Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[N:20]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:25][C:21]1[N:20]=[N:19][CH:24]=[CH:23][CH:22]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: Nc1cccnn1
Solvent: C1CCOC1
Product: O=C(Nc1cccnn1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method C; 200 mg, 0.651 mmol) was added to a stirred suspension of CD (106 mg, 0.651 mmol) in THF (6 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min and pyridazin-3-amine (61.9 mg, 0.651 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography, eluting with hexane:ethyl acetate (4:1) to yield the title compound. 183 mg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCOc1ccc(N)cc1
Yield: 96 %

Procedure:
N-(tert-butoxycarbonyl)-2-(4-nitrophenoxy)ethylamine (5.91 g) was dissolved into methanol (200 ml) and subjected to hydrogeration reaction at ambient pressure by adding 10% palladium carbon catalyst (0.5 g). After completion of hydrogeration reaction, excess catalyst was removed by filtration. Filtrate was concentrated under vacuum to obtain N-(tert-butoxycarbonyl)-2-(4-aminophenoxy)ethylamine (5.07 g) as color-less oily substance. (1-3) N-(tert-butoxycarbonyl)-2-(4-aminophenoxy)ethylamine (1.00 g) was dissolved into pyridine (5 ml) and 2,6-dimethoxybenzoic acid chloride (0.87 g) was added into the solution. After being stirred for one hour, the reaction mixture was concentrated under vacuum and residue was dissolved into chloroform (30 ml). The solution was washed with 1N sodium hydroxide aqueous solution (30 ml) followed by saturated sodium chloride (30 ml). Solvent was distilled out and residue was purified by silica-gel column chromatography (ethyl acetate:hexane=1:1) to obtain 4′-[2-(tert-butoxycarbonylamino)ethoxy]-2,6-dimethoxybenzanilide (1.17 g) as white powder.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[Br:15]Br>C(O)(=O)C>[Br:15][CH:10]([CH3:11])[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:13])([F:14])[F:1])=[CH:8][CH:7]=1)=[O:12]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
Add p-trifluoromethylpropiophenone (75 g, 360 mmol, 1.0 equiv) to acetic acid (375 mL). Add bromine (18.1 mL, 352 mmol, 0.98 equiv) in acetic acid (375 mL) in a drop-wise fashion over 45 minutes. After completion of the addition, warm the mixture to an internal temperature of 40° C., and stir for 90 minutes. Remove the volatile components under reduced pressure, and dissolve the residue in Et2O (300 mL). Treat with a saturated sodium bicarbonate aqueous solution (4×200 mL) being cautious of vigorous gas evolution. Separate the organic phase, and dry over MgSO4. Remove the solids by filtration; collect the filtrate; and concentrate the filtrate under reduced pressure to give the title compound as a colorless oil which solidifies on standing (93 g, 92.0% yield). 1H NMR (400 MHz, d6-DMSO) δ 8.13 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.3 Hz, 2H), 5.27 (q, J=6.5 Hz, 1H), 1.93 (d, J=6.5 Hz, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1.[Cl:11][C:12]1[CH:13]=[C:14](F)[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([O:10][CH:9]2[CH2:8][NH:7][CH2:6][C:5]3[S:1][CH:2]=[CH:3][C:4]2=3)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: OC1CNCc2sccc21
Product: Clc1ccc(OC2CNCc3sccc32)cc1Cl

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 5) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@@H:12]1[CH2:14][O:13]1.[C:15]([O:19][C:20](=[O:28])[NH:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1)([CH3:18])([CH3:17])[CH3:16]>C(O)C>[C:15]([O:19][C:20](=[O:28])[NH:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:14][C@H:12]([OH:13])[C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: CC(C)(C)OC(=O)NCC1CCCN1
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCCC2CNC(=O)OC(C)(C)C)ccc2c1COC2=O

Procedure:
Six vials containing a solution of 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (325 mg, 1.67 mmol) in 12 mL ethanol added to tert-butyl(pyrrolidin-2-ylmethyl)carbamate (333 mg, 1.67 mmol) were prepared. The reaction mixtures were microwaved at 140° C. for 55 minutes. The solutions were combined and the solvents were removed in vacuo. The resulting residue was purified by HPLC to afford two diastereomers of tert-butyl({1-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]pyrrolidin-2-yl}methyl)carbamate:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([F:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13]C)[CH:8]=2)[N:3]=1.[C:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([F:27])[CH:19]=1)([OH:17])=[O:16]>>[F:27][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[C:2]1[CH:11]=[C:10]([F:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[CH:8]=2)[N:3]=1)[C:15]([OH:17])=[O:16]
Reactant: COc1ccc2nc(Cl)cc(F)c2c1
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Product: O=C(O)c1ccc(-c2cc(F)c3cc(O)ccc3n2)c(F)c1

