Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[CH:25][NH:24][C:23]2=O)=[CH:18][CH:17]=1.FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C=CN(C2C=CC(F)=CC=2)C1=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:23]2[N:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=3)[CH:26]=[CH:25][N:24]=2)[CH3:13])[CH2:11][O:10]1
Reactant: O=c1[nH]ccn1-c1ccc(F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: C[C@@H](n1ccn(-c2ccc(F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1nccn1-c1ccc(F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 31.3 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.95 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.39 g of 1-(4-fluorophenyl)-2(1H,3H)-imidazolone, 1.10 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-fluorophenyl)-2(1H,3H)-imidazolone and 0.88 g of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-fluorophenyl)-2-imidazolyloxy]ethyl]oxirane were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[C:9]([C:10]=1[C:11](O)=[O:12])=[CH:8][C:7]([O:14][CH3:15])=[CH:6][CH:5]=2.[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:31]([O:30][C:28]([N:22]1[CH2:27][CH2:26][N:25]([C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=3)[N:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:2]=2[Cl:1])=[O:12])[CH2:24][CH2:23]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COc1ccc2c(c1)c(C(=O)O)c(Cl)n2-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COc1ccc2c(c1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cl)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of 602 mg (1.99 mmol) of the compound of step 4, tert-butyl 1-piperazinecarboxylate (372 mg, 1.99 mmol), EDC (421 mg, 2.19 mmol) and HOAT (312 mg, 2.29 mmol) in DMF (5 ml) was added NMM (0.66 ml, 5.98 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to give 930 mg of the title compound.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:49]=[C:50]([CH2:52][O:53][Si](C(C)(C)C)(C)C)[CH:51]=1)[N:31]([CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH3:48])[CH2:32][C:33]([CH3:38])([S:35][S:36][CH3:37])[CH3:34])(C(C)(C)C)(C)C>C1COCC1>[CH3:48][O:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][N:31]([CH2:32][C:33]([CH3:38])([S:35][S:36][CH3:37])[CH3:34])[C:30]1[CH:29]=[C:28]([CH2:27][OH:26])[CH:51]=[C:50]([CH2:52][OH:53])[CH:49]=1
Reactant: COCCOCCOCCN(CC(C)(C)SSC)c1cc(CO[Si](C)(C)C(C)(C)C)cc(CO[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCCOCCOCCN(CC(C)(C)SSC)c1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (10.57 ml, 10.57 mmol) was added dropwise to stirring solution of 3,5-bis(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(2-(2-methoxyethoxyl)ethoxy)ethyl)-N-(2-methyl-2-(methyldisulfanyl)propyl)aniline (3.5 g, 5.29 mmol) in anhydrous THF (65 ml) at 0° C. in an ice bath. Following addition the mixture was stirred at ambient temperature for two hours. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The extracts were washed with water and brine, dried with magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (MeOH/DCM) yielded (5-((2-(2-(2-methoxyethoxyl)ethoxy)ethyl)(2-methyl-2-(methyldisulfanyl)propyl)amino)-1,3-phenylene)dimethanol (2 g, 87%). 1H NMR (400 Hz, CDCl3): δ 6.76 (s, 2H), 6.63 (s, 1H), 4.55 (s, 4H), 3.65-3.51 (m, 14H), 3.35 (s, 3H), 2.44 (s, 3H), 1.33 (s, 6H); 13C NMR (400 Hz, CDCl3): δ 149.0, 142.35, 114.0, 111.1, 71.98, 70.7, 70.6, 70.5, 67.6, 65.5, 59.75, 59.1, 53.9, 51.9, 26.6, 25.7, 20.75; MS (m/z): found 456.2 (M+Na)+. See FIG. 46.