10° C. The reaction mixture was stirred for 15 min, isopropyl iodide (10 g, 54.0 mmole) was added at 10° C. The resulting mixture allowed coming at room temperature and stirred for 16 hr, refluxed for 3 hr and concentrated to dryness. The residue was triturated with water, extracted with ethyl acetate, dried (Na2SO4) and concentrated to give crude product, which was purified through column chromatography. Elute from 10% ethyl acetate in hexane afforded 1-benzyl-3-isopropylpiperid-4-one. Yield 3.3 g (28%), C15H21NO, m/z 232 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:4](I)[CH:3]=1.[CH2:18]([S:20][CH2:21][C:22]([CH3:26])([OH:25])[C:23]#[CH:24])[CH3:19]>>[CH2:18]([S:20][CH2:21][C:22]([C:23]1[N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[C:5]2[C:4]([CH:24]=1)=[CH:3][C:2]([F:1])=[C:7]([C:8]([F:11])([F:10])[F:9])[CH:6]=2)([OH:25])[CH3:26])[CH3:19]
Reactant: C#CC(C)(O)CSCC
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c(F)cc1I
Product: CCSCC(C)(O)c1cc2cc(F)c(C(F)(F)F)cc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the general Sonagashira procedure as described in the General Procedures Example C. The starting material was N-(4-fluoro-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide (0.77 g, 2.0 mmol) and 1-ethylsulfanyl-2-methyl-but-3-yn-2-ol (0.29 g, 2.0 mmol), reacted to yield the title compound as a golden oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:8]([O:17][CH3:18])=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH3:26][C:27]1[S:31][C:30]([C:32](Cl)=[O:33])=[CH:29][CH:28]=1.[OH-].[Na+]>ClCCl>[CH3:18][O:17][C:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]2[S:3][C:2]([NH:1][C:32]([C:30]3[S:31][C:27]([CH3:26])=[CH:28][CH:29]=3)=[O:33])=[N:6][C:5]=2[CH:7]=1
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: COc1cc(-c2ccccc2)c2sc(N)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-c2ccccc2)c2sc(NC(=O)c3ccc(C)s3)nc2c1
Reaction time: 6 h
Yield: 14.6 %

Procedure:
2-Amino-5-methoxy-7-phenylbenzothiazol (45 mg, 0.18 mmol) is dissolved in dichloromethane (2 ml) and subsequently treated with triethylamine (0.073 ml, 0.53 mmol) and 5-methyl-thiophene-2-carbonyl chloride (56 mg, 0.35 mmol). After 6 h, further 0.073 ml, 0.53 mmol) and 5-methyl-thiophene-2-carbonyl chloride (56 mg, 0.35 mmol) are added and the mixture is stirred for additional 18 h at ambient. After addition of 0.1 M aqueous sodium hydroxide, the mixture is stirred for additional 16 h. The organic layer is separated, dried and evaporated to dryness. Flash chromatography (silica, eluent ethyl acetate/cyclohexane 1:1, containing 0.5% of 25% aqueous ammonia) affords (10 mg, 5%) of the product as white solid. MS: m/e=380 (M+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24].C(OCC)(=O)C>CCCCCC>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 103.4 %

Procedure:
4-Chloro-7-ethoxy-6-nitro-quinoline-3-carbonitrile (26.8 g 96.5 mmol) and 3-chloro-4-fluoroaniline 14.05 g 96.5 mmol) in 900 ml of iso-propanaol were refluxed under N2 for 3.5 hrs. TLC (ethyl acetate: hexane=1:1) showed no starting material left. After standing at room temperature overnight, the hydrochloride salt was filtered off and washed with isopropanol and ether giving 4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-6-nitro-quinoline-3-carbonitrile 38.6 g (95%) as a yellow hydrochloride salt.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:11]([O:13][C:14](=[O:18])[C@H:15]([CH3:17])[NH2:16])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.CN(C=O)C>[C:8]([C:7]1[C:2]([NH:16][C@@H:15]([CH3:17])[C:14]([O:13][CH2:11][CH3:12])=[O:18])=[N:3][CH:4]=[CH:5][CH:6]=1)#[N:9]
Reactant: N#Cc1cccnc1Cl
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](C)Nc1ncccc1C#N
Yield: 22.8 %

Procedure:
A solution of 2-chloro-3-cyanopyridine (2 g, 14.4 mmol), L-alanine ethyl ester hydrochloride (3.3 g, 21.6 mmol), sodium carbonate (5.9 g, 43 mmol) in pyridine (1.75 mL) and DMF (20 mL) was heated to 125° C. for 36 h. The reaction was quenched with water and extracted with ethyl acetate (3×15 mL). The product was purified using column chromatography (10% MeOH in CH2Cl2) to yield a pale yellow solid (720 mg, 23%): 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=4.8 Hz, 1H), 7.69-7.67 (m, 1H), 6.67-6.64 (m, 1H), 4.77-4.74 (m, 1H), 4.23-4.19 (m, 2H), 1.54 (d, J=7.2 Hz, 3H), 1.30-1.26 (m, 3H).