Procedure:
The compound was prepared following Scheme 2, B conditions starting from 2-chloro-4-fluoro-6-methoxyquinoline (Intermediate 7) and 4-carboxy-2-fluorophenylboronic acid. Note: In step 2, after purification by prep HPLC, the collected fractions were immediately neutralized with sat.NaHCO3 to pH 6, followed by extraction with EtOAc/MeOH (v/v=10/1, 50 mL×3). Combined organics were washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to give the desired product. 1H NMR (MeOD 400 MHz): δ 8.10-8.00 (m, 2H), 7.98 (dd, J=8.0, 1.2 Hz, 1H), 7.85 (dd, J=11.6, 1.2 Hz, 1H), 7.62 (dd, J=11.6, 2.0 Hz, 1H), 7.45 (dd, J=9.2, 2.8 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H). MS (ESI): m/z 301.8 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21](O)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26].[NH2:27][C@H:28]1[C@@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH2:31][N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:29]1>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21]([NH:27][C@H:28]3[C@@H:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:32][CH2:31][N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:29]3)=[O:22])[C:15]([C:17]([F:19])([F:18])[F:20])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@H](N)C1
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)O)cc21
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N[C@@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3c3ccccc3)cc21

Procedure:
Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl (3S,4R)-3-amino-4-phenylpiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 541.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.[CH3:27][CH2:28][CH:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br)[CH2:30][CH3:31].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[O:1]=[C:2]1[C@H:7]([CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([CH:29]([CH2:30][CH3:31])[CH2:28][CH3:27])[CH:33]=2)[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Reactant: CCC(CC)c1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)c1cccc(C[C@H]2C(=O)O[C@H](c3ccccc3)[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)c1
Yield: 47.6 %

Procedure:
According to example 142, 3.27 g of tert-butyl (2R, 3S)-(−)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate was alkylated with 2.23 g of 3-(3-pentyl)benzyl bromide in 70 mL of anhydrous TBF using 9.71 mL of 1 M sodium bis(trimethylsilyl)amide in THF. The crude product was subjected to flash chromatography on silica gel (9:1 hexane:EtOAc) and then recrystallization from EtOH-water to afford 2.26 g (48%) of tert-butyl (2R,3S,5S)-6-oxo-2,3-diphenyl-5-(3-(3-pentyl)benzyl)4-morpholinecarboxylate as a white crystalline solid, m.p. 143-144° C.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([S:16]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:9]=1)=O.C([O-])([O-])=O.[K+].[K+].[ClH:34]>CO.O>[ClH:34].[ClH:34].[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][NH2:5])=[CH:9][C:10]=1[S:16]([N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1)(=[O:17])=[O:18]
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1S(=O)(=O)N1CCN(C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(CCN)cc1S(=O)(=O)N1CCN(C)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(2-{4-methoxy-3-[(4-methylpiperazin-1-yl)sulfonyl]-phenyl}ethyl) acetamide (from Step 2), (1.25 g, 3.05 mmol) in MeOH (30 mL) and H2O (8 mL) was added K2CO3 (2.11 g, 15.3 mmol), and the solution was stirred at 60° C. for 2 h. After cooling to rt, the MeOH was evaporated under reduced pressure. The remaining aqueous mixture was extracted with CH2Cl2 (6×50 mL), and the combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then dissolved in MeOH, and 4 equivalents of 1 N HCl in MeOH were added causing the formation of a white precipitate. The solvent was removed under reduced pressure, and the resulting solid was recrystallized from MeOH/Et2O to give the title compound [assumed to be the bis-HCl salt] as a white solid (457 mg, 48%). 1H NMR (400 MHz, CD3OD) δ 2.29 (s, 3H), 2.48 (broad t, 4H), 2.78 (dd, 2H), 2.87-2.92 (m, 2H), 3.23 (broad t, 4H), 3.91 (s, 3H) 7.16 (d, 1H), 7.47 (dd, 1H), 7.68 (d, 1H); ES-MS m/z (MH+) 314.2, HPLC RT (min) 0.70.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12].[CH3:13][O:14][CH:15]([CH3:19])[CH2:16][C:17]#[CH:18].C(NC(C)C)(C)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:18]#[C:17][CH2:16][CH:15]([O:14][CH3:13])[CH3:19])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12]
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Reactant: C#CCC(C)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COC(C)CC#Cc1cc(Cl)c(N)c2c1OCO2
Reaction time: 1.5 h
Yield: 91.5 %

