Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][C:5](=[O:7])[N:4]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C@H:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br[C:22]1[CH:23]=[C:24]2[N:30]([C:31]3[N:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[CH:29]=[CH:28][C:25]2=[N:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.CC(C)([O-])C.[Na+]>COC1C=CC=C(OC)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1.C1C=[C-]C=C(CCN)C=1.[Cl-].[Pd+2].ClCCl>[CH3:1][C:2]1([CH3:20])[O:6][C:5](=[O:7])[N:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:22]3[CH:23]=[C:24]4[N:30]([C:31]5[N:36]=[CH:35][CH:34]=[CH:33][N:32]=5)[CH:29]=[CH:28][C:25]4=[N:26][CH:27]=3)[CH2:12][CH2:13]2)[C@H:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C)OC(=O)N(C2CCNCC2)[C@H]1c1ccccc1
Reactant: Brc1cnc2ccn(-c3ncccn3)c2c1
Agent: [Pd+2]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CC1(C)OC(=O)N(C2CCN(c3cnc4ccn(-c5ncccn5)c4c3)CC2)[C@H]1c1ccccc1
Temperature: 100 °C

Procedure:
A glass microwave reaction vessel was charged with (S)-5,5-dimethyl-4-phenyl-3-(piperidin-4-yl)oxazolidin-2-one (50 mg, 0.182 mmol), 6-bromo-1-(pyrimidin-2-yl)-1H-pyrrolo[3,2-b]pyridine (50.1 mg, 0.182 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (8.50 mg, 0.018 mmol, Sigma-Aldrich), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II)-dichloromethane (13.81 mg, 0.018 mmol, Sigma-Aldrich) and sodium tert-butoxide (26.3 mg, 0.273 mmol). The vessel was capped and evacuated and refilled with argon three times. Dioxane (364 μl) was then added to the reaction mixture. The mixture was stirred and heated at 100° C. overnight. After cooling to room temperature, the material was purified by Waters Auto purification HPLC (Column: Xbridge 19×100 mm; Flow rate: 40 mL/min; Mobile phase: 0.1% NH4OH in ACN and water; Gradient: 20-75% B in 8 min with total run time of 10 min) to provide (S)-5,5-dimethyl-4-phenyl-3-(1-(1-(pyrimidin-2-yl)-1H-pyrrolo[3,2-b]pyridin-6-yl)piperidin-4-yl)oxazolidin-2-one as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.73 (d, J=5.56 Hz, 2H), 8.52-8.60 (m, 1H), 8.32 (d, J=4.49 Hz, 1H), 8.07-8.20 (m, 1H), 7.26-7.42 (m, 3H), 7.15-7.25 (m, 4H), 6.63 (d, J=3.53 Hz, 1H), 4.59 (s, 1H), 3.70 (d, J=11.22 Hz, 1H), 3.51-3.64 (m, 2H), 2.76 (qt, J=2.89, 12.50 Hz, 1H), 2.04-2.18 (m, 1H), 1.83-1.94 (m, 1H), 1.59-1.70 (m, 1H), 1.48-1.58 (m, 1H), 1.46 (s, 3H), 0.80 (s, 3H). m/z (ESI) 469.2 (M+H)+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.C(O[C:14](=[O:16])[CH3:15])(=O)C.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([NH:36][C:37]4[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][N:38]=4)[N:30]=3)=[CH:25][CH:24]=2)[CH2:19]1>C1COCC1>[CH3:35][C:33]1[CH:32]=[C:31]([NH:36][C:37]2[CH:42]=[C:41]([C:43]([F:44])([F:46])[F:45])[CH:40]=[CH:39][N:38]=2)[N:30]=[C:29]([C:26]2[CH:27]=[N:28][C:23]([N:20]3[CH2:21][CH2:22][C@H:18]([NH:17][C:14](=[O:16])[CH3:15])[CH2:19]3)=[CH:24][CH:25]=2)[CH:34]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(N3CC[C@H](N)C3)nc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1CCN(c2ccc(-c3cc(C)cc(Nc4cc(C(F)(F)F)ccn4)n3)cn2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N,N-Diisopropylethylamine (0.032 mL, 0.181 mmol), acetic anhydride (6.26 μL, 0.066 mmol), 6′-[(3S)-3-aminopyrrolidin-1-yl]-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]-2,3′-bipyridin-6-amine (Example 5, 25 mg, 0.060 mmol), and THF (1 mL) were added to a flask and stirred at room temperature for 16 hours. The crude solution was purified via reverse phase high pressure liquid chromatography to afford N-[(3S)-1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)pyrrolidin-3-yl]acetamide. MS ESI calcd. for C23H24F3N6O [M+H]+ 457. found 457. 