Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10](=O)[N:11]([CH3:18])[C:12]2=O>O1CCCC1>[CH3:18][N:11]1[CH2:10][C:9]2[C:8]([NH2:7])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:12]1
Reactant: CN1C(=O)c2cccc(N)c2C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1Cc2cccc(N)c2C1
Yield: 85.5 %

Procedure:
A 5-L flask was set up with an overhead stirrer, temperature probe, and 500-mL addition funnel. The flask was charged with lithium aluminum hydride (100 g) and anhydrous tetrahydrofuran (1.5 L). The resulting suspension was treated with 4-amino-2-methyl-1H-isoindole-1,3(2H)-dione (100 g, 0.56 mol) at a rate such that the reaction did not become too vigorous. The resulting suspension was heated at reflux for 18 hours. The reaction vessel was cooled, placed in an ice bath, and cautiously quenched with 100 mL water, 100 mL 1N NaOH, and 300 mL water. The resulting suspension was treated with chloroform (1.5 L) and the pH of the suspension adjusted to 12 with 50% aqueous sodium hydroxide solution. The resulting suspension was treated with acetic anhydride (300 mL) while maintaining the pH at approximately 12. The reaction mixture was treated with sodium sulfate (800 g) and potassium carbonate (200 g), and the reaction mixture was filtered. The filter cake was washed with additional chloroform, and the combined filtrates were concentrated. The residue was crystallized from ethyl acetate to give 71 g (66%) of the desired product, mp 157° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 1 (40 mg, 0.1 mmol) in dioxane (0.5 mL) was added HCl (4 N in dioxane 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was removed and the crude was purified by recrystallization with MeOH-ether to yield the title product (27 mg, 90%); LCMS; 95% ESI+, Calcd: 238.4 m/z. Found: 284.4 (M+1) m/z. 1H NMR (400 MHz, DMSO-d6); δ 1.68-1.76 (m, 1H), 1.86-2.04 (m, 2H), 2.07-2.14 (m, 1H), 3.20 (br, 2H), 3.87 (br, 1H), 4.05 (dd, J1=10.4 Hz, J2=8.4 Hz, 1H), 4.18 (dd, J/=10.4 Hz, J2=3.6 Hz, 1H), 5.05 (s, 2H), 6.91-6.99 (m, 4H), 7.30-7.44 (m, 5H):
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[CH:16][CH:15]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH:35]=[CH:36][CH:37]=[N:38]3)=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[CH:18][CH:19]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][CH2:36][CH2:37][NH:38]3)=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC3CC3)cc2)[C@@H](OCc2ccc3cccnc3c2)C1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC3CC3)cc2)[C@@H](OCc2ccc3c(c2)NCCC3)C1

Procedure:
In analogy to the procedure described in example 1(c), the (3R,4R)-4-[4-(3-cyclopropylmethoxy-propoxy)-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was reduced with sodium borohydride in presence of Ni(II) chloride hexahydrate to yield the (3R,4R)-4-[4-(3-cyclopropylmethoxy-propoxy)-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 551 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[CH3:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[NH:29][CH2:28][CH2:27][CH2:26]2.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:29]2[C:30]3[C:25](=[CH:24][CH:23]=[CH:22][C:21]=3[O:20][CH3:19])[CH2:26][CH2:27][CH2:28]2)=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Reactant: COc1cccc2c1NCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2c1N(C(=O)c1cccnc1Oc1cc(Cl)ccc1Cl)CCC2
Temperature: 50 °C
Yield: 12.3 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (56.6 mg, 0.2 mmol, 1.0 equiv; Example 31, Step 1) in anhydrous DMF (1 mL) was added 8-methoxy-1,2,3,4-tetrahydro-quinoline (39.2 mg, 0.24 mmol, 1.2 equiv; [CAS RN 53899-17-5]), N-ethyldiisopropylamine (129.0 mg, 175 μL, 1.0 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (91.2 mg, 0.24 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and the reaction mixture stirred at 50° C. over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 10.6 mg (12%) of the title compound. MS (ISP): 429.3 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:4][CH2:3]1.[C:36]([O:39][C:40]([CH3:45])([CH3:44])[C:41](Cl)=[O:42])(=[O:38])[CH3:37].C(OCC)(=O)C.O>N1C=CC=CC=1>[C:36]([O:39][C:40]([CH3:45])([CH3:44])[C:41]([O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:6][CH2:7]1)=[O:42])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(=O)C(C)(C)OC(C)=O)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.47 g) in pyridine (3 mL) was added 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.44 mL) and the mixture was stirred for 2 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.47 g, 79%).
Reaction SMILES: [O-]CC.[Na+].[C:5]1([CH3:16])[CH:10]=[CH:9][C:8]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[CH:7][CH:6]=1.Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][CH2:18][N:13]1[N:14]=[N:15][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH3:16])=[CH:10][CH:9]=2)=[N:12]1)[CH3:24]
Reactant: CCOC(=O)CCBr
Reactant: Cc1ccc(-c2nnn[nH]2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCn1nnc(-c2ccc(C)cc2)n1

