Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=[C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:30]=1[CH3:45].ClC1C=CC2C(=CC=CC=2)N=1>CCOC(C)=O>[CH3:45][C:30]1[C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:32][C:33]2[C:38]([C:29]=1[N:13]1[C:11]3[C:10](=[CH:9][CH:8]=[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:12]=3)[C:15]3([CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:14]1)=[CH:37][CH:36]=[CH:35][CH:34]=2
Reactant: Cc1c(-c2ccccc2)nc2ccccc2c1Cl
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: Clc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)nc2ccccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under a N2 atmosphere, 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (0.216 g, 0.788 mmol) was dissolved in DMF (2.00 mL, 26.0 mmol) and treated with sodium hydride (0.0208 g, 0.867 mmol). The reaction was allowed to stir at rt for 10 minutes and 4-chloro-3-methyl-2-phenylquinoline (0.100 g, 0.394 mmol) was added. The reaction was placed in a preheated oil bath at 140° C. for 6 h. LCMS showed no starting chloroquinoline remained. The reaction was diluted with EtOAc and washed with 2% sodium bicarbonate followed by brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography eluting with 40% to 60% EtOAc in hexane. The fractions that contained product were further purified by preparative reverse phase chromatography to afford 1-(3-methyl-2-phenyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. Mass Spectrum (ESI) m/e=492.3 (M+1) 1H NMR (500 MHz, DMSO-d6) δ ppm 8.06-8.10 (1H, m), 7.80-7.84 (1H, m), 7.74 (1H, ddd, J=8.4, 6.8, 1.5 Hz), 7.64-7.69 (2H, m), 7.48-7.59 (4H, m), 7.11 (1H, d, J=8.3 Hz), 6.27 (1H, dd, J=8.3, 2.2 Hz), 5.58 (1H, d, J=2.2 Hz), 4.01 (1H, d, J=9.8 Hz), 3.83-3.97 (3H, m), 3.56-3.63 (4H, m), 3.48 (2H, tt, J=12.0, 2.1 Hz), 2.82-2.91 (4H, m), 2.22 (3H, s), 1.93-2.05 (2H, m), 1.82-1.88 (1H, m), 1.65-1.73 (1H, m)
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([Cl:14])=[CH:6][C:5]=1[CH2:15]Br.[CH2:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1)[CH3:19].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:14][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([C:10]([F:11])([F:12])[F:13])[CH:8]=1)[C:3](=[O:17])[N:25]([CH2:24][C:23]1[CH:26]=[CH:27][C:20]([CH2:18][CH3:19])=[CH:21][CH:22]=1)[CH2:15]2
Reactant: COC(=O)c1c(CBr)cc(Cl)cc1C(F)(F)F
Reactant: CCc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1ccc(CN2Cc3cc(Cl)cc(C(F)(F)F)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
A mixture of 4-chloro-2-bromomethyl-6-trifluoromethyl-benzoic acid methyl ester (0.995 g, 3.0 mmol), 4-ethyl-benzylamine (0.520 mL, 3.6 mmol), and K2CO3 (0.621 g, 4.5 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-chloro-2-(4-ethyl-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.30 g, 28%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.24 (t, 3H), 2.63 (q, 2H), 4.27 (s, 2H), 4.76 (s, 2H) 7.20 (m, 4H), 7.59 (s, 1H), 7.78 (s, 1H). GC-MS: m/z 353 (M)+, 338 (M−15)+, 324 (M−29)+.