1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.76 (s, 1H), 8.60 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.11 (m, 1H), 7.24 (s, 1H), 7.17 (d, J=5.0 Hz, 1H) 7.12 (s, 1H), 6.46 (d, J=8.8 Hz, 1H), 3.52-3.60 (m, 3H), 3.43 (m, 1H), 3.12 (m, 1H), 2.30 (s, 3H), 2.05 (s, 1H), 1.87-1.80 (m, 2H), 1.72 (s, 1H). rhSyk IC50=17 nM.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([NH2:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(F)c(N)cc1C(=O)O
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of 2-methyl-5-nitro-4-fluorobenzoic acid (1.77 g, 8.9 mmol, for preparation see Coll. Czech. Chem. Commun. 1977, 42, 2001) in ethanol (15 mL) was added 10% Pd/C (50 mg) and the mixture was subjected to hydrogenation under 30 psi of pressure. After 3 h, hydrogen was removed and the mixture was filtered and the filtrate was concentrated in vacuo to afford 2-methyl-5-amino-4-fluorobenzoic acid (1.45 g, 97%). LC/MS; (M+H)+=170.
Reaction SMILES: C([Li])CCC.C1(C)C=CC(S([CH:15]([N+:23]#[C-:24])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)(=O)=O)=CC=1.[Br-].[Li+].[N:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:30][CH:29]=1>CCCCCC.O1CCCC1>[CH2:39]([O:38][C:36]([C:35]1[C:34]([C:31]2[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=2)=[C:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[NH:23][CH:24]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)C=Cc1ccncc1
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
36 ml (54.7 mmol) of a 1.53 N solution of butyllithium in hexane were added to 240 ml of tetrahydrofuran. A solution of 15.90 g (54.7 mmol) of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile in 120 ml of tetrahydrofuran was then added to the resulting solution at −45° C., followed by stirring of the resulting mixture for 10 minutes at the same temperature. At the end of this time, 25.00 g (273 mmol) of 95% lithium bromide were added, the resulting mixture was stirred for 30 minutes and then a solution of 8.73 g (49.2 mmol) of ethyl 3-(4-pyridyl)acrylate in 120 ml of tetrahydrofuran was added. The resulting mixture was stirred at the same temperature for 1 hour and then the cooling bath was removed and the mixture was stirred at room temperature for a further 1 hour. At the end of this time, 500 ml of water were added and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with water and then dried over anhydrous sodium sulfate, after which it was concentrated by evaporation under reduced pressure to afford a solid. The solid was washed with diethyl ether to give 13.61 g (yield 89%) of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][CH:7]=[C:6]([O:12]C)[CH:5]=2.Cl.N1C=CC=CC=1>O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][CH:7]=[C:6]([OH:12])[CH:5]=2
Reactant: COc1ccc2c(C)c(C)[nH]c2c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1[nH]c2cc(O)ccc2c1C
Temperature: 200 °C
Reaction time: 0.25 h

Procedure:
2,3-Dimethyl-6-methoxy-1H-indole (2.0 g; synthesized by the process reported by Ockenden et al., J. Chem. Soc., pp. 3175-3180 (1957)) was mixed with pyridine hydrochloride (7.91 g; mfd. by KANTO KAGAKU). The resulting mixture was stirred at 200° C. for 15 minutes and then cooled. After adding water (100 mL), the mixture was then extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate (10 g). The solvent was distilled off under reduced pressure to yield crude 2,3-dimethyl-6-hydroxy-1H-indole (1.86 g) as a gray crystal.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[C:25](=O)[CH3:26])=[O:15])=[O:6])#[N:2].C([O-])(=O)C.[K+].Cl.[NH2:34][NH:35][C:36]([NH2:38])=[O:37]>CO>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[C:25](=[N:34][NH:35][C:36](=[O:37])[NH2:38])[CH3:26])=[O:15])=[O:6])#[N:2]
Reactant: CC(=O)c1cccc2cc(C(=O)N[C@H]3CCCC[C@H]3C(=O)NCC#N)[nH]c12
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CC(=NNC(N)=O)c1cccc2cc(C(=O)N[C@H]3CCCC[C@H]3C(=O)NCC#N)[nH]c12

Procedure:
7-Acetyl-1H-indole-2-carboxylic acid [(1S,2R)-2-(cyanomethylcarbamoyl)-cyclohexyl]-amide was reacted with potassium acetate and semicarbazide hydrochloride in methanol and purified by preparative TLC plate to yield 7-[1-(carbamoyl-hydrazono)-ethyl]-1H-indole-2-carboxylic acid [(1S,2R)-2-(cyanomethylcarbamoyl)cyclohexyl]-amide MS: 367 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[CH2:5][CH2:6]Br.CC(C)([O-])C.[K+]>C1COCC1>[CH3:1][O:2][C:3]([C:4]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH2:6][CH2:5]1)=[O:17]
Reactant: COC(=O)C(CCBr)Oc1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1(Oc2ccc(F)cc2F)CC1
Temperature: 60 °C
Yield: 80.9 %

Procedure:
A solution of 4-Bromo-2-(2,4-difluoro-phenoxy)-butyric acid methyl ester (3.167 g, 10.29 mmol) in THF (40 ml) was added to a suspension of potassium tert butoxide (1.148 g, 10.26 mmol) in THF (20 ml) and the reaction mixture was heated at 60° C. for 4 hr. Reaction mixture was cooled to room temp, quenched with brine (5 ml) extracted in ether (50 ml) and washed with brine (2×5 ml), dried over Na2SO4 and concentrated under reduced pressure to obtain crude product, 1-(2,4-Difluoro-phenoxy)-cyclopropanecarboxylic acid methyl ester (1.9 g, 81%) which was used as such in the next step.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:12]1[CH2:15][NH:14][CH2:13]1.Cl.[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[CH:24][C:23](/[CH:28]=[CH:29]/[C:30](O)=[O:31])=[CH:22][C:21]=2[CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:12]1[CH2:13][N:14]([C:30](=[O:31])/[CH:29]=[CH:28]/[C:23]2[CH:22]=[C:21]3[C:26](=[N:25][CH:24]=2)[NH:27][C:18](=[O:17])[CH2:19][CH2:20]3)[CH2:15]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: Cc1c(C2CNC2)oc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C2CN(C(=O)/C=C/c3cnc4c(c3)CCC(=O)N4)C2)oc2ccccc12
Temperature: 25 °C
Reaction time: 21 h
Yield: 58.3 %

Procedure:
To a solution of 3-(3-methylbenzofuran-2-yl)azetidine hydrochloride (19.9 mg, 0.089 mmol) in DMF (2 mL) were added (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (15.8 mg, 0.062 mmol), EDCI.HCl (19.9 mg, 0.104 mmol), HOAt (14.0 mg, 0.103 mmol) and N,N-diisopropylethylamine (58 μL, 0.339 mmol). The reaction was stirred at rt for 21 h, after which the mixture was partitioned between EtOAc and H2O. The layers were separated and the aqueous layer extracted with EtOAc. The combined organic layers were washed with brine (3×), dried with Na2SO4 and concentrated. The residue was triturated twice with Et2O and the dried to yield (the title compound (14.0 mg, 58%) as a pale orange solid.
