Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C@@H:19]3[C@@H:14]([C:15]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:16]=4[CH2:17][CH2:18]3)[CH2:13][CH2:12]2)[CH2:5][CH2:4]1.[OH-].[Na+].C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[C:36]([Cl:38])=[O:37].Cl>O.CN(C)C1C=CN=CC=1>[ClH:38].[ClH:1].[CH3:34][N:35]([CH3:39])[C:36](=[O:37])[O:24][C:20]1[C:16]2[CH2:17][CH2:18][C@H:19]3[C@H:14]([CH2:13][CH2:12][N:11]3[CH2:10][CH2:9][N:6]3[CH2:7][CH2:8][O:3][CH2:4][CH2:5]3)[C:15]=2[CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)C(=O)Cl
Reactant: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCN1CCOCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCN1CCOCC1
Yield: 42.6 %

Procedure:
1.00 g (0.003 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-(2-morpholinoethyl)-1H-benzo[e]indol-6-ol dihydrochloride dissolved in 50 ml of water was neutralized with 5.6 ml of 1N sodium hydroxide solution (5.6 mmol, 2.1 eq.). The mixture was extracted with ether, the organic phase was washed with saturated aqueous NaHCO3 and NaCl solutions, dried with Na2SO4, filtered and the filtrate was concentrated. The oily residue was dissolved in 50 ml of toluene. 0.30 g (0.41 ml, 0.003 mol) of triethylamine, 3.25 mg (266 μmol, 0.1 eq.) of 4-dimethylaminopyridine and 0.27 ml (0.003 mol) of dimethylcarbamoyl chloride were added thereto in succession. The mixture was boiled under reflux for 2 hours, poured into water and extracted with CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3 and NaCl solutions, dried with Na2SO4, filtered, the filtrate was concentrated and the residue was chromatographed on 220 g of silica gel with methylene chloride/methanol (9:1). The resulting oil (0.8 g) was dissolved in 10 ml of ethanol. 0.92 ml (0.0045 mol) of 4.89N ethanolic HCl solution was added dropwise thereto and precipitation was effected with ethyl acetate. The crystals were filtered off, dissolved in hot ethanol and treated with active charcoal. After filtration, concentration and recrystallization from ethanol/ethyl acetate there was obtained 0.57 g (48%) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-(2-morpholinoethyl)-1H-benzo[e]indol-6-yl dimethylcarbamate dihydrochloride as white crystals with m.p. 170°-220° (dec.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1.Cl[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].C1(C)C=CC=CC=1.CCCCCCC>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.O.C1OCCOCCOCCOCCOCCOC1>[Cl:7][C:8]1[C:9]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][CH:17]=2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: CCOC(=O)C(C)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCOC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Temperature: 85 °C
Reaction time: 48 h
Yield: 64.5 %

Procedure:
Potassium carbonate (867 g, 6.29 mol) is added to a mixture of p-[(3,5-dichloro-2-pyridyl)oxy]phenol (1,609 g, 6.29 mol), 18-crown-6 (50 g, 0.19 mol) and tetrabutylammonium hydrogen sulfate (50 g, 0.15 mol) in dimethylformamide (20 L). Ethyl 2-chloropropionate (1,380 g, 10.10 mol) is then added and the reaction mixture is stirred for 2 days at 85° C., diluted with water and extracted with methylene chloride. The combined organic extracts are washed sequentially with water, 2% sodium hydroxide solution and water and concentrated in vacuo to give a residue. The residue is dissolved into a 1:1 toluene/heptane solution, washed with 2% sodium hydroxide solution and concentrated in vacuo to obtain the title product as a dark red-brown liquid (1,445 g) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([OH:6])=O)[CH3:3].CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[NH:28]([CH3:43])[C@H:29]([C:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32]>C(Cl)(Cl)Cl.O>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([N:28]([CH3:43])[C@H:29]([C:34]([CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:35])[CH2:30][CH:31]([CH3:32])[CH3:33])=[O:6])[CH3:3]
Reactant: CN[C@@H](CC(C)C)C(=O)Cc1ccccc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)C[C@@H](C(=O)Cc1ccccc1)N(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: -20 °C

