Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(OCC)C>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=3)=[O:15])=[CH:21][CH:20]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2cc(I)ccc2c1O
Solvent: CCOCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(I)ccc2c1O
Temperature: 180 °C

Procedure:
3-Iodoaniline (8.50 mL) and diethyl ethoxymethylenemalonate (14.30 mL) are heated at 130° C. for 1 hour. The reaction is cooled to room temperature and 70 mL diphenyl ether is added. The solution is heated at 250° C. for 1.5 hours with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature and the resulting solid filtered, washed with hexanes, and dried. The solid is triturated in ethyl acetate to give 12.82 g of ethyl 4-hydroxy-7-iodoquinoline-3-carboxylate. A mixture of this ester (0.35 g) and 4-chlorobenzylamine (3.0 mL) are heated at 180° C. for 1 hour. The reaction is cooled to 70° C. and poured into 50 mL diethyl ether. A tan solid which crystallizes slowly out of diethyl ether is obtained. The solid is recrystallized from ethyl acetate/hexanes to give the desired product (0.22 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.O1CCCC1.[I-].[K+].Cl[CH2:25][CH2:26][CH2:27][C:28]([N:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)=[O:29]>CC(=O)CC.C(OCC)(=O)C.C(N(CC)CC)C.CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:25][CH2:26][CH2:27][C:28]([N:30]2[CH2:39][CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31]2)=[O:29])[CH2:13][CH2:12]1
Reactant: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: O=C(CCCCl)N1CCc2ccccc2C1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: O=C(CCCN1CCC(c2c[nH]c3ccc(F)cc23)CC1)N1CCc2ccccc2C1

Procedure:
A mixture of 5-fluoro-3-(piperidin-4-yl)-1H-indole (3.0 g), butanone (200 mL), tetrahydrofuran (200 mL), methanol (30 mL), potassium iodide (11.4 g) and triethylamine (7.6 mL) was heated until reflux temperature followed by the addition of a solution of 4-chloro-1-(3,4-dihydro-1H-isoquinolin-2-yl)butan-1-one (14.6 g) in butanone (50 mL). The mixture was boiled under reflux for 2 h, filtered hot and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/ethanol/triethylamine 100:5:5) to give the crude product. The title compound was isolated as the free base from ethyl acetate as a white crystalline compound (0.9 g). Mp 146-148° C. 1H NMR (DMSO-d6): 1.55-1.70 (m, 2H); 1.70-1.80 (m, 2H); 1.85-1.95 (m, 2H); 2.00 (q, 2H); 2.30 (q, 2H); 2.35-2.45 (m, 2H); 2.60-2.70 (m, 1H); 2.75 (t, 0.8H); 2.80-3.00 (m, 3.2H); 3.65 (t, 2H); 4.60 (s, 1.2H); 4.70 (s, 0.8H); 6.85-6.95 (m, 1H); 7.10-7.20 (m, 5H); 7.25 (d, 1H); 7.30-7.35 (m, 1H); 10.85 (s, 1H). MS m/z: 420 (MH+), 202.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2OC(C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=[O:37])C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])[O:13][C:14]=1[C:15]([OH:37])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(c1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1)S(=O)(=O)c1ccccc1
Reactant: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C=O)o1
Product: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1

Procedure:
3-Benzyloxy-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-4H-pyran-2-carboxylic acid (12-02) (2.0 g, crude) was synthesized as a white solid from N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-2-methyl-benzenesulfonamide (11-02) (2.8 g, 6.74 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (12-01).
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[CH:24]([S:25][CH2:26][C:27]#[C:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[NH:23][C:22]2=[O:35])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]([O:40][CH3:41])(=[O:39])[CH:37]=[O:38].O>C1C=CC=CC=1>[OH:38][CH:37]([N:23]1[CH:24]([S:25][CH2:26][C:27]#[C:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:21]([NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:22]1=[O:35])[C:36]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)C=O
Reactant: O=C1NC(SCC#Cc2ccccc2)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C(O)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccccc1
Yield: 64 %

