Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([OH:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:13]1[CH:14]=[CH:15][C:16]2[CH2:17][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:20][O:21][C:22]=2[N:23]=1.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([CH:7]([O:9][C:13]2[CH:14]=[CH:15][C:16]3[CH2:17][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:20][O:21][C:22]=3[N:23]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Reactant: CC(O)C1CCCCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2)C1CCCCC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To a solution of 1-cyclohexylethanol (0.23 g) in toluene (4 mL) was added sodium hydride (0.14 g), and the resulting mixture was stirred at 100° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.50 g), BINAP (0.033 g), Pd2(dba)3 (0.024 g) and toluene (4 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-(1-cyclohexylethoxy)-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.49 g, 74%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:37]([NH:36][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[F:29])=[O:38])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: O=C=Nc1ccccc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)Nc4ccccc4F)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), 2-fluorophenyl isocyanate (0.00597 g, 0.0436 mmol), DIPEA (0.033 mL, 0.19 mmol) in DMF (1 mL) was stirred at rt for 3 h. Purification by HPLC afforded the title compound. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=6.8 Hz, 3H), 2.58 (br. s., 2H), 3.69-3.80 (m, 2H), 4.25 (d, J=2.5 Hz, 2H), 6.31 (br. s., 1H), 6.51 (q, J=6.7 Hz, 1H), 7.08-7.16 (m, 3H), 7.22 (t, J=8.7 Hz, 1H), 7.40 (dd, J=9.0, 4.9 Hz, 1H), 7.45-7.52 (m, 1H), 7.68 (s, 1H), 8.22 (s, 1H). MS (ES+): m/z 559.05/561.04 (100/75) [MH+]. HPLC: tR=3.42 min (ZQ3, polar—5 min).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C[O-].[Na+].[Cl-].[NH4+]>CO>[OH:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:3]1
Reactant: COC(=O)[C@@H]1[C@@H]2C[C@@H](O)[C@@H](C2)N1C(=O)OC(C)(C)C
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@H](C2)N1C(=O)OC(C)(C)C
Yield: 35.9 %

Procedure:
To 2-tert-butyl 3-methyl (1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (3.04 g), was added 1N sodiummethoxide solution in methanol (34 mL). The mixture was stirred at reflux for 4 hrs. To the resulting mixture was added ammonium chloride solution and evaporated in vacuo. Water was added to the residue, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was recrystalized from hexane-diethyl ether to give the target compound (1.09 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].Cl.Cl[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>C(#N)C>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]=[CH:4]1
Reactant: Clc1nc[nH]c1Cl
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Clc1ncn(Cc2ccc3ccccc3n2)c1Cl