Reaction SMILES: [N:1]1[C:5]2=[CH:6][CH:7]=[C:8]([C:10]([OH:12])=O)[CH2:9][C:4]2=[N:3][N:2]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>CN(C=O)C.C(OCC)(=O)C>[C:35]1([NH:34][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][N:2]=[N:3][C:4]=3[CH:9]=2)=[O:12])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C1=CC=C2N=NN=C2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)c1ccc2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzotriazole-5-carboxylic acid (856 mg), HOAt (715 mg) and EDAC (1.00 g) were dissolved in DMF (17.5 mL) and the mixture was stirred at room temperature 1 hour. A 0.5 mL aliquot of this mixture was added to aniline (13.7 μL, 0.15 mmol) and the resulting mixture was vigorously shaken at room temperature for 16 hours. 1N hydrochloric acid (2 mL) and ethyl acetate (1 mL) were added and the mixture was vigorously shaken at room temperature for 2 hours. The organic phase was isolated and concentrated in vacuo to afford the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.[C:14]([O-])([O-])=[O:15].[Cs+].[Cs+].[N:20]([C:23]1[CH:28]=[C:27](C2C=CC=C(OC)C=2)[N:26]=[CH:25][N:24]=1)=[C:21]=S.C(N=C=NC(C)C)(C)C>CN(C)C=O>[CH3:14][O:15][C:27]1[N:26]=[CH:25][N:24]=[C:23]([NH:20][C:21]2[O:13][C@:5]3([CH2:4][N:3]=2)[CH:10]2[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]2)[CH2:6]3)[CH:28]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(-c2cc(N=C=S)ncn2)c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(NC2=NC[C@@]3(CN4CCC3CC4)O2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.363 g, 1.583 mmol) in N,N-dimethylformamide (20 mL) was added Cs2CO3 (1.289 g, 3.96 mmol) and 4-isothiocyanato-6-(3-methoxyphenyl)pyrimidine. The suspension was stirred at room temperature for 30 minutes. N,N′-diisopropylcarbodiimide (0.740 mL, 4.75 mmol) was then added and the mixture was continued to stir at room temperature for 18 hours. The mixture was concentrated and purified by silica gel chromatography (5-25% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford (R)—N-(6-methoxypyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.294 g, 0.788 mmol, 50% yield) as a a pale yellow solid. M.P 80-5° C. 1H NMR (400 MHz, MeOD) δ ppm 8.77 (1 H, s), 7.47-7.58 (2 H, m), 7.39 (1 H, t), 7.20 (1 H, br. s.), 7.04 (1 H, dd), 4.05 (1 H, d), 3.85 (3 H, s), 3.74 (1 H, d), 3.23 (1 H, d), 3.10 (1 H, d), 2.71-3.00 (4 H, m), 2.03-2.22 (2 H, m), 1.53-1.85 (3 H, m). MS (LC/MS) R.T.=1.58; [M+H]+=366.15.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:14]=[C:15]([C@@H:20]2[CH2:24][NH:23][C:22](=[O:25])[CH2:21]2)[CH:16]=[CH:17][C:18]=1[Cl:19].C[O:27]C>>[ClH:19].[NH2:23][CH2:24][C@@H:20]([C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)[CH:14]=1)[CH2:21][C:22]([OH:25])=[O:27]
Reactant: O=C1C[C@H](c2ccc(Cl)c(Br)c2)CN1
Reactant: COC
Reactant: COc1cccc(B(O)O)c1
Product: Cl
Product: NC[C@H](CC(=O)O)c1ccc(Cl)c(-c2cccc(O)c2)c1

Procedure:
Following the cross-coupling procedure according to Example 25 using 3-methoxyphenyl boronic acid and (4R)-4-(3-bromo-4-chlorophenyl)pyrrolidin-2-one followed by hydrolysis of the methyl ether using 48% HBr provided the title compound (34). 1H-NMR (400 MHz, CD3OD): δ 2.67-2.73 (dd, J=16.4, 6.4 Hz, 1H), 2.80-2.85 (dd, J=16.4, 7.6 Hz, 1H), 3.19-3.25 (dd, J=12.4, 12.0 Hz, 1H), 3.32-3.37 (m, 1H), 3.39-3.47 (m, 1H), 6.79-6.81 (m, 1H), 6.85-6.87 (m, 2H), 7.21-7.25 (m, 1H), 7.28-7.33 (m, 2H), 7.48-7.50 (d, J=8 Hz, 1H); MS (ESI) m/z 306.14 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH:8]=[CH:9][CH:10]=[C:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH:3](OC)[O:4]C.O1CCCC1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O>[CH3:1][CH:2]([CH:8]=[CH:9][CH:10]=[C:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH:3]=[O:4]
Reactant: COC(OC)C(C)C=CC=C(C)CCC=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CC=CC(C)C=O
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 101.8 %

Procedure:
To a 250 mL four-neck reaction flask protected from atmospheric moisture by nitrogen gas throughout the course of the reaction a solution of 12.6 g in 2,6,10-trimethyl-1,1-dimethoxy-3,5,9-undecatriene (2C, 0.05 mol), 100 mL tetrahydrofuran and 1.2 g of PTSA was added. After stirred until homogeneous, 22 g of water was added, and further 24 h of stirring at 20-25° C. was needed until the reaction completed according to GC. Then a solution of 2 g of NaHCO3 in 20 mL water was added for neutralization. Removal of THF by vacuum distillation, 100 mL of cyclohexane was added and then stratification. The organic layer was washed with 30 mL of water, dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the volatile organic solvents by evaporation at reduced pressure afforded 10.5 g of crude 2,6,10-trimethyl-3,5,9-undecatriene-1-aldehyde of formula (12).