Reaction SMILES: [Cl-].[CH3:2][N:3]([CH3:6])[Al+]C.[CH2:7]([CH:14]([OH:19])[C:15](OC)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1(C)C=CC=CC=1>[CH2:7]([CH:14]([OH:19])[C:15]([N:3]([CH3:6])[CH3:2])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(O)Cc1ccccc1
Reactant: C[Al+]N(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To dimethyl-amino(methyl)aluminum chloride [prepared from dimethylamine hydrochloride (3.4 g, 42 mmoL) and trimethyl aluminum (21 mL of 2 M solution, 42 mmol)] in toluene (40 mL) was added methyl benzylglycolate (3.0 g, 17 mmol). After stirring at rt for 1.5 h, the mixture was poured into 3 N HCl and extracted with Et2O. The organic extract was washed with saturated aqueous NaCl, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 9-50% EtOAc/Hex. The title compound was obtained as a colorless oil (1.2 g, 37%): 1H NMR (CDCl3): d 7.4-7.1 (m, 5H); 4.61 (s, 2H); 4.18 (s, 2H); 2.98 (s, 3H); 2.95 (s, 3H).
Reaction SMILES: [N+]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]=1[CH2:19][C:20]#[N:21])([O-])=O.[OH:22]S(O)(=O)=O.O>O.C(O)(=O)C.[Zn]>[C:11]1([C:9]2[S:10][C:6]3[C:7]([N:8]=2)=[CH:17][CH:18]=[C:4]2[C:5]=3[CH2:19][C:20](=[O:22])[NH:21]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCc1c([N+](=O)[O-])ccc2nc(-c3ccccc3)sc12
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2c(ccc3nc(-c4ccccc4)sc23)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of (6-nitro-2-phenyl-benzothiazole-7-yl)-acetonitrile (40 mg 0.23 mmol) (Starting Material 8) was suspended in concentrated H2SO4/H2O (1/1, 2 mL) and stirred at 100° C. for 30 min. The resulting solution was diluted with water and extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude acid. Subsequently, to a solution of the crude acid in acetic acid (3 mL) heated at reflux was added excess zinc dust (88.4 mg, 1.36 mmol) portionwise during thirty minutes. The mixture was filtered through a Celite® pad and washed with hot DMF. The solvent was removed in vacuo and residue was suspended and stirred for 30 minutes in 3M hydrochloric acid. The insoluble solid material was collected, washed with water, and air dried to give 2-phenyl-6,8-dihydro-thiazolo[5,4-e]indol-7-one. (Yield 12 mg, 33%)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[C:31]([F:34])([F:33])[F:32])[CH:26]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:26][C:25]1[CH:28]=[CH:29][C:30]([C:31]([F:32])([F:33])[F:34])=[C:23]([F:22])[CH:24]=1
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: O=C(C=Cc1ccc(C(F)(F)F)c(F)c1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and 3-fluoro-4-(trifluoromethyl)benzaldehyde (91 ul, 0.633 mmol) similar to Example 18 as a yellow solid (164 mg, 53%). 1H NMR (CDCl3): 7.65-7.60 (m, 2H), 7.52 (d, J=15.9 Hz, 1H), 7.43-7.37 (m, 2H), 7.32 (d, J=3.3 Hz, 1H), 7.15 (dd, J=3.3, 8.7 Hz, 1H), 6.92 (d, J=9.0 Hz, 1H), 4.45-4.32 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17](O)=[O:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[F:38][C:39]([F:49])([F:48])[O:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1>C(#N)C>[F:38][C:39]([F:48])([F:49])[O:40][C:41]1[CH:42]=[CH:43][C:44]([NH:45][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])[CH2:16][CH2:15]2)=[O:18])=[CH:46][CH:47]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(C(=O)O)CC2)cc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2CCC(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
1-[(4-Methylphenyl)sulfonyl]-4-piperidinecarboxylic acid (0.283 g) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in acetonitrile (40 ml) were treated at RT and under an argon atmosphere with N-methyl-morpholine (0.2 g) and the mixture was stirred for 2 h at RT. 4-trifluoromethoxy-aniline (0.176 g) was then added and stirring was continued for 20 h at RT until completion of the reaction. The reaction mixture was partitioned between ethyl acetate and aqueous 1M HCl, the layers were separated and the organic layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 30%) to give 1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.298 g) as a white solid. MS (ESI): 443.1 (MH+).