Procedure:
4,5-Dichloroimidazole (2.00 g, 14.6 mmol) was dissolved in 15 mL acetonitrile in a round bottom flask. Potassium hydroxide (0.90 g, 16.0 mmol) was added and the mixture was refluxed for 15 min. Concurrently, 2-chloromethylquinoline hydrochloride (3.13 g, 14.6 mmol) and potassium hydroxide (0.82 g, 14.6 mmol) were added to a second round bottom flask and stirred in 60 mL acetonitrile at reflux for 10 min. The contents of the second flask were added to the first, and the combined mixture was refluxed overnight, during which time a white precipitate formed. The reaction mixture was filtered hot, yielding a clear, tan filtrate. Slow evaporation and cooling of the filtrate yielded tan crystals of 1-(quinolin-2-ylmethyl)-4,5-dichloroimidazole, which were collected by a second filtration. The crystals (0.278 g, 1.0 mmol) will be dissolved in a minimum volume of DMF. Iodomethane (0.62 mL, 10.0 mmol) will be added and the mixture will be heated at 80° C. for 12 h. Removal of the volatile components under reduced pressure will yield the product.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[C:18]([Cl:26])=[N:19][CH:20]=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23].[I:27]I>C1COCC1>[Br:16][C:17]1[C:18]([Cl:26])=[N:19][CH:20]=[C:21]([C:25]=1[I:27])[C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)c(Br)c1I
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
n-Butyllithium (1.6M in hexanes, 172 mL, 276 mmol) was added to a solution of 2,2,6,6-tetramethylpiperidine (48.5 mL, 285 mmol) in anhydrous THF (200 mL) at −50° C. After 20 min, solid 5-bromo-6-chloronicotinic acid (21.6 g, 92 mmol) was added portionwise and the resultant slurry was allowed to warm to −20° C. over 1 h and stirred at that temperature for 1 h. After this time, the reaction mixture was cooled to −60° C. and transferred via cannula to a solution of iodine (70 g, 276 mmol) in anhydrous THF (100 mL) at −60° C. at such a rate that the internal temperature of the solution remained below −40° C. On complete addition, the reaction mixture was allowed to warm slowly to ambient temperature and stirred for 18 h. The reaction mixture was concentrated in vacuo and the resultant dark red slurry was dissolved in water (500 mL) and washed with diethyl ether (3×200 mL). The pH of aqueous layer was adjusted to 2 by the addition of 1M aqueous hydrochloric acid and the resulting beige precipitate was collected by filtration and dried under vacuum to afford the title compound (17.7 g, 53%). 1H NMR (DMSO-D6, 400 MHz): 8.30 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:13]4)[CH:10]=[CH:9][C:8]1=[CH:7][C:6](=[O:28])[CH2:5][CH2:4]2.C[O-].[Na+].OC1CC[C@@]2(CO)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2OC(=O)C(C)(C)C)C=1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C=CC=CC=1.C(O)(=O)C.CS(C)=O>[OH:1][CH2:2][C@@:3]12[C@@H:20]3[C:11](=[C:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([O:21][C:22](=[O:27])[C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:14][CH2:13]4)[CH:10]=[CH:9][C:8]1=[CH:7][C:6](=[O:28])[CH2:5][CH2:4]2
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@]12C
Agent: CC(C)(C)C(=O)O[C@H]1CC[C@H]2C3=CC=C4C=C(O)CC[C@]4(CO)[C@H]3CC[C@]12C
Agent: C[O-]
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)O[C@H]1CCC2=C3C=CC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@@]21C

Procedure:
A solution of 200 mg. of 19-hydroxy-17β-pivaloxyandrosta-4,6-dien 3-one in 2 ml. of dimethyl sulfoxide was treated with 400 mg. of sodium methoxide under nitrogen for 15 seconds. The mixture was then poured into 20 ml. of half-frozen 10% aqueous acetic acid, stirred for a few minutes under nitrogen and filtered to yield a precipitate, which had λ max 321 mμ and consisted essentially of 3,19-dihydroxy-17β-pivaloxyandrosta-3,5, 7-triene. The latter product was then treated with an equal amount of chloranil in 20 volumes of toluene at room temperature for 10 minutes. Extraction with aqueous potassium hydroxide and evaporation afforded 19-hydroxy-17β-pivaloxyandrosta-4,6,8(14)-trien 3-one as indicated by tlc and uv-spectroscopy.
Reaction SMILES: ClC1C=CC=C(Cl)C=1[N:9]1[C:13]2=[N:14][C:15](CC3C=CC(CC(OCC)=O)=CC=3)=[N:16][C:17](=[O:18])[C:12]2=[C:11](C(C)C)[NH:10]1.C1COCC1.[OH-].[Li+]>O>[N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17](=[O:18])[C:12]2=[CH:11][N:10]=1
Reactant: CCOC(=O)Cc1ccc(Cc2nc3n(-c4c(Cl)cccc4Cl)[nH]c(C(C)C)c-3c(=O)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1N=CN=C2N=NC=C12
Yield: 313.8 %