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH2:35])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1.FC1C=CC(C2C3C(=NC=C(F)C=3)NC=2)=CC=1N[C@H]1CCC[C@@H](N)C1.Cl[C:62]1[O:63][CH:64]=[C:65]([C:67]([O:69][CH3:70])=[O:68])[N:66]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C.CCOC(C)=O.O>[F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:62]3[O:63][CH:64]=[C:65]([C:67]([O:69][CH3:70])=[O:68])[N:66]=3)[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](N)C4)n3)c3cc(F)cnc32)cc1
Reactant: COC(=O)c1coc(Cl)n1
Agent: N[C@@H]1CCC[C@H](Nc2cc(-c3c[nH]c4ncc(F)cc34)ccc2F)C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1coc(N[C@@H]2CCC[C@H](Nc3nc(-c4cn(S(=O)(=O)c5ccc(C)cc5)c5ncc(F)cc45)ncc3F)C2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)—N1-[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-1,3-diamine, 44e, (0.089 g, 0.178 mmol) in DMF (1.5 mL) was added methyl 2-chlorooxazole-4-carboxylate (0.031 g, 0.195 mmol), followed by DBU (0.029 mL, 0.195 mmol). The reaction mixture was allowed to stir at room temperature overnight. The reaction was warmed to 75° C. and allowed to stir for 3 hours. Added an additional 16 mg of the chlorooxazole ester and the reaction was heated at 75° C. overnight. The mixture was diluted into water and EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (0-20% MeOH/CH2Cl2) to afford 28 mg of desired product: LCMS RT=3.73 (M+1) 624.12.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][C:6]=1[C:13]([F:16])([F:15])[F:14])([CH3:3])[CH3:2].S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:19][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:7]=1
Reactant: CC(C)Oc1ccc(CO)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(CCl)cc1C(F)(F)F
Temperature: 75 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of (4-isopropoxy-3-(trifluoromethyl)phenyl)methanol (11.27 mmol) in toluene (20 mL) was added thionyl chloride (67.7 mmol). The reaction was stirred at 75° C. for 3 h. The mixture was diluted with hexanes, washed with water (twice), saturated NaHCO3, dried over MgSO4, and filtered. The solvent was removed under vacuum to give the title compound as an oil (10.4 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.06 Hz, 6H), 4.75-4.85 (m, 3H), 7.30 (d, J=8.46 Hz, 1H), 7.63-7.70 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][C:35](=[O:37])[NH:34][CH:33]=2)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[O:36][C:35](=[O:37])[NH:34][CH:33]=4)=[CH:30][CH:31]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc(-c2c[nH]c(=O)o2)cc1
Product: CCC(C(=O)Nc1ccc(-c2c[nH]c(=O)o2)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
87 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 60 mg (0.30 mmol, 1.2 eq.) of 5-(4-aminophenyl)-1,3-oxazol-2(3H)-one were reacted according to General Method 1. Yield: 23 mg (purity 93%, 17% of theory)
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[CH3:6][N:7]1[C@H:11]2[C:12]([C:15](OC)=O)=[CH:13][CH2:14][C@@H:8]1[CH2:9][CH2:10]2>C1COCC1>[CH3:2][C:1]1[N:3]=[C:15]([C:12]2[CH:11]3[N:7]([CH3:6])[CH:8]([CH2:14][CH:13]=2)[CH2:9][CH2:10]3)[O:5][N:4]=1
Reactant: COC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Reactant: CC(N)=NO
Solvent: C1CCOC1
Product: Cc1noc(C2=CCC3CCC2N3C)n1
Temperature: 60 °C