Procedure:
18.9 g (100 m mol) Boc-(D)-Ala-OH are dissolved in 250 ml chloroform and cooled with stirring to -20° C. 23.1 ml (21.2 g=210 m mol) N-methylmorpholine and 12.2 ml (12.0 g=100 m mol) pivaloyl chloride are then added and the whole stirred for 2 hours, still at -20° C. Anhydride formation is followed by means of IR control. When anhydride formation is complete 23.5 g (100 m mol) H-MeLeu-Bzl dissolved in 50 ml chloroform are added dropwise to the obtained reaction mixture at -20° C. and over a period of 5 minutes. Formation of the dipeptide is followed using thin-layer chromatography and IR-spectrometry. After 19 hours no further anhydride can be detected. The obtained reaction solution is poured onto 300 ml water and diluted with 300 ml chloroform. The organic phase is separated, washed with 100 ml water, dried over sodium sulphate, filtered and the solvent carefully evaporated off at max. 40° C. The obtained residue is recrystallised from hexane to yield the title compound: rotation, [α]D25 =-35.3° C. (c=1.05 m chloroform; M.P.=81° C.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=[O:4].O[N:14]1[C:19](=[O:20])[CH2:18][CH2:17][C:15]1=[O:16]>C(Cl)(Cl)Cl>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([O:5][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][C:15]1=[O:16])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=C1CCC(=O)N1O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reaction time: 8 h

Procedure:
Boc-Gly-OH (1.54 g, 8.82 mmol) was put in a 500-mL eggplant flask and dissolved in distilled CHCl3. Then, DCU (2.18 g, 10.6 mmol) and HOSu (1.21 g, 10.6 mmol) were added thereto, and the stirring was started under cooling. After having been left standing overnight, the completion of the reaction was confirmed with TLC and the resultant was concentrated. After filtered, DCUrea was dissolved in AcOEt and the reprecipitated DCUrea was filtered. After that, the filtrate was concentrated and recrystallized with AcOEt-distilled Et2O twice, whereby Boc-Gly-OSu was obtained. The yield was 1.74 g (63.9%). 1H NMR (CDCl3, 300 MHz): 5.04 (1H, Boc-Gly NH); 4.27, 4.23 (2H, Gly αCH2); 2.79 (4H, OSu); 1.40 (9H, Boc t-Bu).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[S:17]([N:27]1[C:35]2[C:30](=[C:31]([CH2:36][NH2:37])[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:37][CH2:36][C:31]4[CH:32]=[CH:33][CH:34]=[C:35]5[C:30]=4[CH:29]=[CH:28][N:27]5[S:17]([C:20]4[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=4)(=[O:19])=[O:18])[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CN)cccc32)cc1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CNc4nccc(Nc5cc(C6CC6)[nH]n5)n4)cccc32)cc1
Temperature: 120 °C
Yield: 47.9 %

Procedure:
A tube was charged with 53 (415 mg, 1.38 mmol), 46 (486 mg, 2.07 mmol), DIPEA (1.0 ml) and IPA (3 mL), degassed, sealed and heated at 120° C. overnight. The mixture was concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (3.3 to 5% MeOH) to afford 330 mg (48%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-tosyl-1H-indol-4-yl)methyl)pyrimidine-2,4-diamine (50) as yellow solid: MS (ESI) m/z=500.3 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12]Br)[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH2:34][OH:35])[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.CC(C)([O-])C.[K+].CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH2:12][O:35][CH2:34][C:21]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[F:14])[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: FC(F)(F)c1cc(Br)cc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccccc2F)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A flask was charged with 1-bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (0.149 g, 0.47 mmol) and tert-butyl 4-(2-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.112 g, 0.36 mmol) in tetrahydrofuran (2 mL) at 0° C. The reaction was treated with potassium tert-butoxide (0.41 mg, 0.36 mmol), stirred at 0° C. for 20 min, and treated with another aliquot of potassium tert-butoxide (0.41 mg, 0.36 mmol). The reaction was allowed to warm to room temperature and was stirred for 16 h. The reaction mixture was evaporated in vacuo and the crude oil was purified by silica gel chromatography (5% ethyl acetate/95% hexanes→30% ethyl acetate/70% hexanes) to afford 0.138 g (70%) of the desired ether. Mass spec.: 546.03 (MH)+ LC tr=4.501 min. (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[O:10][CH3:11].P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)Cl.[S-:22][C:23]#[N:24].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[O:10][CH2:11][S:22][C:23]#[N:24]
Reactant: N#C[S-]
Reactant: COc1cc(Cl)c(Cl)cc1Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [K+]
Solvent: ClP(Cl)Cl
Product: N#CSCOc1cc(Cl)c(Cl)cc1Cl
Temperature: 160 °C
Yield: 65.1 %