Procedure:
5-chloro-7-iodo-1,3-benzodioxol-4-amine (600 mg, 2.02 mmol) and 4-methoxypent-1-yne (500 mg, 5.10 mmol) in ethyl acetate (8 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine)palladium(II) dichloride (141 mg, 10 mol %) followed by copper(I) iodide (38 mg, 10 mol %) and diisopropylamine (407 mg, 5.69 mmol). The reaction was allowed to warn to room temperature and stirred 90 min then filtered through Celite. The filtrate was purified by column chromatography on silica using a 1:1 mixture of methyl tert-butyl ether and iso-hexane as eluent to give 5-chloro-7-(4-methoxypent-1-yn-1-yl)-1,3-benzodioxol-4-amine (495 mg, 92%) as a dark brown oil;
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[C:27]([F:33])[C:3]=1[C:4]([N:6](C(=O)C1C(F)=CC(C#N)=CC=1Cl)[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14])=[O:5].[OH-].[Na+]>CO.O1CCOCC1>[Cl:1][C:2]1[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[C:27]([F:33])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14])=[O:5]
Reactant: N#Cc1cc(F)c(C(=O)N(C(=O)c2c(F)cc(C#N)cc2Cl)c2ccnc(Cl)c2F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1cc(F)c(C(=O)Nc2ccnc(Cl)c2F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.2 %

Procedure:
To a solution of 2-chloro-N-(2-chloro-4-cyano-6-fluorobenzoyl)-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-cyano-6-fluoro-benzamide (0.865 g, 1.7 mmol) in MeOH (8.5 mL) and dioxane (8.5 mL) was added sodium hydroxide (0.102 g, 2.5 mmol). The resulting mixture stirred at room temperature for 2.5 hours and then concentrated under reduced pressure. The residue was partitioned between DCM and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-100% DCM in pentane to give the desired compound as an off-white solid (0.308 g, 55% yield). 1H NMR (300 MHz, CDCl3): δ 8.49-8.40 (m, 1H), 8.25 (d, J=5.4 Hz, 1H), 7.98 (br s, 1H), 7.64 (t, J=1.3 Hz, 1H), 7.47 (dd, J=7.9, 1.5 Hz, 1H). LCMS (Method D): RT=3.33 min, m/z: 328 [M+H+].
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]4[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[CH2:26][CH2:25]4)=[O:23])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.CO>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]4[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:26][CH2:25]4)=[O:23])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CCOC(=O)CCCC1CCN(C(=O)Nc2cc(Oc3ccc4c(ccn4C(=O)NC)c3)ccn2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(CCCC(=O)O)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 64.8 %