Procedure:
The ester, 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(carbethoxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (1.20 g, 2.4 mmol) was stirred at RT overnight with THF (50 mL), water (15 mL) and 1 N lithium hydroxide (7.20 mL). The solution was evaporated to near dryness, diluted with 1 N hydrochloric acid, vigorously stirred and the solid was collected by filtration and dried under high vacuum to give 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-carboxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (1.01 g, 89% yield) as a white solid, mp 212-214° C. Mass Spec.: 471 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][O:16]1)C.[NH2:22][C:23]([NH2:25])=[S:24].C([O-])([O-])=O.[K+].[K+].Cl>COCCO.O>[O:16]1[CH2:17][CH2:18][CH2:19][CH:15]1[CH2:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[NH:25][C:23](=[S:24])[NH:22][C:4](=[O:3])[CH:5]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccccc1OCC1CCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCO
Product: O=c1cc(-c2ccccc2OCC2CCCO2)[nH]c(=S)[nH]1
Yield: 64 %

Procedure:
To a solution of 3-oxo-3-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-propionic acid ethyl ester (0.9 g, 3.08 mmol) in 2-methoxyethanol (5 mL) was added thiourea (0.31 g, 4.08 mmol) and K2CO3 (0.56 g, 4 mmol). The reaction mixture refluxed 5-6 h. After cooling, a mixture poured into water (10 mL), adjusted to pH 3 with 10% HCl and extracted with ethyl acetate (2×10 mL). Organic layers were combined, washed with water (10 mL), then dried over anhydrous sodium sulfate, concentrated and triturated with diethyl ether to obtained 0.6 g (64%) 6-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one as a beige solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][C@@H:5]2[CH2:7][CH2:8][CH2:9][C@@H:10]([N:11]3C(=O)C4C(=CC=CC=4)C3=O)[C@@H:4]2[O:3]1.NN>C(O)C>[CH3:1][C:2]1([CH3:22])[O:6][C@@H:5]2[CH2:7][CH2:8][CH2:9][C@@H:10]([NH2:11])[C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@H]2[C@H](N3C(=O)c4ccccc4C3=O)CCC[C@H]2O1
Agent: NN
Solvent: CCO
Product: CC1(C)O[C@H]2[C@H](N)CCC[C@H]2O1
Temperature: 0 °C
Yield: 29 %

Procedure:
The mixture of 2-[(3aS,4R,7aR)-2,2-dimethylhexahydro-1,3-benzodioxol-4-yl]-1H-isoindole-1,3(2H)-dione (20) (191.4 mmol, 50.00 g), hydrazine (308.4 mmol, 15.0 mL) in ethanol (500 mL) was refluxed for 4 h. The reaction was monitored by HPLC. HPLC analysis showed the reaction did not go to completion (86% conversion). Additional 3 mL of hydrazine was added to the reaction mixture and refluxed for 2 h. The reaction was cooled to 0° C. and filtered. The filter cake was washed with IPA and dried to afford the desired product 21 (9.52 g, 21% yield, purity in weight: 84% based on NMR). The filtrate was concentrated and the residue was taken up in IPA (about 200 mL). The by-product crystallized and was filtered out, and the filtrate was stripped of volatiles and dried to afford a second crop of the desired product 21(28.46 g, 64% yield). TLC (80% MeOH/EtOAc with 1 drop of acetic acid, stained by ninhydrin dip).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[C:5]([O:8][C@H:9]1[C@H:14]([N:15]=[C:16]=[S:17])[C@@H:13]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]([O:22][C:23](=[O:25])[CH3:24])[C@@H:11]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:10]1)(=[O:7])[CH3:6].C(N(CC)CC)C>C(#N)C>[C:5]([O:8][C@H:9]1[C@H:14]([NH:15][C:16]([NH:4][O:3][CH3:2])=[S:17])[C@@H:13]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]([O:22][C:23](=[O:25])[CH3:24])[C@@H:11]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:10]1)(=[O:7])[CH3:6]
Reactant: CON
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CONC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a suspension of methoxyamine hydrochloride (180 mg, 2.16 mmol) in acetonitrile (7 mL) was added (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (560 mg, 1.44 mmol) followed by triethylamine (300 μL, 2.16 mmol). The mixture was stirred at room temperature for 2 h. Solvents were removed by concentration. The residue was purified by flash chromatography on silica gel (hexane/EtOAc 1:1) to give (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-methoxythioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white solid (545 mg, 87% yield). 1H NMR (500 MHz, CDCl3) δ 2.05 (s, 3H), 2.09 (s, 3H), 2.10 (s, 6H), 2.13 (s, 3H), 3.67 (s, 3H), 3.82-3.85 (m, 1H), 4.15 (dd, 1H, J=2.5, 12.5 Hz), 4.28 (dd, 1H, J=4.5, 12.5 Hz), 5.03 (dd, 1H, J=10.0, 13.0 Hz), 5.20-5.30 (m, 2H), 5.84 (d, 1H, J=8.5 Hz), 7.01 (d, 1H, J=10.0 Hz).
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C@@H:14]([CH2:17][CH2:18][CH3:19])CO.CCN(CC)CC>C1COCC1>[CH2:17]([C@H:14]1[CH2:2][O:4][C:5](=[O:11])[NH:13]1)[CH2:18][CH3:19]
Reactant: CCC[C@H](N)CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC[C@H]1COC(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 185.8 %