Procedure:
Acetamide oxime (500 mg, 6.75 mmol) suspended in THF (50 mL) under nitrogen was heated at 60° C. with Nail (132 mg, 5.5 mmol in oil dispersion) for 1 h. Anhydroecgonine methyl ester (2.76 mmol) and 4 A· molecular sieves (2 g) were added and the reaction mixture heated under reflux for 3 h, After cooling, the reaction mixture was filtered and the solvent removed in vacuo. The residue was chromatographed on a silica gel column eluting with CHCl3 --CH3OH (95:5) to give the free base.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[C:21](=[O:23])=[O:22]>>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:21]([OH:23])=[O:22])=[CH:11][C:12]([F:15])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)nc1
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)O
Yield: 25 %

Procedure:
Reaction of 5-[N-(tert-butoxycarbonyl)amino]-2-fluoropyridine (5.3 g, 25 mmol) sequentially with n-BuLi and CO2 as described in the following example gives 5-[N-(tert-butoxycarbonyl)amino]-2-fluoropyridine-4-carboxylic acid (1.60 g, 25%). 1H NMR (DMSO) δ 9.83 (1H, brs), 8.84 (1H, s), 7.49 (1H, d, J=2.9 Hz), 1.47 (9H, s).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15]>CN(C)C=O>[CH2:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]([O:25][Si:2]([CH3:5])([CH3:4])[CH3:3])=[CH2:24])=[CH:21][CH:22]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)c1ccc(CC(C)C)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C)c1ccc(CC(C)C)cc1
Yield: 29 %

Procedure:
To a solution of chlorotrimethylsilane (16.3 g) and triethylamine (30.3 g) in N,N-dimethylformamide (50 ml) was added 4'-isobutylacetophenone (22.0 g). The yellow solid was immediately filtered off, and the filtrate was refluxed for 20 hours. The mixture was cooled, diluted with hexane, and washed with cooled aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated. The residue was distilled under reduced pressure to give 4-isobutyl-α-trimethylsilyloxystyrene (9.0 g) as an oil.
Reaction SMILES: [Br:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][OH:10])[CH2:5][CH2:4]1.[C:11]1([CH:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][C:19](O)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][O:10][C:19](=[O:20])[CH2:18][CH:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:5][CH2:4]1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Reactant: OC[C@H]1CC[C@H](CBr)CC1
Product: O=C(CC(c1ccccc1)c1ccccc1)OC[C@H]1CC[C@H](CBr)CC1

Procedure:
From 4-bromomethyl[trans]cyclohexylmethanol and 3,3-diphenylpropionic acid. Yield: 60% (oil).
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@@:16]4([CH3:22])[CH2:17][CH2:18][C@H:19](O)[CH2:20][C@@H:15]4[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].C(N(S(F)(F)F)CC)C>ClCCl>[CH3:1][C:2](=[O:3])[C@@H:4]1[C@:8]2([CH3:23])[C@H:7]([C@H:12]3[C@H:11]([CH2:10][CH2:9]2)[C@:16]2([CH3:22])[C@H:15]([CH2:20][CH:19]=[CH:18][CH2:17]2)[CH2:14][CH2:13]3)[CH2:6][CH2:5]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -78 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To a solution of 5α-pregnan-3β-ol-20-one (3.75 g, 11.8 mmol) in anhydrous dichloromethane (200 mL) at −78° C. under argon atmosphere was added diethylaminosulfur trifluoride (DAST) (2.30 mL, 17.7 mmol) and the resulting solution stirred over a period of 1 h at −78° C. The solution was then directly evaporated with silica gel and purified by FCC with EtOAc/hexanes (2:98) as eluant to give the desired compound 11 (880 mg, 25%) with a ratio of C2-C3 alkene vs. C3-C4 alkene isomer of 96:4. 1H NMR (acetone-d6) δ: 0.60 (s, 18-CH3), 0.78 (s, 19-CH3), 0.75-2.40 (residual CH and CH2), 2.07 (s, 21-CH3), 2.60 (t, J=9.1 Hz, 17α-CH), 5.57 (m, 2-CH and 3-CH). 13C NMR (CDCl3) δ: 11.7, 13.4, 20.9, 22.7, 24.4, 28.6, 30.2, 31.6, 31.7, 34.6, 35.6, 39.1, 39.7, 41.4, 44.2, 53.9, 56.7, 63.9, 125.8, 125.9, 209.8. LRMS for C21H32O [M+H]+: 301.1 m/z.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[N:14][CH:13]=[CH:12]3)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][N:28]=1>N1C=CC=CC=1>[ClH:26].[N:28]1[CH:27]=[CH:32][CH:31]=[N:30][C:29]=1[N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[N:14][CH:13]=[CH:12]3)[CH2:4][CH2:3]1
Reactant: Clc1ccncn1
Reactant: c1cc2cc(OC3CCNCC3)ccc2cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: c1cnc(N2CCC(Oc3ccc4cnccc4c3)CC2)nc1
Temperature: 65 °C
Reaction time: 6 h