Procedure:
3-(Triphenylmethylamino)-4-(3-phenylprop-2-ynylthio) azetidin-2-one (526mg) and methyl glyoxylate (1.17g) were refluxed in dry benzene (25ml) with provision for the removal of water. After 11/2 hours the solvent was evaporated and the residue was chromatographed on silica to give 1-(1-hydroxy-1-methoxycarbonylmethyl)-3-(triphenyl methylamino)-4-(3-phenylprop-2-ynylthio)azetidin-2-one as an amorphous solid (399 mg).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[Br:21][C:22]1[CH:27]=[C:26]([Br:28])[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:23]=1[CH2:36]Br>C1COCC1.C(O)(=O)C>[Br:21][C:22]1[CH:27]=[C:26]([Br:28])[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:23]=1[CH2:36][CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: Clc1ccccc1-c1nc(Br)cc(Br)c1CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CCc1c(Br)cc(Br)nc1-c1ccccc1Cl
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 48 %

Procedure:
n-Butyllithium in hexanes (1.6 Molar (hereinafter “M”), 3.75 millilitre (hereinafter “ml”), 6.0 millimole (hereinafter “mmol”)) was added to di-isopropylamine (0.84 ml, 6.0 mmol) in dry THF (15 ml) at −10° under nitrogen. After 5 minutes (hereinafter “min”). the solution was cooled to −70° and tert-butyl acetate (0.5 ml, 3.71 mmol) added dropwise. After stirring at −70° C. for 10 min. under nitrogen, 4,6-Dibromo-3-(bromomethyl)-2-(2-chlorophenyl)pyridine (0.405 grams (hereinafter “g”), 0.92 mmol) in dry THF (15 ml) was added, and the mixture stirred at −70° for 2 h. Glacial acetic acid (2 ml) was added, the temperature allowed to rise to 22° and the solution evaporated in vacuo. The residue was purified by column chromatography over silica (50 g) eluting with cyclohexane-ethyl acetate (9:1)-(5:1) to give the product as an oil (0.21 g).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#N)[CH:14]=1.Cl.CC[O:24]CC>ClC1C=CC=CC=1>[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[O:24])[CH:14]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Clc1ccccc1
Product: O=Cc1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of diisobutylaluminum hydride (92 ml, 1M in hexanes, 92 mmol) was added dropwise via syringe pump injector over a period of 45 min to a solution of α-bromo-m-tolunitrile (15.000 g, 76.5 mmol) in 155 ml of chlorobenzene at 0° C. The resulting mixture was stirred at 0° C. for 1 h, then 100 ml of 10% aqueous HCl was added and stirring continued at 0° C. for 10 min. The layers were separated and the aqueous layer extracted with ether (2x). The organic solutions were combined and washed vigorously with 10% HCl for 10 min, then water (2x) and brine, dried over MgSO4 and evaporated to give a crystalline solid which was then dissolved in a minimal amount of ether (10-15 ml) and layered with petroleum ether (30-40 ml). The resulting spiny white crystals were collected and washed with ice-cold petroleum ether to yield 10.791 g (71%) of aldehyde 1: m.p. 46°-49° C.; 1H NMR δ 4.54 (s, 1, CH2Br), 7.52 (t, 1, J=8 Hz, H-5), 7.67 (br d, 1, J=8 Hz, H-4), 7.82 (dt, 1, J=8, 1 Hz, H-6), 7.90 (br s, 1, H-2), 10.02 (s, 1, CHO); 13C NMR δ 32.0 (CH2Br), 129.6, 129.7 and 129.8 (C-2, C-5 and C-6), 134.8 (C-4), 136.8 (C-1), 138.9 (C-3), 191.6 (CHO); IR ν 1595 and 1610 (m, C=C), 1710 (s, C=O), 2740 and 2820 (m, CHO) cm-1.
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:31]([O:33]CC1C=CC=CC=1)=[O:32])[CH2:13][CH2:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@H:18]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:16])=O)C1C=CC=CC=1.C(O)(=O)C.C([O-])=O.[NH4+]>CO.O.[C].[Pd]>[NH2:11][C@@H:12]([C:31]([OH:33])=[O:32])[CH2:13][CH2:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@H:18]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:16]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)CC[C@@H](N)C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
An aliquot (5.0 g) of this ester was suspended in a mixture of 100 ml of methanol and 30 ml of water, and 5 ml of acetic acid, 4.6 g of ammonium formate and 0.5 g of 10% palladium-carbon were added to the suspension. The mixture was stirred at 50° C. for 1 hour. The catalyst was removed by filtration. The mother liquor was adjusted to pH 7 and concentrated. The residual solution was cooled. The precipitated crystals were collected by filtration and recrystallized from ethanol/water (1/1) to give 2.2 g of ethyl 1-(gamma-D-glutamyl)indoline-2(S)-carboxylate (mp. 197°-200° C., decomp.). An aliquot (2.0 g) of this ester and 0.66 g of sodium carbonate were dissolved in 25 ml of water, and a solution of 3.3 g of N2 -benzyloxycarbonyl-N6 -t-butoxycarbonyl-L-lysine N-hydroxysuccinimide ester in 25 ml of THF was added. The mixture was stirred overnight at room temperature. Tetrahydrofuran was evaporated, and 5% aqueous potassium hydrogensulfate solution was added. The precipitated crystals were collected by filtration and recrystallized from ethanol/ether to give 3.3 g of ethyl 1-(N2 -benzyloxycarbonyl-N6 -t-butoxycarbonyl-L-lysyl-gamma-D-glutamyl)indoline-2(S)-carboxylate. An aliquot (0.7 g) of this ester was stirred with 10 ml of trifluoroacetic acid under ice cooling for 20 minutes. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was subjected to CHP20P column chromatography (0%→50% acetonitrile/water gradient). Fractions containing the desired product were concentrated, and the precipitated crystals were collected by filtration to give 0.34 g of the captioned compound.
Reaction SMILES: [C:1]([CH:5]1[C@@:9]([CH2:13][CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)([C:10]([OH:12])=[O:11])[CH2:8][C:7](=[O:24])[N:6]1[C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:43]N1C(=O)CCC1=O.[Cl-].[NH4+].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C>[C:1]([CH:5]1[C@@:9]([CH2:13][CH2:14][CH2:15][OH:16])([C:10]([OH:12])=[O:11])[CH:8]([Cl:43])[C:7](=[O:24])[N:6]1[C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](c1ccccc1)N1C(=O)C[C@](CCCO[Si](C)(C)C(C)(C)C)(C(=O)O)C1C(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C(=O)C(Cl)[C@](CCCO)(C(=O)O)C1C(C)(C)C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
Under nitrogen atmosphere, to a solution of tert-butyl (3S)-3-[3-(tert-butyldimethylsilyloxy)propan-1-yl]-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid (960 mg, 2.08 mmol) in THF (15 mL) was added 1.0M lithium bis(trimethylsilyl)amide in THF solution (2.29 mL, 2.29 mmol) at −78° C., and the mixture was stirred for 30 minutes. Then, N-chlorosuccinimide (333 mg, 2.50 mmol) added and the mixture was stirred for 1 hour at −60° C., and further stirred for 10 minutes at 0° C. To the mixture were added saturated aqueous solution of ammonium chloride and ethyl acetate. The separated organic layer was washed with water and brine. The solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. At 0° C., to a solution of this residue in THF (20 mL) were added acetic acid (0.24 mL, 4.16 mmol) and 1.0M tetrabutylammonium fluoride in THF solution (4.16 mL, 4.16 mmol), the mixture was stirred for 16 hours at room temperature. To the mixture were added 10% aqueous solution of citric acid and ethyl acetate. The separated organic layer was washed with water and brine. The solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flush column chromatography (ethyl acetate/hexane=1:1→1:2) to afford 506 mg of the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[N:3]=1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C(OCC)C>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:17]([CH2:18][CH3:19])[CH2:15][CH3:16])[N:3]=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[N:5]=1
Reactant: CCNCC
Reactant: CC(C)Nc1nc(Cl)c(C#N)c(Cl)n1
Solvent: CCOCC
Product: CCN(CC)c1nc(NC(C)C)nc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
To a stirred solution of 4.3 grams of 4,6-dichloro-2-isopropylamino-5-pyrimidinecarbonitrile in 125 ml of diethyl ether was added dropwise 2.6 grams of diethylamine. Upon complete addition, the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed with water. The diethyl ether layer was separated and dried over magnesium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure to a residue. The residue was recrystallized from methylcyclohexane to give 2.5 grams of 4-chloro-6-diethylamino-2-isopropylamino-5-pyrimidinecarbonitrile; mp, 74°-76°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[CH2:24]([O:26][C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:28])[C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:20]([F:23])([F:22])[F:21])[C:9]=3[CH:17]=2)[CH:34]=1)[CH3:25]
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Product: CCOC(=O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (7.5 g) was reacted with 3-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A. The title compound was obtained as a white solid (72% yield). m.p.=174° C., LCMS: m/z=475.95 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.40 (t, 3H), 3.48 (m, 2H), 3.69 (m, 2H), 4.32 (q, 2H), 4.63 (s, 2H), 5.51 (bs, 1H), 6.52 (s, 1H), 7.35 (m, 1H), 7.42 (m, 1H), 7.48 (s, 1H), 7.54 (m, 1H), 7.65 (d, 1H), 7.70 (s, 1H), 7.90 (d, 1H), 8.03 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][C@@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CCl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 19.8 %