Procedure:
In a 50 ml. flask equipped with a thermometer, magnetic stirrer, oil bath, and fractionating distillation head place 20.0 g. (0.095 mole) 2,4,5-trichloroanisole and 19.7 g. (0.095 mole) phosphorous pentachloride. The mixture is stirred and heated at 160° C. for 3 hours. As reaction takes place, phosphorous trichloride distills out of the flask. The mixture is heated at 180° C. for 0.5 hour, cooled, and the intermediate product α,2,4,5-tetrachloroanisole is distilled; b. p. 123° C. at 1.5 mm Hg., yield 18.6 g. (81%). This product is dissolved in 120 ml. acetone and 8.1 g. (0.083 mole) dried potassium thiocyanate is added in one portion. The mixture is stirred at ambient temperature for 48 hours, poured into 900 ml. ice water, and extracted with ether. The ether extracts are washed with cold 0.5 N sodium hydroxide and water, dried (MgSO4), and concentrated. The crude product is recrystallized from hexane to give compound (I) 14.5g (71%), as colorless needles, m.p. 103°-105° C. Calcd. for C8H4Cl3NOS: C, 35.78; H, 1.50; Cl, 39.61; N, 5.22; S, 11.94. Found: C, 35.71; H, 1.68; Cl, 39.2; N, 5.14; S, 11.99.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[C:7]([Cl:14])=[N:8][C:9]([CH3:13])=[N:10][C:11]=1Cl.[K+].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH-:30])(=[O:29])=[O:28])=[N:25][CH:26]=1>>[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:11]2[C:6]([O:5][C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=3[O:2][CH3:1])=[C:7]([Cl:14])[N:8]=[C:9]([CH3:13])[N:10]=2)(=[O:29])=[O:28])=[N:25][CH:26]=1
Reactant: Cc1ccc(S([NH-])(=O)=O)nc1
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1Cl
Agent: [K+]
Product: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C)cn1

Procedure:
According to the procedure described in Example 1g) 1.00 g 5-(o-methoxyphenoxy)-4,6-dichloro-2-methyl-pyrimidine was reacted with 5-methyl-2-pyridine sulfonamide potassium salt to give 1.5 g 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.57 min, [M+1]+=421.42, [M−1]−=419.46.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:20][CH:21]1[O:25][CH:24]([CH3:26])[CH:23]([CH3:27])[O:22]1>>[CH3:27][CH:23]1[CH:24]([CH3:26])[O:25][CH:21]([CH2:20][NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[O:22]1
Reactant: CC1OC(CBr)OC1C
Reactant: CCCCOc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCOc1ccccc1NCC1OC(C)C(C)O1
Temperature: 100 °C

Procedure:
2-n-Butoxyaniline (99 grams; 0.6 moles) and sodium carbonate (31.6 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Bromomethyl-4,5-dimethyl-1,3-dioxolane (25 ml) was added and the reaction mixture was heated at a temperature of about 100° C. for a period of about 4 hours. After this time the reaction mixture was filtered and additional sodium carbonate (5.0 grams) was added to the filtrate. The mixture was then vacuum distilled and the fraction boiling at 123° C. and 0.05 mm of Hg pressure was collected to yield the desired product N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)-2-n-butoxyaniline.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:12]=[C:25]3[NH:19][C:20](=[O:21])[NH:22][C:23]3=[O:24])[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
A mixture of 24.43 g (100 moles) of 3-phenylmethoxy-4-methoxybenzaldehyde (Berichte 67, 1214/1934/), 10.01 g. (100 mmoles) of hydantoin, 38 ml of anhydrous acetic acid and 19.5 g of anhydrous sodium acetate is heated to 140° C. with shaking and the solution obtained is refluxed at 158°-162° C. for 2.5 hours, then cooled and poured into 250 ml of ice-water. The gum obtained becomes crystalline after 30 minutes. The crystals are filtered, washed successively with water, ethanol and ether and dried to give 14.75 g (45.5%) of the title compound, m.p. 249°-251° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7](O)=[O:8])=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[O:14][CH:15]([CH3:17])[CH3:16].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[NH2:37][C:38]1[NH:42][N:41]=[N:40][N:39]=1.C(C1NN=NN=1)(=O)N>C(#N)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:37][C:38]2[NH:42][N:41]=[N:40][N:39]=2)=[O:8])=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: Nc1nnn[nH]1
Reactant: Cc1oc(C(=O)O)c(OC(C)C)c1OC(C)C
Agent: NC(=O)c1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1oc(C(=O)Nc2nnn[nH]2)c(OC(C)C)c1OC(C)C
Yield: 27.4 %