Procedure:
150 mg of 6-(Piperidine-4-yloxy)-isoquinoline hydrochloride (124) are dissolved in 10 mL of dry pyridine. 177 mg of triethylamine and 69 mg of 4-chloropyrimidine are added and the solution is stirred at 65° C. for 6 hours. The reaction mixture is poured on brine and extracted three times with ethyl acetate. The combined organic layers are dried over magnesium sulfate, evaporated to dryness and the crude product is purified by preparative HPLC. The product is converted into the corresponding HCl salt by taking up the product in 20 mL of 1 N hydrochloric acid followed by lyophilization. Yield: 47 mg. Rt=1.05 min (Method #2). Detected mass: 307.1 (M+H+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11].[CH3:18][N:19]1[CH2:23][CH2:22][CH:21](O)[CH2:20]1.O.[OH-].[Na+]>CS(O)(=O)=O>[CH3:18][N:19]1[CH2:23][CH2:22][CH:21]([O:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH2:20]1
Reactant: OC(c1ccccc1)c1nc2ccccc2[nH]1
Reactant: CN1CCC(O)C1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(OC(c2ccccc2)c2nc3ccccc3[nH]2)C1
Temperature: 25 °C

Procedure:
A mixture of (1H-benzimidazol-2-yl)phenylmethanol (611 mg) and 1-methyl-3-pyrrolidinol (263 mg) in methanesulfonic acid (1.3 mL) is heated for 4 hours in a sealed tube at a temperature close to 140° C. The mixture is cooled back to room temperature, poured into water which is then made alkaline with concentrated sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate, concentrated under reduced pressure. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 90/10) to give 2-[(1-methylpyrrolidin-3-yloxy)phenyl-methyl]-1H-benzimidazole melting at 53° C.
Reaction SMILES: [CH:1]1([Ru:6][CH:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:16](O)[CH2:17][CH3:18]>O>[CH2:16]([Ru:6]([CH:1]1[CH:2]=[CH:3][CH:4]=[CH:5]1)[CH:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1)[CH2:17][CH3:18]
Reactant: C1=CC([Ru]C2C=CC=C2)C=C1
Reactant: CCCO
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CCC[Ru](C1C=CC=C1)C1C=CC=C1
Temperature: 120 °C
Yield: 19 %

Procedure:
8.0 g of bis(cyclopentadienyl)ruthenium, 3.0 g of aluminum chloride, and 80 g of polyphosphoric acid were mixed. The mixed solution was heated to 100° C. under a nitrogen atmosphere, to which 4.0 g of n-propyl alcohol was added dropwise over 30 minutes, and then the mixture was heated to 120° C. to carry out the reaction for 4 hours. After the reaction was completed, hot water was added to the solution to remove the polyphosphoric acid, and then distillation treatment gave 1.8 g of n-propylcyclopentadienyl(cyclopentadienyl)ruthenium.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:11]=[C:12]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:13][C:14]=1[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)=O)(C)(C)C.[ClH:27].O1CCOCC1>>[ClH:27].[NH2:8][CH2:9][C:10]1[N:11]=[C:12]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:13][C:14]=1[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1nc(-c2ccc(F)cc2)oc1-c1ccsc1