Reaction SMILES: [ClH:1].CCOC(C)=O.C(OC([N:15]1[CH2:18][CH:17]([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26]4[N:27]3[CH:30]([CH3:35])[C:31](=[O:34])[NH:32][N:33]=4)=[CH:22][CH:21]=2)[CH2:16]1)=O)(C)(C)C>>[ClH:1].[NH:15]1[CH2:16][CH:17]([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26]4[N:27]3[CH:30]([CH3:35])[C:31](=[O:34])[NH:32][N:33]=4)=[CH:22][CH:21]=2)[CH2:18]1
Reactant: CC1C(=O)NN=C2CCc3ccc(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1C(=O)NN=C2CCc3ccc(NC4CNC4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of HCl in EtOAc (4M, 5 mL, 20 mmol) was added slowly tert-butyl-3-(1-methyl-2-oxo-2,3,5,6-tetrahydro-1H-[1,2,4]triazino[4,3-a]quinolin-9-ylamino)azetidine-1-carboxylate (0.022 g, 0.057 mmol) and the reaction mixture was stirred at ambient temperature for 2 h. The solution was concentrated in vacuo to give 9-(azetidin-3-ylamino)-1-methyl-5,6-dihydro-1H-[1,2,4]triazino[4,3-a]quinolin-2(3H)-one hydrochloric acid (0.015 g, 95%). LC/MS (Table 1, Method 5) Rt=2.252 min; MS m/z: 286 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH2:28]([Mg]Cl)[C:29]([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)([OH:20])[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CC(C)(C)C[Mg]Cl
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Solvent: C1CCOC1
Product: CCOc1nc2c(C(O)(CC(C)(C)C)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0° C. Neopentylmagnesium chloride (1.0 M, 0.55 mL, 0.55 mmol) was added dropwise and the reaction was allowed to stir for 10 mins and then quenched with water. Reaction was extracted three times with EtOAc and combined organic layers were washed once with water, concentrated, and purified by reverse-phase HPLC to give 1-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-3,3-dimethyl-1-(pyridin-2-yl)butan-1-ol intermediate. The intermediate was taken up in EtOH (1.5 mL) and 4.0 M HCl/dioxane and heated to 65° C. for 2 hours, concentrated and purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[O:16][CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]3)=[C:5]([N+:26]([O-])=O)[CH:4]=1)#[N:2].NC1C=CC=CC=1.C1(C2CCC3C(=CC=C(OC4C=CC=CC=4N)C=3)O2)C=CC=CC=1>[Zn].C(O)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[O:16][CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]3)=[C:5]([CH:4]=1)[NH2:26])#[N:2]
Reactant: N#Cc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)c([N+](=O)[O-])c1
Agent: Nc1ccccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: Nc1ccccc1
Product: N#Cc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)c(N)c1

Procedure:
4-Cyano-2-nitro-1-(2-phenylchroman-6-yloxy)-benzene (0.155 g; 0.4 mmol) was reduced to the corresponding aniline as described for 2-(2-phenylchroman-6-yloxy)-aniline in Example 29 except that 40 ml of glacial acetic acid and 0.93 g of zinc powder were used. Product was purified by column chromatography (100% CH2Cl2 as the eluant). 1H-NMR (300 MHz; d6-DMSO): δ 7.57-7.28 (m, 5H), 7.06 (d, 1H, J=2.0 Hz), 6.95-6.78 (m, 4H), 6.65 (d, 1H, J=8.3 Hz), 5.46 (s, 2H), 5.11 (dd, 1H, J=10.0 Hz, J=2.1 Hz), 3.03-2.88 (m, 1H), 2.78-2.66 (m, 1H), 2.23-2.10 (m, 1H), 2.08-1.89 (m, 1H).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([F:15])[CH:7]=1>C(O)C.[Cl-].[Na+].O>[F:15][C:8]1[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:6]([CH2:5][S:2][CH3:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)cc(CCl)c1
Reactant: C[S-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSCc1cc(F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.9 %

Procedure:
Sodium methanethiolate (1.22 g; 17.4 mmol) was added in three portions to a stirred solution of 1-(chloromethyl)-3-fluoro-5-nitrobenzene (3.00 g; 15.8 mmol, HE Chemical) in ethanol (33 ml) at 0° C. The ice bath was removed and the batch was stirred at room temperature for 18 hours. Further sodium methanethiolate (0.33 g; 4.7 mmol) was added and the batch was stirred for 5 additional hours at room temperature. The batch was diluted with brine and extracted with ethyl acetate (2×). The combined organic phases were washed with water, dried (sodium sulfate), filtered and concentrated to give the desired product (3.4 g) that was used without further purification. 1H NMR (400 MHz, CDCl3, 300K) δ=8.00 (m, 1H), 7.81 (m, 1H), 7.42 (m, 1H), 3.74 (s, 2H), 2.02 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1)(=O)C.CO>O>[CH3:17][C:14]1([CH3:18])[O:13][C@@H:12]([CH2:11][OH:10])[CH2:16][O:15]1