Procedure:
Sodium ethoxide (21%, 173 μL, 0.536 mmol) was dissolved in 650 μL absolute ethanol along with 5-p-tolyl tetrazole (65.9 mmol) at reflux. Ethyl 3-bromo-propionate (69 μL, 0.536 mmol) was added at reflux and the mixture was maintained at reflux overnight. The crude mixtures were filtered, concentrated and extracted with diethyl ether and sat. NaHCO3. The organic layers were dried and evaporated. When necessary, further purification was performed by RP-HPLC to provide ethyl-3-(5-p-tolyl-2-tetrazolyl)propionate.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:21][O:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:18][C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)([OH:20])[CH3:21])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC1(c2cccnc2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN(C)C1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (290 mg, 1.4 mmol) in DMF (6 mL) was added sodium hydride (38 mg, 1.6 mmol) and the solution was stirred at 120° C. for 1 h. The reaction mixture was cooled to 0° C. and 3-(2-methyloxiran-2-yl)pyridine (400 mg, 2.96 mmol) was added dropwise over a period of 5 min. The reaction mixture was stirred at 120° C. for 2 h, quenched with ice-water (15 mL) and extracted with EtOAc (60 mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (5-15% MeOH/EtOAc) to yield 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-3-yl)propan-2-ol. Separation by chiral HPLC provided enantiomers 5a and 5b. 1H NMR (CDCl3, freebase) δ (ppm): 8.79 (s, 1H), 8.42 (d, 1H), 7.56 (d, 1H), 7.04 (s, 1H), 6.9 (m, 2H), 6.8 (d, 1H), 4.17 (dd, 2H), 3.42 (s, 2H), 2.8 (t, 2H), 2.62 (t, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 1.61 (s, 3H). Optical rotations: Compound No. 5a, (−) 39.27 (c 0.43, Chloroform, 99.69% HPLC purity); Compound No. 5b, (+) 58.97 (c 0.58, Chloroform, 99.49% HPLC purity).
Reaction SMILES: C([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][C:10]=1[CH2:19][CH:20]([OH:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])C1C=CC=CC=1>[Pd]>[Si:23]([O:22][CH2:21][CH:20]([OH:30])[CH2:19][C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[C:9]=1[OH:8])([C:26]([CH3:28])([CH3:29])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)Cc1ccc2c(c1OCc1ccccc1)CCCC2
Agent: [Pd]
Product: CC(C)(C)[Si](C)(C)OCC(O)Cc1ccc2c(c1O)CCCC2
Yield: 89.9 %