Procedure:
A solution of 4-(t-butoxycarbonylamino)methyl-2-(4-florophenyl)-5-(3-thienyl)oxazole (455 mg) in 4N hydrogen chloride-dioxane solution was stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure and the remaining volatiles were removed by evaporation with toluene, and the resulting residue was triturated with diethyl ether to obtain 4-aminomethyl-2-(4-fluorophenyl)-5-(3-thienyl)oxazole hydrochloride (288 mg) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]4[C:25](=O)[C:24]([CH3:28])([CH3:27])[C:23]([CH3:29])=[N:22]4)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]4[C:25](=[S:39])[C:24]([CH3:28])([CH3:27])[C:23]([CH3:29])=[N:22]4)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=NN(c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)C(=O)C1(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC1=NN(c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)C(=S)C1(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 2-{4-[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-4,4,5-trimethyl-2,4-dihydro-pyrazol-3-one (0.21 g, 0.0005 mol) and Lawesson reagent (0.22 g 0.0005 mol) in toluene (3 ml) is stirred at 100° C. for one hour. After cooling the resulting solution is directly purified by silicagel column chromatography to the title compounds (IVb) (0.19 g, 88.1%) m.p. 167–168° C.,
Reaction SMILES: [CH3:1][N:2]([CH:30]([CH3:32])[CH3:31])[C:3]1[C:4]([C:17]2[C:21]3[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:20]=3[O:19][CH:18]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH:30]([CH3:32])[CH3:31])[C:3]1[C:4]([C:17]2[C:21]3[CH:22]=[C:23]([C:26]([F:29])([F:27])[F:28])[CH:24]=[CH:25][C:20]=3[O:19][CH:18]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3coc4ccc(C(F)(F)F)cc34)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1coc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-[5-(trifluoromethyl)-1-benzofuran-3-yl]quinoxaline-6-carboxylate (135 mg, 0.30 mmol) in methanol (30 mL) and water (1.0 mL) was added sodium hydroxide (48.8 mg, 1.22 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (20 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-[5-(trifluoromethyl)-1-benzofuran-3-yl]quinoxaline-6-carboxylic acid as a light yellow solid (42.6 mg, 33%).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25](N(OC)C)=[O:26])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25](=[O:26])[CH3:31])[CH2:20]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To an ice-cooled solution of 3-((tert-butyldiphenylsilyl)oxy)-N-methoxy-N-methylbicyclo[3.1.0]hexane-6-carboxamide (37 g, 87 mmol) in anhydrous tetrahydrofuran (500 mL) was added dropwise methylmagnesium bromide (87 mL, 262 mmol, 3.0 M in diethyl ether). After 3 h, saturated aqueous ammonium chloride was added to the reaction mixture. The resulting aqueous solution was extracted with ethyl acetate (3×100 mL). The combined organics were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to yield crude 1-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)ethanone as a light brown solid (30.0 g, 91%) which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[CH:10]([SiH](C)C)[C@@H:11]1[N:14](C(C)(C)C)[C:13](=[O:19])[C@H:12]1[C:20]([OH:23])([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.O>[CH2:1]([O:8][C:9](=[O:27])[CH2:10][CH:11]1[NH:14][C:13](=[O:19])[CH:12]1[C:20]([OH:23])([CH3:21])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[SiH](C)C(C(=O)OCc1ccccc1)[C@H]1[C@H](C(C)(C)O)C(=O)N1C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(O)C1C(=O)NC1CC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of 3.7 g 1-tert.butyldimethylsilyl-2-oxo-3-(trans)-(1-hydroxy-1-methylethyl)azetidine-4-yl-acetic acid benzylester in 130 ml of methanol/water (9/1) are added 6.6 ml of conc. HCl. This mixture is stirred for 30 minutes at 0° and 31/2 hours at 25°. The solution is concentrated and the residue taken up in ethylacetate, washed once with aq. NaCl, dried over MgSO4 and evaporated to dryness to yield the title compound
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].ON1C2C=CC=CC=2N=N1.[OH:60][CH2:61][C@@H:62]([C@@H:64]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[OH:67])[OH:65])[NH2:63].C(N=C=NC(C)C)(C)C.Cl>C(Cl)(Cl)Cl>[C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:63][C@H:62]([C@@H:64]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[OH:67])[OH:65])[CH2:61][OH:60])=[O:49])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.1 %

Procedure:
A mixture of 27-oleoyloxyheptacosanoic acid (2 g, 2.9 mmoles), chloroform (76 ml), dried 1-hydroxybenzotriazole (1.28 g, 10.9 mmoles), phytosphingosine (1.23 g, 3.9 mmoles) and N,N'-diisopropylcarbodiimide (0.88 ml, 5.64 mmoles) was stirred under nitrogen for 24 hours at room temperature. After adding 50 ml of a lN hydrochloric acid solution and stirring the organic layer was filtrated, washed with brine and concentrated. The title product (2.07 g) was obtained by crystallization from hot isopropanol (50 ml).