Procedure:
Following the procedure described in Example 120, 2.00 g (8.84 mmol) of the above carboxylic acid, 1.65 g (10.18 mmol, 1.15 equiv) of 1,1'-carbonyl diimidazole, 2.2 g (21.5 mmol, 2.4 equiv) of triethylamine, and 0.89 g (10.46 mmol, 1.18 equiv) of 5-aminotetrazole in refluxing (2.5 hours) acetonitrile (46 mL) is converted to the carbamoyltetrazole. Recrystallization from toluene afforded 0.75 g (2.73 g theo., 27%) of 5-methyl-3,4-diisopropoxy-N-1H-tetrazol-5-yl-2-furancarboxamide; mp 190°-192° C. (dec).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1.C([O:24][B:25](OCCC)[O:26]CCC)CC>C1COCC1>[F:13][C:14]1[C:19]([B:25]([OH:26])[OH:24])=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1
Reactant: CCCOB(OCCC)OCCC
Reactant: Cc1ccc(F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cnc(F)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
n-Butyllithium (2.5M solution in hexane, 9.6 mL, 24 mmol) was added to a mixture of diisopropylamine (3.4 mL, 24 mmol) in THF (5.00 mL, 61 mmol) at 0° C. and the resulting pale yellow solution was stirred at the same temperature for 30 min and then cooled down to −78° C. A suspension of 2-fluoro-5-methylpyridine (Aldrich, St. Louis, Mo.) (2.22 g, mmol) in THF (5.00 mL, not complete dissolved) was slowly added. The resulting bright yellow solution was stirred at −78° C. for 1 h, treated with a solution of tri-1-propylborate (6.9 mL, 30 mmol) in THF (10.00 mL) and then allowed to warm up to room temperature. The yellow suspension was quenched with 1 N NaOH until basic (pH about 10) and the organic layer was separated. The aqueous layer was collected and carefully acidified with 6N aqueous HCl until slightly acidic, and then extracted with EtOAc(×3). The combined organic layers were dried (Na2SO4), filtered and concentrated. The resulting white solid was washed with ether to give 2-fluoro-5-methylpyridin-3-ylboronic acid (2.9196 g, 94% yield) as a white solid. LCMS (API-ES) m/z 156 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:11]([OH:12])[CH:10]([C:13]2[C:14](=[O:26])[N:15](CC3C=CC=CC=3)[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[O:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:28])[CH:11]([OH:12])[CH:10]([C:13]2[C:14](=[O:26])[NH:15][CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc(Br)cc2C(c2cccn(Cc3ccccc3)c2=O)C1O
Agent: [Pd]
Solvent: CO
Product: CC1(C)Oc2ccccc2C(c2ccc[nH]c2=O)C1O

Procedure:
A solution of 280 mg of 2,2-dimethyl-4-(1-benzyl-1,2-dihydro-2oxo-3pyridyl)-6-bromo-3-chromanol is hydrogenated on 140 mg of 20% Pd-C in 80 ml of methanol at 20° and 1 bar, the mixture is filtered, the filtrate is evaporated and 2,2-dimethyl-4-(1,2-dihydro-2-oxo-3-pyridyl)-3-chromanol, m.p. 244°-246°, is obtained after chromatographic purification on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH3:22])=[CH:12][C:11]=2[CH:23]([CH3:25])[CH3:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])(=[O:28])C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH:22]=[O:28])=[CH:12][C:11]=2[CH:23]([CH3:25])[CH3:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Reactant: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Product: CC(C)c1cc(C=O)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 18 h
Yield: 13.9 %