Reaction SMILES: O[C:2]([CH3:9])(C)[C:3]([O:5][CH2:6][CH3:7])=O.CS(C1C=C[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][N:15]=1)(=O)=O.[H-].[Na+]>CN(C=O)C>[CH2:6]([O:5][C:3]1[CH:2]=[CH:9][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][N:15]=1)[CH3:7]
Reactant: CCOC(=O)C(C)(C)O
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(S(C)(=O)=O)cn1
Temperature: 80 °C

Procedure:
A mixture of ethyl 2-hydroxyisobutyrate (0.41 mL, 3.0 mmol), 2,5-bis(methyl sulfonyl)pyridine (J. Heterocycl. Chem. 1985, 22, 1583) (0.70 g, 3.0 mmol) and sodium hydride (60% dispersion in mineral oil, 0.14 g, 3.6 mmol) in 30 mL of anhydrous DMF was heated at 80° C. overnight. The reaction mixture was cooled to room temperature, and was partitioned between saturated aqueous ammonium chloride (200 mL) and ether (200 mL). The organic layer was separated and was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluting with 0 to 80% ethyl acetate in hexane to give the title compound as a 1:1 mixture with 2-ethoxy-5-methylsulfonylpyridine. LC-MS: m/e 288 (M+H)+ (0.70 min).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:2]1.C1C=C[NH+]=CC=1.[Br:29][Br-]Br>O1CCCC1.C(Cl)(Cl)Cl>[Br:29][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[CH2:10][CH2:11][N:12]1[C:13](=[O:22])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]1=[O:21])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccccc12
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCc1c(Br)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-[2-(1H-indol-3-yl)-ethyl]-isoindole-1,3-dione (1.0 g in a mixture of 10 mL dry tetrahydrofuran and 10 mL dry chloroform) at 0° C. was added pyridinium bromide perbromide (1.14 g) and the reaction stirred at 0° C. After 50 minutes, the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate (3×) and 0.3M sodium bisulfate (3×) then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 3:1) gave the title compound (1.2 g).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:5]([SH:12])=[N:6][C:7]([SH:11])=[N:8][C:9]=1[NH2:10].[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.O>CO>[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH2:17][S:11][C:7]2[N:8]=[C:9]([NH2:10])[C:4]([NH2:3])=[C:5]([S:12][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[C:15]=3[F:22])[N:6]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1nc(S)nc(S)c1N
Reactant: Fc1c(Cl)cccc1CBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1nc(SCc2cccc(Cl)c2F)nc(SCc2cccc(Cl)c2F)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a solution of potassium hydroxide powder (2.5 g) in methanol (80 ml) was added first 5,6-diamino-2,4-pyrimidinedithiol (3.6 g) followed by 3-chloro-2-fluorobenzyl bromide (6.3 g). The reaction mixture was stirred for one hour at room temperature then poured into water (180 ml), giving a brown precipitate. This was isolated by filtration, washing with isopropyl alcohol and diethyl ether, to give the subtitled compound as a pale brown solid (5.4 g).