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:15][N:14]=3)[C:10]([CH3:25])=[N:9]2)=CC=1.COC1C=CC(CN2C(C)=C(C(=N)N)C=N2)=CC=1>>[CH3:25][C:10]1[C:11]([C:13]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[S:15][N:14]=2)=[CH:12][NH:8][N:9]=1
Reactant: COc1ccc(Cn2cc(-c3nsc(Nc4ccccn4)n3)c(C)n2)cc1
Agent: COc1ccc(Cn2ncc(C(=N)N)c2C)cc1
Product: Cc1n[nH]cc1-c1nsc(Nc2ccccn2)n1
Yield: 37 %

Procedure:
According to Scheme 1 Step 4: The title compound was prepared according to Example 2 Step 4, from a mixture of 3-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-5-amine and of 1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-4-carboximidamide (0.11 mmol, 43 mg). 11 mg (43 μmol, 37%) of 3-(3-methyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-5-amine were obtained as a white solid.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[F:35][C:30]1[CH:29]=[C:28]([C:23]2[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=3)=[C:26]([CH3:27])[O:25][N:24]=2)[CH:33]=[CH:32][C:31]=1[F:34]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C)nc1
Reactant: NCC(F)(F)F
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2ccc(F)c(F)c2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 1.1 mL, 2.2 mmol) was added dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine (250 mg, 2.2 mmol) in dioxane (10 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) in dioxane (10 mL) was added. The resulting mixture was then heated at 85-95° C. for 16 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 1:1) afforded the title compound (150 mg, 63%) which was obtained as a white solid. MS: m/e=482.2 [M+H]′.
Reaction SMILES: [C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:34]=[CH:33][C:15]([O:16][C:17]2[CH:26]=[C:25]3[C:20]([CH:21]([C:27]([O:29]CC)=[O:28])[CH2:22][CH2:23][O:24]3)=[CH:19][C:18]=2[Cl:32])=[CH:14][CH:13]=1)=[O:11].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[C:1]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[CH:26]=[C:25]3[C:20]([CH:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][O:24]3)=[CH:19][C:18]=2[Cl:32])=[CH:33][CH:34]=1)=[O:11]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccccc4-c4ccccc4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccccc1-c1ccccc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Ethyl 7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (29 mg, 0.052 mmol) was diluted with THF (1 mL) followed by the addition of NaOH (261 μl, 0.26 mmol) and ethanol (500 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid (26 mg, 0.049 mmol, 94% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][CH2:12][OH:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.O>C1COCC1>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][C:5]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3]
Reactant: Cc1cccc(C)c1CCO
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C)c1CCOCCCCCCBr
Yield: 52.7 %

Procedure:
NaH (46% dispersion in oil; 4.2 g) was added portionwise to a solution of 2,6-dimethylbenzenethanol (6.0 g) and 1,6-dibromohexane (19.52 g) in THF (50 ml) under nitrogen. The mixture was refluxed for 18 h and treated cautiously with H2O (20 ml). The resulting emulsion was extracted with ER (3×100 ml) and the dried extract was evaporated to leave a yellow oil. Excess 1,6-dibromohexane was removed under reduced pressure and the residue was purified on a column of silica (300 ml) [B] to give the title compound as a colourless oil (6.6 g) b.p. 110°-115°/0.4 mmHg.