Procedure:
Treatment of (±)-1-[1-(benzyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol (7.93 g, 0.019 mol) with palladium on carbon (10 wt. %, 0.80 g) generally according to the procedure described for Intermediate 4 gave 5.75 g (92%) of (±)-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxypropyl)-5,6,7,8-tetrahydronaphthalen-1-ol as a colorless oil. Rf=0.55 (silica, ethyl acetate:hexanes 1:3); Anal. calcd. for C19H32O3Si.0.3C4H8O2: C, 66.84; H, 9.55. Found: C, 66.47; H, 9.74.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH2:27]([O:37][C:38]([NH:40][C:41]1[NH:42][C:43](=[O:54])[C:44]2[N:45]=[CH:46][N:47]([CH2:50][C:51](O)=[O:52])[C:48]=2[N:49]=1)=[O:39])[C:28]1[CH:36]=[CH:35][C:34]2[O:33][CH2:32][O:31][C:30]=2[CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:51](=[O:52])[CH2:50][N:47]2[CH:46]=[N:45][C:44]3[C:43](=[O:54])[NH:42][C:41]([NH:40][C:38]([O:37][CH2:27][C:28]4[CH:36]=[CH:35][C:34]5[O:33][CH2:32][O:31][C:30]=5[CH:29]=4)=[O:39])=[N:49][C:48]2=3)[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccc4c(c3)OCO4)nc21
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2c(ncn2CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)[nH]1)OCc1ccc2c(c1)OCO2

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [2-N-(piperonyloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.40 (brs, 2H), 8.36 (m, 1H), 8.27 (m, 1H), 7.84 (s, 0.6H), 7.78 (s, 0.4H), 7.73 (m, 2H), 7.02 (s, 1H), 6.93 (s, 2H), 6.04 (s, 2H), 5.15 (m, 3.2H), 5.05 (s, 0.8H), 4.55 (s, 0.8H), 4.30 (s, 1.2H), 4.27 (t, 1.2H), 4.11 (t, 0.8H), 4.07 (t, 1.2H), 3.88 (t, 0.8H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:3]1[CH3:30].[H-].[Na+].[CH3:33]I>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4]([CH2:20][CH2:21][N:22]([CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[C:3]1[CH3:30]
Reactant: CI
Reactant: Cc1c(CCNC(=O)OC(C)(C)C)c2cc(S(=O)(=O)c3ccccc3)ccc2n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CCN(C)C(=O)OC(C)(C)C)c2cc(S(=O)(=O)c3ccccc3)ccc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A solution of tert-butyl 2-[1,2-dimethyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethylcarbamate (2.99 g, 6.98 mmol) in DMF (20.0 mL) was added to a 0° C. suspension of 60% sodium hydride (0.75 g, 18.82 mmol) in DMF (5.0 mL) and stirred at room temperature for one hour. Methyl iodide (0.55 mL, 8.83 mmol) was added and the reaction was stirred at room temperature for 22 hours. The reaction was cooled to 0° C., quenched with water (10.0 mL) and filtered. The filtrate was concentrated in vacuo, combined with the previously filtered solid and partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo and recrystallized from EtOAc/hexane to give 2.56 g (83%) of colorless crystals as the title compound: mp 147.1-149.0° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.15-8.10 (m, 1H), 7.92 (d, J=7.1 Hz, 2H), 7.62-7.53 (m, 5H), 3.67 (s, 3H), 3.32 (m, 2H), 2.91-2.88 (m, 2H), 2.79 (br, 3H), 2.33 (br, 3H), 1.35-0.99 (2 br, 9H); 13C NMR (100 MHz, DMSO-d6) δ 154.4, 142.9, 138.0, 137.1, 132.7, 130.4, 129.3, 126.9, 126.7, 119.0, 117.7, 109.9, 109.4, 77.7, 48.8, 33.7, 29.7, 27.9, 27.4, 22.0, 9.8; IR (diffuse reflectance) 1692, 1482, 1446, 1364, 1303, 1219, 1192, 1164, 1152, 1140, 1095, 725, 689, 655, 609 cm−1; HRMS (FAB) calcd for C24H30N2O4S+H 443.2004, found 443.2025. Anal. Calcd for C24H30N2O4S: C, 65.13; H. 6.83; N, 6.33. Found: C, 65.06; H, 6.86; N, 6.33.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([N+:8]([O-])=O)[CH:7]=1>CO.O=[Pt]=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)ccc1Oc1ccccc1
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1cc(F)ccc1Oc1ccccc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 96.1 %