Procedure:
A solution of triphosgene (0.431 g, 1.45 mmol) in THF (5 mL) was added dropwise to a stirred solution of (S)-2-aminopentan-1-ol (0.500 g, 4.85 mmol) and Et3N (1.49 mL, 10.7 mmol) in THF (22 mL) at 0° C. under N2. The reaction mixture was stirred at ambient temperature for 2 hours. After cooling, the suspension was filtered through GF/F paper and concentrated in vacuo. The residue was taken up in EtOAc and washed with 10% HCl, dried and concentrated to give (S)-4-propyloxazolidin-2-one (0.348 g, 55%) as a clear oil.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[CH2:4]([CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:20][CH2:19][C:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(O)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][CH3:8].C(OC(=O)C)(=O)C.Cl(O)(=O)(=O)=O.[Cl-].[Na+]>C(O)(=O)C>[CH2:4]([CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:20][CH2:19][C:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([S:3][CH2:1][CH3:2])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCS
Reactant: CCCCCCCC1(O)CCC(C2CCC(CCCCC)CC2)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCC1(SCC)CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7.2 g of ethanethiol and 35 g of 4-pentyl-4'heptyl-4'-hydroxybicyclohexane in 70 ml of glacial acetic acid are added dropwise to a mixture of 30 ml of glacial acetic acid, 11.1 g of acetic anhydride and 7 g of 72% aqueous perchloric acid solution at -20°. The mixture is stirred at room temperature for 24 hours, poured into 250 ml of saturated sodium chloride solution, extracted with petroleum ether and worked up in the customary manner. 4-Pentyl-4'-heptyl-4'-ethylthiobicyclohexane is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=C[CH:13]=1>C([O-])([O-])(OCC)C>[CH3:12][C:13]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[S:8](=[O:10])(=[O:9])[N:11]=1
Reactant: Nc1cccnc1S(N)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCOC(C)([O-])[O-]
Product: CC1=NS(=O)(=O)c2ncccc2N1
Reaction time: 0.17 h

Procedure:
1 g of 3-aminopyridine-2-sulfonamide (Preparation 1) and 1 g of p-toluenesulfonic acid are dissolved in 6 cm3 of ethyl orthoacetate. After 10 minutes at room temperature, the precipitate obtained is collected on a filter, washed with diethyl ether and dried. It is recrystallized from hot water.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:12]1([CH:15](O)[CH3:16])[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH:12]1([CH:15]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH3:16])[CH2:14][CH2:13]1
Reactant: COC(=O)c1cccc(O)c1
Reactant: CC(O)C1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(OC(C)C2CC2)c1
Temperature: 25 °C