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C@H:4]1[O:9][C:8](=[O:10])[CH2:7][C@H:6]([OH:11])[CH2:5]1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClCCl>[Si:19]([O:11][C@@H:6]1[CH2:5][C@@H:4]([CH:3]([O:12][CH3:13])[O:2][CH3:1])[O:9][C:8](=[O:10])[CH2:7]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(OC)[C@@H]1C[C@@H](O)CC(=O)O1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(OC)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 0.5 g of (4R,6S)-6-(dimethoxymethyl)-4-hydroxy-tetrahydropyran-2-one (II′) in 50 mL of dichloromethane, 280 mg of imidazole are added at 25° C. After cooling to 0° C., 400 mg of tert-butyldimethylsilyl chloride are added. The reaction mixture is then stirred for 18 hours and dichloromethane is distilled off. The residue is flash chromatographed (DIPE/acetonitrile=5/1). The solvents are distilled off to get the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([Cl:24])[N:18]=1>>[ClH:24].[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:19]3[N:20]=[C:21]([CH3:23])[CH:22]=[C:17]([CH3:16])[N:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: Cc1cc(C)nc(Cl)n1
Product: Cc1cc(C)nc(NC2CCCc3c2[nH]c2ccc(Br)cc32)n1
Product: Cl

Procedure:
6-Bromo-N-(4,6-dimethylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (50 mg, 0.19 mmol) and 4,6-dimethyl-2-chloropyrimidine (134 mg, 0.94 mmol) in a similar manner as described in Example 22 to give 12 mg (16%) of a yellow solid. 1H-NMR (DMSO-d6): δ10.98 (s, 1H), 8.40 (brs, 2H), 7.59 (s, 1H), 7.26 (d, 1H), 7.16 (d, 1H), 6.77 (s, 1H), 5.52-5.48 (m, 1H), 2.68-2.61 (m, 2H), 2.41 (2 s, 6H), 2.15-2.06 (m, 1H), 2.04-1.96 (m, 1H), 1.91-1.76 (m, 2H); MS m/z (M+1) 371, 373; (M−1) 369, 371.
Reaction SMILES: [S:1]1[C:5](=[O:6])[CH2:4][NH:3][C:2]1=[O:7].[CH3:8][C:9]([CH3:15])=[CH:10][CH2:11][N:12]=[C:13]=[O:14].CC(C)=CCN.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1.ClCCl.N1C=CC=CC=1>[CH3:8][C:9]([CH3:15])=[CH:10][CH2:11][NH:12][C:13]([N:3]1[CH2:4][C:5](=[O:6])[S:1][C:2]1=[O:7])=[O:14]
Reactant: O=C1CNC(=O)S1
Reactant: CC(C)=CCN=C=O
Agent: CC(C)=CCN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)=CCNC(=O)N1CC(=O)SC1=O

Procedure:
To a stirred solution or partial solution of 2,5-thiazolidinedione (0.010 mol) in tetrahydrofuran (THF) is added neat (or a solution in dichloromethane or THF) (3-methyl-but-2-en-1-yl)-isocyanate (0.010 mol), prepared by allowing (3-methyl-but-2-en-1-yl)amine with 0.33 mol equivalents of triphosgene in dichloromethane optionally in the presence of a tertiary amine base or pyridine, and the mixture is stirred. Reaction progress may be followed by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC). When a sufficient amount of desired product is formed, the mixture (or, optionally, the residue which is obtained after first rotary evaporating off the reaction solvent) is partitioned between ethyl acetate and an excess of about 0.1 M hydrochloric acid. The organic layer is washed with brine, dried over sodium sulfate, and rotary evaporated to give 3-(3-methyl-but-2-en-1-yl)aminocarbonyl-2,5-thiazolidinedione, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O[CH2:17][C:18]([CH2:20][Si](C)(C)C)=[CH2:19])(=O)C>C1COCC1.[Pd].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.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.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:17]=[C:18]1[CH2:20][C@@H:2]([C:1]([O:11][CH3:12])=[O:10])[C@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:19]1
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Reactant: COC(=O)/C=C/c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(=O)OC)[C@H](c2ccccc2)C1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