Procedure:
A mixture of 5-fluoro-2-phenoxynitrobenzene 2 (15.2 g, 65 mmol) and PtO2 (131 mg) in MeOH (65 mL) was stirred at 50° C. for 5 hours under a hydrogen atmosphere. The mixture was filtered through celite. The filtrate was evaporated to dryness to yield 5-fluoro-2-phenoxyaniline 3 as brown oil (12.7 g, 97%): 1H-NMR (300 MHz, CDCl3) δ 3.88 (br s, 2H), 6.40 (ddd, J=8.6, 8.6, 3.1 Hz, 1H), 6.53(dd, J=9.9, 3.1 Hz, 1H), 6.84 (dd, J=8.6, 5.5 Hz, 1H), 6.86-7.13 (m, 3H), 7.21-7.40 (m, 2H); MS (GC) m/z 203(M., 100%). The product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[OH-].[K+].CN(C)C=O.[F:18][C:19]([F:23])=[C:20]([F:22])[F:21]>CCOCC.O>[F:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([O:8][C:20]([F:22])([F:21])[CH:19]([F:23])[F:18])[CH:7]=1
Reactant: FC(F)=C(F)F
Reactant: COc1ncc(O)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COc1ncc(OC(F)(F)C(F)F)cc1F
Temperature: 70 °C
Reaction time: 3 h

Procedure:
3-Fluoro-2-methoxy-5-pyridinol (1.60 g, 11.2 mmol) and 0.04 g (0.7 mmol) of potassium hydroxide were added to 10 ml of dimethylformamide and the mixture blanketed with nitrogen and heated to 70° C. with stirring. An excess of tetrafluoroethylene was introduced into the liquid by means of a sparge tube. After stirring 4 hours at 70° C. no reaction was observed so another 0.04 g of potassium hydroxide was added and the tetrafluoroethylene addition continued. The reaction was indicated to be complete by F19 nmr after 3 hours. The mixture was allowed to cool and was then poured into a mixture of 50 ml of water and 60 ml of ether. The ethereal layer was extracted with 2-25 ml portions of water and one of saturated aqueous sodium chloride and dried over sodium sulfate. The combined aqueous extracts were extracted with ether and the ethereal layer dried. The combined ethereal solutions were concentrated by evaporation under reduced pressure to obtain 1.65 g of the title compound as a yellow oil. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH:1]1[C:5]2=[C:6]([OH:15])[C:7]3[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=3[CH:9]=[C:4]2[O:3][CH:2]=1.[O:16]([CH2:23][CH2:24][CH2:25]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[O:16]([CH2:23][CH2:24][CH2:25][O:15][C:6]1[C:7]2[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=2[CH:9]=[C:4]2[O:3][CH:2]=[CH:1][C:5]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1ccc2c(O)c3ccoc3cc2o1
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=c1ccc2c(OCCCOc3ccccc3)c3ccoc3cc2o1
Reaction time: 0.29 h