Procedure:
Methyl 3-hydroxybenzoate (10.0 g, 65.7 mmol) in toluene (65.7 ml) was cooled to 0° C. and added 1-cyclopropylethanol (6.43 ml, 65.7 mmol), triphenylphosphine (18.9 g, 72.3 mmol), and DIAD (14.1 ml, 72.3 mmol). The reaction warmed to rt for sixteen hours. The reaction mixture was filtered through a fritted funnel to remove precipitated triphenylphosphine oxide and washed with toluene. The filtrate was concentrated. The residue was purified by column chromatography on silica gel Biotage 65i, eluting with 10% ethyl acetate/hexanes to give a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7](=[O:17])[NH:8][C@@H:9]([CH:14]([CH3:16])[CH3:15])[C:10](OC)=[O:11].CCN(CC)CC>CO>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[C@H:9]([CH:14]([CH3:16])[CH3:15])[NH:8][C:7]1=[O:17]
Reactant: COC(=O)[C@@H](NC(=O)NCc1ccc(OC)cc1OC)C(C)C
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(CN2C(=O)N[C@@H](C(C)C)C2=O)c(OC)c1
Temperature: 100 °C
Yield: 70.6 %

Procedure:
A solution of (S)-methyl 2-(3-(2,4-dimethoxybenzyl)ureido)-3-methylbutanoate (1.00 g, 3.10 mmol) in MeOH (7.5 mL) and NEt3 (0.430 mL, 3.10 mmol) in a sealed vessel was placed in preheated sand bath (at 100° C.) and heated for 18 hours. The cooled reaction mixture was concentrated and the residue was taken up in ether, washed with water, dried over sodium sulfate and filtered. Purification of the crude material by column chromatography, eluting with 1-3% MeOH/dichloromethane, afforded (S)-3-(2,4-dimethoxybenzyl)-5-isopropylimidazolidine-2,4-dione as an ivory colored solid (0.640 g, 71%). LCMS (APCI+) m/z 293 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@H:12]1[O:16][C:15](=[O:17])[NH:14][C@@H:13]1[CH3:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][C:28]=2[CH3:37])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][C:28]=2[CH3:37])=[CH:25][C:26]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@H:12]1[O:16][C:15](=[O:17])[NH:14][C@@H:13]1[CH3:18]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(B3OC(C)(C)C(C)(C)O3)c2)c(C)c1
Reactant: C[C@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)ccc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3[C@H]3OC(=O)N[C@@H]3C)c2)c(C)c1

Procedure:
(4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 12, 100 mg, 0.269 mmol), methyl 4′-methoxy-2-methyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (INTERMEDIATE 11, 124 mg, 0.323 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (44 mg, 0.054 mmol), aqueous potassium carbonate (270 μL, 2M, 0.538 mmol) and 1,4-dioxane (2 mL) were sealed in a microwave vessel. The vessel was irradiated by microwave at 140° C. for 30 minutes. LCMS of the aliquot indicated complete consumption of starting iodide. The crude mixture was purified by SiO2 (preparative TLC plates, 50% ethyl acetate in hexanes) to give a glassy residue. The residue was further purified by SiO2 (preparative TLC plates, 10% ethyl acetate in dichloromethane) to afford methyl 4′-methoxy-2-methyl-2″-[(4R,5R)-4-methyl-2-oxo-1,3-oxazolidin-5-yl]-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. LCMS calc.=499.16; found=500.08 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O1CCCC1>[OH:3][CH:1]([C:4]1[C:5]([C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)=[N:6][C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:9]=1[CH3:10])[CH3:2]
Reactant: CC(=O)c1c(C)nc(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)nc(-c2ccc([N+](=O)[O-])cc2)c1C(C)O
Reaction time: 2 h
Yield: 19.9 %

Procedure:
The mixture of 5-acetyl-6-methyl-4-(4-nitrophenyl)-2-phenyl-pyrimidine (1.5 g) and sodium borohydride (170 mg) in methanol (15 ml) and tetrahydrofuran (20 ml) was stirred for 2 hours at 5°-7° C. with ice cooling. The mixture was extracted with chloroform (100 ml) and 10% aqueous hydrochloric acid (50 ml). The separated organic layer was washed successively with saturated sodium hydrogen carbonate, saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue is recrystallized from ether to give 5-(1-hydroxyethyl)-6-methyl-4-(4-nitrophenyl)-2-phenylpyrimidine (0.3 g).