Procedure:
To a solution of the crude (S)-tert-butyl 4-chloro-1-cyclohexyl-3-oxobutan-2-ylcarbamate (5.8 g, 0.019 mol) in 9:1 THF/H2O (100 mL) at 0° C. was added NaBH4 (1.8 g, 0.047 mmol). After stirring for 45 min at rt, the solvent was removed in vacuo. The residue was diluted with water (50 mL) and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product which was purified by flash chromatography to give a mixture of isomeric alcohols, which was recrystallized from n-hexane three times to give pure tert-butyl (2S,3S)-4-chloro-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (1.15 g, 40%). 1H NMR: 0.82 (m, 1H), 0.96 (m, 1H), 1.08-1.40 (m, 5H), 1.43 (s, 9H), 1.65 (m, 4H), 1.82 (m, 1H), 3.08 (m, 1H), 3.52 (m, 1H), 3.58 (r, 1H), 3.79 (m, 2H), 4.51 (m, 1H). MS (E/Z): 306 (M+H+). The mother liquor was concentrated and recrystallized from n-hexane three times to give pure tert-butyl (2S,3R)-4-chloro-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (0.3 g, 10.3%).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].C[O-].[Na+].C(O[C:12](=[O:27])[CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[C:14]([O:16]CC)=O)C.O>CN(C)C=O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][CH:13]1[C:12](=[O:27])[N:2]([CH3:1])[C:3](=[O:4])[NH:5][C:14]1=[O:16]
Reactant: CNC(N)=O
Reactant: CCOC(=O)C(Cc1cccc(Cl)c1)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)NC(=O)C(Cc2cccc(Cl)c2)C1=O
Temperature: 130 °C

Procedure:
Methylurea (1.18 g, 16.0 mmol) and freshly prepared sodium methoxide (1.04 g, 19.2 mmol) were combined in dimethylformamide (15 mL) and a solution of 2-(3-chlorobenzyl)malonic acid diethyl ester (2.85 g, 10.0 mmol) in dimethylformamide (5 mL) was added. The reaction temperature was raised to 130° C. for 2 hours and then cooled to ambient temperature before water was added and the solution acidified with 2N HClaq. The resulting solid was filtered then washed with water and the dried to afford the product as a white solid, 840 mg. LC-MS: RT=2.87 mins, 267 (M+H)+265 (M−H)−.
Reaction SMILES: [CH:1]1[C:6](Cl)=[CH:5][CH:4]=[C:3](Cl)[CH:2]=1.[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][Mg]Br)[CH3:10]>O>[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:12][CH:11]([CH2:9][CH3:10])[CH2:15][CH2:16][CH2:17][CH3:18])[CH3:10]
Reactant: CCCCC(CC)C[Mg]Br
Reactant: Clc1ccc(Cl)cc1
Solvent: O
Product: CCCCC(CC)Cc1ccccc1CC(CC)CCCC
Temperature: 0 °C
Yield: 20.9 %

Procedure:
A dry 1 L three-neck round bottom flask, equipped with a condenser and an addition funnel, was charged with Ni(dppp)2Cl2 (0.99 g, 1.83 mmol) and dichlorobenzene (26.7 g, 182 mmol). The reaction solution was cooled down to 0° C. and then (2-ethylhexyl)magnesium bromide solution (400 mmol) was added dropwise via the addition funnel under nitrogen. After addition was complete, the reaction was heated to reflux for 12 hours and then cooled down to room temperature. The reaction solution was poured into 100 mL of DI water. The mixture was extracted with MTBE (3×100 mL). The organic phase was combined, dried over anhydrous MgSO4, filtered and the solvent was removed by rotary evaporation. The mixture was purified by distillation under a reduced pressure to give the product (11.5 g, 21%) as colorless oil.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[C:13]2[C:16]([OH:31])=[C:17]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[C:18]([OH:25])=[C:19]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[C:12]=2[O:11][C:10]=1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=1)C1C=CC=CC=1>CO.[Pd]>[F:39][C:34]1[CH:33]=[C:32]([C:10]2[O:11][C:12]3[C:19]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[C:18]([OH:25])[C:17]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=[C:16]([OH:31])[C:13]=3[C:14](=[O:15])[C:9]=2[OH:8])[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: CC(C)=CCc1c(O)c(CC=C(C)C)c2oc(-c3ccc(F)c(F)c3)c(OCc3ccccc3)c(=O)c2c1O
Agent: [Pd]
Solvent: CO
Product: CC(C)=CCc1c(O)c(CC=C(C)C)c2oc(-c3ccc(F)c(F)c3)c(O)c(=O)c2c1O
Reaction time: 5 h
Yield: 24.1 %