Procedure:
To a solution of 160 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methyl-1-[(4-pyridyl)methyl]-1H-pyrrole in 3 ml of acetic acid was added 200 mg of lead tetraacetate over 30 min. After stirring for 2 h at room temperature a further 100 mg of lead tetraacetate was added and the mixture stirred for 18 h. After this time a further 100 mg of lead tetraacetate was added and the mixture stirred for 18 h. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using petrol/ethyl acetate (1:4 then 1:2) then ethyl acetate for the elution to give 23 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-1-[(4-pyridyl)methyl]-1H-pyrrole-2-carbaldehyde, mass spectrum (ESI) m/z 405 [M+H]+, as a brown oil and 51 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-1-[(4-pyridyl)methyl]-1H-pyrrole-2-acylmethanol as an impure yellow foaming oil, Mass spectrum (ESI) m/z 447 [M+H]+.
Reaction SMILES: [CH2:1]([C@@H:9]1[NH:14][C:13](=O)[CH2:12][NH:11][C:10]1=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].[H][H]>C1COCC1>[CH2:1]([C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:14]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: O=C1CNC(=O)[C@H](CCc2ccccc2)N1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CC[C@H]2CNCCN2)cc1
Temperature: 0 °C
Yield: 90.8 %

Procedure:
Add 3-(S)-phenethyl-piperazine-2,5-dione (2.5 g, 11 mmol) portionwise to lithium aluminum hydride (1.75 g, 46 mmol) in THF (46 mL). Reflux the resulting suspension for an hour and cool to 0° C. Add sodium sulfate decahydrate carefully until hydrogen evolution ceases and stir the mixture for an additional three hours at room temperature and filter. Wash the solids with THF several times. Combine the filtrates, concentrate, and recrystallize the residue with THF/pentane to afford 2-(S)-phenethyl-piperazine as white crystals (1.9 g, 90%): mp 114–115° C.; 1H NMR (CDCl3): δ1.58–1,70 (m, 2H), 2.41 (dd, 1H), 2.58–3.02 (m, 8H), 7.16–7.30 (m, 5H); MS (APCI) m/z (rel intensity) 191 (100).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH2:3]1.ClC1C=CC(OCCCOC2C=CC3C(=O)CC(CCC(OCC)=O)(CCC(OCC)=O)OC=3C=2CCC)=CC=1>C(OCC)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:3]1
Reactant: CCCc1c(OCCCOc2cccc(C(F)(F)F)c2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Agent: CCCc1c(OCCCOc2ccc(Cl)cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Solvent: CCOCC
Product: CCCc1c(OCCCOc2cccc(C(F)(F)F)c2)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O
Yield: 60.4 %

Procedure:
The title compound was prepared by the method of Example 22 except that the title product of Example 36 (487 mg) was substituted for the title product of Example 21. Trituration with diethyl ether produced 267 mg of the titled compound as a solid, m.p. 129°-129.5° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][NH2:43]>C(Cl)(Cl)Cl.CO>[CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][NH-:43]
Reactant: NCc1ccccn1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)C/C=C/C=C(/C#N)[C@H](O)[C@@H](C)C1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)CC=CC=C(C#N)[C@H](O)[C@@H](C)C1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: [NH-]Cc1ccccn1
Reaction time: 3 h

Procedure:
To a mixed anhydride solution prepared from 200 mg (0.41 mmol) of borrelidin according to Example 3 206 μl (2 mmol, 216 mg) of 2-picolylamine were added. After stirring for 3 hours, the starting borrelidin (Rf=0.52) disappeared and the product (Rf=0.29) appeared, which was proved by thin-layer chromatography (silica gel plate, eluent system: chloroform/methanol 3:7). The reaction mixture was evaporated to dryness. The dry residue was dissolved in 100 ml of chloroform, washed with 3×30 ml of water, dried over sodium sulfate and evaporated to dryness. The dry residue was chromatographed on a silica gel column with mixtures of chloroform and ethyl acetate of increasing ethyl acetate content. The fractions containing the product eluting with a 1:1 eluting mixture were combined and evaporated to dryness. The structure of the thus-obtained solidifying oily product (188 mg) was confirmed by spectroscopic (PMR, CMR, TS) data.