A mixture of methyl trans-cinnamate (5.0 g, 31 mmol), tetrakis(triphenylphosphine) palladium(0) (2.6 g, 2.3 mmol), 1,2-bis(diphenylphosphino)ethane (0.70 g, 1.8 mmol) and 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (6.90 g, 37 mmol) in THF (60 mL) under argon was heated to reflux for 4 h. An additional aliquot of 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (3.40 g) was added and the reaction was continued for another 16 h. The volatiles were then removed in vacuo and the residue was purified by FC (10% ethyl acetate in hexanes) to afford the title compound (6.2 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([C:12](OCC)=[O:13])=[CH:7][C:6]=2[C:5]2[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:4]=2[N:3]=1.[Li+].[B-](CC)(CC)CC>C1COCC1>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][OH:13])=[CH:7][C:6]=2[C:5]2[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:4]=2[N:3]=1
Reactant: CCOC(=O)c1cnc2c(N)nc3cc(C)ccc3c2c1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)nc(N)c1ncc(CO)cc12

Procedure:
To a stirred solution of ethyl 5-amino-8-methylbenzo[f][1,7]naphthyridine-2-carboxylate (from the previous step) in THF (0.2 M) cooled in an ice-water bath was added 1 N solution of super hydride in THF (10 eq.). Upon completion of the reaction the reaction was quenched with 1 N HCl, and extracted with EtOAc. Combined organic extracts were concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give (5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)methanol as a white solid. 1H NMR (CDCl3): δ 8.68 (d, 1H), 8.52 (d, 1H), 8.04 (d, 1H), 7.44 (s, 1H), 7.12 (dd, 1H), 6.00 (bs, 2H), 4.90 (s, 2H), 2.45 (s, 3H). LRMS [M+H]=240.1
Reaction SMILES: ClCC(SC1C(Cl)=CC=CC=1Cl)C[O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.Br[CH2:23][CH2:24][C:25]([OH:27])=[O:26]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:7][CH:8]=1
Reactant: O=C(O)CCBr
Reactant: ClCC(COc1ccc(Cl)cc1)Sc1c(Cl)cccc1Cl
Product: O=C(O)CCOc1ccc(Cl)cc1

Procedure:
38.2 g of 1-chloro-2-(2,6-dichlorophenylthio)-3-p-chlorophenoxypropane [obtainable by reaction of 3-bromo-propionic acid with Na p-chlorophenolate to give 3-p-chlorophenoxypropionic acid, bromination to give 2-bromo-3-p-chlorophenoxypropionic acid, reaction with Na 2,6-dichlorothiophenolate to give 2-(2,6-dichlorophenylthio)-3-p-chlorophenoxypropionic acid, LiAlH4 reduction to give the alcohol and reaction with SOCL2 ]is heated at 120° with 40 g of imidazole for 5 hours, then cooled, worked up as usual and Ia of m.p. 175°-177° is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.C(N(C(C)C)C(C)C)C>C(Cl)Cl.CCOC(C)=O>[C:13]12([NH:12][C:4](=[O:5])[C:3]3[CH:7]=[CH:8][C:9]([Cl:11])=[N:10][C:2]=3[Cl:1])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
A solution of 2,6-dichloronicotinoyl chloride (4.21 g, 20 mmol) in DCM (20 mL) was added dropwise to a stirred suspension of 1-aminoadamantane (3.03 g, 20 mmol) and N-ethyldiisopropylamine (4.19 mL, 24 mmol) in DCM (20 mL) at 0° C., over a period of 30 minutes under nitrogen. The resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (500 mL), and washed sequentially with water (100 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% Et2O in DCM. Pure fractions were evaporated to dryness to afford N-adamantan-1-yl-2,6-dichloronicotinamide (5.57 g, 76%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([S:18](Cl)(=[O:20])=[O:19])=[CH:10][CH:9]=1)=[O:6].[N:26]([CH:29]([CH3:31])C)=[C:27]=[O:28]>C(N(CC)CC)C>[C:27]([N:26]1[CH2:29][CH2:31][CH:5]([NH:7][S:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=3[O:2][CH3:1])=[CH:9][CH:10]=2)(=[O:20])=[O:19])[CH2:4][CH2:3]1)(=[O:28])[CH2:9][CH2:8][CH3:17]
Reactant: COc1ccccc1C(=O)Nc1ccc(S(=O)(=O)Cl)c2ccccc12
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3OC)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2-methoxy-benzoylamino)-naphthalene-1-sulfonyl chloride, and substituting butyric chloride and triethylamine for 2-isocyanato-propane. LC/MS m/z 508 (M−H)−, 510 (M+H)+