Procedure:
700 mg (3.5 mmol) of 5-hydroxypsoralen and 750 mg (3.5 mmol) of 3-phenoxypropyl bromide were refluxed in 30 ml of 2-butanone in the presence of an excess of anhydrous potassium carbonate (3.0 g) and catalytic amounts of potassium iodide for 36 hours. The progress of the reaction was monitored by thin layer chromatography. After 36 hours the reaction mixture was concentrated under reduced pressure. The oily residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 3×30 ml of dichloromethane. The dichloromethane layer was extracted with 25 ml of 1% sodium hydroxide to separate the un-reacted 5-hydroxypsoralen. The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid, dried over anhydrous sodium sulfate and concentrated. The resulting oily residue was dissolved in methanol, treated with charcoal and re-crystallized from a methanol-ethyl acetate (10:90) mixture.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([N:13]2[CH2:17][CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH2:14]2)=[O:12])[CH2:3][CH2:2]1.Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36].C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([N:13]2[CH2:17][CH:16]=[C:15]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[C:35]([F:36])([F:38])[F:37])[CH2:14]2)=[O:12])[CH2:3][CH2:2]1
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Reactant: CC1(C)OB(C2=CCN(C(=O)N3CCOc4ccccc43)C2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(N1CC=C(c2ccc(F)cc2C(F)(F)F)C1)N1CCOc2ccccc21
Yield: 70.4 %

Procedure:
0.4 g of (2,3-dihydrobenzo[1,4]oxazin-4-yl)[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,5-dihydropyrrol-1-yl]methanone, 0.4 g of 1-bromo-4-fluoro-2-(trifluoromethyl)benzene, 1.4 ml of a 2N solution of sodium carbonate in water and 15 ml of ethylene glycol dimethyl ether are placed in a 100 ml three-necked flask equipped with a magnetic stirrer and placed under an inert atmosphere. The reaction mixture is degassed with nitrogen for 30 minutes and then the reaction mixture is heated at reflux for 14 h. After filtering and concentrating to dryness, the crude reaction product obtained is chromatographed on silica gel, elution being carried out with a gradient of ethyl acetate in dichloromethane varying from 0% to 10%. 0.31 g of (2,3-dihydrobenzo[1,4]oxazin-4-yl)[3-(4-fluoro-2-(trifluoromethyl)phenyl)-2,5-dihydropyrrol-1-yl]methanone is obtained.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:29]([O:31][CH3:32])=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1>CO>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:29]([O:31][CH3:32])=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reaction time: 1 h

Procedure:
19.8 (34.1 mmol) g Z-D-Trp-Lys(BOC)-OMe are dissolved in 220 ml methanol, 2.2 g catalyst PdC 10% added and hydrogenated at RT. The hydrogenation is finished after 1 hour at RT, the catalyst filtered off and the filtrate evaporated at 30°: white solid. HPLC: 98.1% b.a. (16.2 min).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][C@H:19]([C@H:21]([N:25]1[CH:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:27]=[CH:26]1)[CH2:22][CH2:23][OH:24])[CH3:20])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.O>[Si:11]([O:18][C@H:19]([C@H:21]([N:25]1[CH:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:27]=[CH:26]1)[CH2:22][CH:23]=[O:24])[CH3:20])([C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1cn([C@H](CCO)[C@H](C)O[Si](C)(C)C(C)(C)C)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn([C@H](CC=O)[C@H](C)O[Si](C)(C)C(C)(C)C)cn1
Reaction time: 0.17 h
Yield: 93.2 %

Procedure:
Under N2, a cold (−75° C.) solution of oxalyl chloride (285 mg, 2.24 mmol) in CH2Cl2 (10 ml) was treated with DMSO (0.215 ml, 3.03 mmol) and stirred for 10 min. A solution of ethyl 1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-hydroxy-3-pentyl]imidazole-4-carboxylate (400 mg, 1.12 mmol) in CH2Cl2 (5 ml) was slowly added, the resulting mixture was stirred for 50 min at −75 to −45° C. and finally treated with triethylamine (0.59 ml). The reaction mixture was allowed to warm to 0° C., hydrolyzed with water (10 ml) and extracted with CH2Cl2 (20 ml×2). The combined organic layers were dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel (13 g) chromatography eluting with chloroform/methanol (100:1) to give ethyl 1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-oxo-3-pentyl]imidazole-4-carboxylate (370 mg, 93%) as a colorless syrup.