Procedure:
3-benyloxy-2-(3,4-difluorophenyl)-5,7-dihydroxy-6,8-di(3-methyl-2-buten-1-yl)-4H-benzopyran-4-one (30 mg) was dissolved in 10 mL methanol, and 5% Pd/C (10 mg) was added. The reaction mixture was hydrogenated at 0° C. under atmospheric pressure for 5 hr. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent:methol/dichloromethane, 1:50) to give the desired compound (6 mg, yield 24%). 1H NMR (400 MHz, CDCl3): δ=11.94 (s, 1H), 8.08-7.98 (m, 2H), 7.31 (dd, 1H, J1=18.4 Hz, J2=8.8 Hz), 6.76 (s, 1H), 6.45 (s, 1H), 5.28-5.22 (m, 2H), 3.56 (d, 2H, J=6.8 Hz), 3.47 (d, 2H, J=7.2 Hz), 1.86 (s, 3H), 1.85 (s, 3H), 1.77 (s, 3H), 1.76 (s, 3H); LC-MS (ESI) m/z 442.9 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:16][C:17]#[N:18]>>[CH2:8]([N:9]1[CH2:10][CH2:11][N:12]([CH2:16][C:17]#[N:18])[CH2:13][CH2:14]1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCN2CCNCC2)cc1
Reactant: N#CCBr
Product: N#CCN1CCN(CCc2ccccc2)CC1

Procedure:
The title compound is synthesized by coupling of 4-Phenylethyl-piperazine (commercially available from ABCR GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=230.2: CtRet=4.20.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10].C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]#[C:9][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: Brc1ccc(I)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(Br)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
2-Bromo-5-iodopyridine (2.5 g, 8.8 mmol) was dissolved under nitrogen in 50 ml THF. Bis-(triphenylphosphine)-palladium(II)dichloride (618 mg, 880 μmol, 0.1 equiv.), ethynyltrimethylsilane (950 mg, 1.34 ml, 9.6 mmol, 1.1 equiv.), triethylamine (1.78 g, 2.44 ml, 17.6 mmol, 3 equiv.) and copper(I) iodide (84 mg, 440 μmol, 0.05 equiv.) were added and the mixture was stirred for 3 hours at 50° C. The reaction mixture was cooled and evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting with an ethyl acetate:heptane gradient 0:100 to 15:85. The desired 2-bromo-5-trimethylsilanylethynyl-pyridine (1.95 g, 7.7 mmol, 87% yield) was obtained as a white solid, MS: m/e=254.1/256.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:11]([F:14])([F:13])[F:12])[C:6]([N+:21]([O-])=O)=[CH:5][CH:4]=1.C(OCC)(=O)C>C(O)(=O)C.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:11]([F:12])([F:13])[F:14])[C:6]([NH2:21])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(OC(c2cccnc2)C(F)(F)F)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(OC(c2cccnc2)C(F)(F)F)n1
Reaction time: 1.7 h
Yield: 41 %

Procedure:
6-Methoxy-3-nitro-2-[2,2,2-trifluoro-1-(pyridin-3-yl)-ethoxy]pyridine (243 mg, 0.738 mmol) was dissolved in acetic acid (3.6 mL) and water (3.6 mL). To this, reduced iron (124 mg, 2.21 mmol) was added under a nitrogen atmosphere at room temperature and the mixture was stirred for 1.7 hours. After water and brine were added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with saturated sodium bicarbonate and brine, and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=30/1) to give Compound HA (89.6 mg, yield: 41%).