Reactant: CC(=O)OC[C@H]1COC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(C)OC[C@H](CO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Then potassium carbonate (66.96 g, 0.485 mol) was added to a mixture of (R)-4-acetoxymethyl-2,2-dimethyl-1,3-dioxolane (56.32 g, 0.323 mol) and methanol (400 ml) and resulting mixture was stirred for 8 hours at 25° C. After completion of the reaction the salt was filtered off and the filtrate was condensed in vacuo. Water was added to the residue and the mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo. The crude product was distilled to give 38.27 g of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol (yield 87%, b.p. 65° C. at 3 mmHg, optical purity 97.5% e.e., specific rotation [α]D20+ 10.87°(c=1,MeOH)).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[CH:19][CH:18]=1
Reactant: Oc1ccc(-c2cccc(F)c2F)cc1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Yield: 63.8 %

Procedure:
First, 5 g of 6-bromo-1-hexanol, 5.7 g of 2,3difluoro-4'-hydroxybiphenyl, 7.6 g of potassium carbonate, and 70 ml of methyl ethyl ketone were placed in a 100 ml flask. Then, the mixture was stirred under reflux for 20 hours. The reaction mixture was poured into water, and an organic layer was extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was recrystallized from acetone to obtain 5.4 g of 2,3-difluoro-4'-(6-hydroxyhexyl)oxybiphenyl (Y: 63.5%). The compound thus obtained had a purity of 99.9% by GC.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:11](Br)[C:12]#[CH:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:13]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])[C:12]#[CH:11]
Reactant: C#CCBr
Reactant: O=C1NCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C#CCN1Cc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To 2,3-dihydro-isoindol-1-one (250.0 mg, 1.85 mmol) in acetonitrile (9 mL) was added propargyl bromide (308.6 uL, 2.77 mmol) and cesium carbonate (2.4 g, 7.39 mmol) and the mixture was allowed to stir at 80° C. for two hours. An aqueous workup was done to provide the title compound (303.3 mg, 96%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][C@@H:17]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:21]4=[CH:20][CH:19]=[C:18]3[C@@H:13]2[CH2:12][CH2:11]1)/[CH:3]=[CH:4]/[C@@H:5]([CH:7]([CH3:9])[CH3:8])[CH3:6].N1C=CC=CC=1.[C:36](Cl)(=[O:38])[CH3:37].CO>ClCCl>[C:36]([O:27][CH:25]1[CH2:24][CH2:23][C@@:22]2([CH3:28])[C:21](=[CH:20][CH:19]=[C:18]3[C@@H:17]2[CH2:16][CH2:15][C@@:14]2([CH3:29])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[C@H:2]([CH3:1])[CH:3]=[CH:4][C@H:5]([CH3:6])[CH:7]([CH3:8])[CH3:9])[CH2:26]1)(=[O:38])[CH3:37]
Reactant: CC(C)[C@@H](C)/C=C/[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@H](C)C=C[C@H](C)C(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
Ergosterol (5.00 g, 12.6 mmol) was dissolved in dichloromethane (100 mL), and pyridine (4 mL) and acetyl chloride (2 mL) were sequentially added at 0° C. thereto, followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated to yield a residue and then methanol was added to the obtained residue for trituration to obtain the title compound (5.21 g, 94%).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[OH-].[Na+].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].S(=O)(=O)(O)O>O.CC(C)=O>[C:13]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
108 g of L-glutamine was dissolved in 343 g of water and 102 g of aqueous 27% sodium hydroxide solution, and cooled to 10° C. 138 g of acetone was added, and 152 g of lauroyl chloride and 108 g of aqueous 27% sodium hydroxide solution were dropwise added. 300 g of the acylation liquid was diluted with water, neutralized with 35 g of 75% sulfuric acid, and filtered to obtain a white powder substance, N-lauroyl-L-glutamine. 367 g of isopropyl alcohol and 30 g of 95% sulfuric acid were added to 101.7 g of the product, and refluxed for 3.5 hours. After solvent removal, 350 g of isopropyl alcohol was added to it, and refluxed for 3 hours. After further solvent removal, 350 g of isopropyl alcohol was added and refluxed for 4 hours. The reaction liquid was left cooled to 35° C., and a white solid was collected by filtration, and dried in vacuum at 50° C. to obtain 73.14 g of a crude crystal of N-lauroyl-L-glutamine isopropyl ester (N-lauroyl-L-glutamine isopropyl ester/2-(lauroylamino)glutarimide/isopropyl N-lauroyl-2-pyrrolidone-5-carboxylate/diisopropyl N-lauryl-L-glutamate (ratio by weight)=100/16/9/16). Further, this was recrystallized from acetone to obtain 30.00 g of a pure crystal of N-lauroyl-L-glutamine isopropyl ester.