Procedure:
5-(2-((4-(3-Ethoxycarbonylpropyl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylic acid methylamide (271 mg, 0.54 mmol, Production example 43-3) was dissolved in tetrahydrofuran (3.0 ml) and methanol (1.5 ml); 4N lithium hydroxide (0.54 ml) was added; and the reaction mixture was stirred at room temperature for 3.5 hours. 1N hydrochloric acid (2.2 ml) was added thereto while the stirred at room temperature. After the precipitated crystals were filtered off, the crystals were washed with water and diethyl ether sequentially, and dried under aeration to yield the title compound (170 mg, 0.35 mmol, 66%) as colorless crystals.
Reaction SMILES: Cl.[OH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:12])[CH2:6][CH2:5]1.[Cl:19][C:20]1[C:21]([CH3:30])=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C>C(#N)C>[Cl:19][C:20]1[C:21]([CH3:30])=[C:22]([S:26]([N:15]2[CH2:16][CH2:17][CH2:18][C@H:13]([C:11]([NH:10][C@H:7]3[CH2:6][CH2:5][C@H:4]([CH2:3][OH:2])[CH2:9][CH2:8]3)=[O:12])[CH2:14]2)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(N[C@H]1CC[C@H](CO)CC1)[C@H]1CCCNC1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](C(=O)N[C@H]2CC[C@H](CO)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3S)—N-[trans-4-(hydroxymethyl)cyclohexyl]piperidine-3-carboxamide hydrochloride (170 mg, 0.61 mmol), 3-chloro-2-methylbenzenesulfonyl chloride (138 mg, 0.61 mmol), and triethylamine (0.21 mL, 1.54 mmol) in acetonitrile (3 mL) was stirred at r.t. for 2 hours. After removal of solvent, the residue was loaded on flash column with methylene chloride and eluted with ethyl acetate-hexane. 110 mg final product was obtained. (Yield: 41%). LCMS: m/z 429.0 (M+H)+; 879.2 (2M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C1C=C(Cl)C=[C:11]([C:16]([O:18]O)=[O:17])C=1>ClCCl>[C:16]([O:18][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)(=[O:17])[CH3:11]
Reactant: Cc1ccc(Br)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)OCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
To a solution of 2-methyl-5-bromopyridine (40 g, 0.23 mol) in dichloromethane (500 ml) was added m-CPBA (64 g, 0.25 mol) in batches at 0° C. After stirring for 16 h at room temperature, the mixture was washed with sat. aq. NaHCO3, aq. NaHSO3 and brine successively. The organic layer was dried over MgSO4 and then concentrated to give 35 g, (79.2%) of 2-acetoxymethyl-5-bromopyridine as a yellow solid. A mixture of 35 g (0.19 mol) 2-acetoxymethyl-5-bromopyridine and Ac2O (160 ml) was heated to reflux for 1 hour. To this mixture was cautiously added 150 mL EtOH (until the excess Ac2O was converted to EtOAc and AcOH). After concentration, the residue was neutralized with aq. KHCO3 and extracted with CH2Cl2. The extract was dried over MgSO4 and purified by silica gel chromatography to give 2-(acetoxymethyl)-5-bromopyridine. 1H-NMR (400 MHz, CDCl3) δ 8.65 (d, J=2.4 Hz, 1H), 7.82 (q, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.25 (q, J1=7.8 Hz, J2=0.6 Hz, 1H), 5.17 (s, 2H), 2.16 (s, 3H) m/z: 231.15 (M+1)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.[BH4-].[Li+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1
Reactant: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(Cl)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1cc(CO)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
Methyl 2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylate (3.15 g) was dissolved in dry THF (20 mL) and cooled to 0° C. under nitrogen. To this is added dropwise a solution of lithium borohydride (2.0M in THF, 6.09 mL). The solution was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with water (20 mL) then evaporated to dryness. The residue was dissolved in ethyl acetate (150 mL) and washed with water (150 mL) followed by brine (50 mL). The organics were concentrated in vacuo to give to the desired compound (2.44 g) as white solid.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:17][C:13]1[S:14][CH:15]=[CH:16][C:12]=1[O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCOc1ccsc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCOc1ccsc1Br
Temperature: 25 °C
Yield: 94 %

Procedure:
3-decyloxy-thiophene (5.50 g, 0.023 mol) was dissolved in CHCl3 (50 mL) under argon atmosphere. N-Bromosuccinimide (NBS) (4.09 g, 0.023 mol) was added to the solution as one portion. The mixture was reacted under argon and protected from light for 4˜8 hours at room temperature (25° C.). Afterwards it was distilled to remove CHCl3, allowed to cool to room temperature, and diluted with hexane (100 mL). The mixture was filtered and the filtrate was concentrated in vacuum. The residue was applied to silica gel, eluted with 1:9 ethyl acetate/hexane to give 6.97 g (94% yield) of light yellow liquid. Mw=319.30. Element Anal. Calcd. for C14H23BrOS: C, 52.66; H, 7.26; Br, 25.02; 0, 5.01; S, 10.04. Found: C, 52.62; H, 7.25; Br, 24.90; 0, 5.09; S, 10.04.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[CH:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].N1C=CC=CC=1>O>[C:21]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: COc1ccc(C2COc3cc(O)ccc3C2=O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2coc3cc(OC(C)=O)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 7-hydroxy-4′-methoxyisoflavanone (2.0 g, 7.5 mmol), acetic anhydride (10 ml) and pyridine (2 ml) was heated on an oil bath at 105-110 C. for 1 hour. After cooling the mixture to room temperature, it was poured into water (100 ml), stirred for 2 hours and then extracted with dichloromethane (3×50 ml). The dichloromethane layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The white residue was crystallised from methanol to yield 7-acetoxy-4′-methoxyisoflavone as colourless prisms (2.1 g, 91%). 1H NMR (CDCl3): δ 2.36 (s, 3H, OCOCH3), 3.84 (s, 3H, OCH3), 6.98 (d, 2H, J 8.7 Hz, ArH), 7.16 (dd, 1H, J 1.9 Hz 8.6 Hz, H6), 7.30 (d, 1H, J 1.9 Hz H8), 7.50 (d, 2H, J 8.7 Hz, ArH), 8.00 (s, 1H, H2), 8.32 (d, 1H, J 8.6 Hz, H5).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][Mg]Br>O1CCCC1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:16])[CH:7]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2ccnc(Cl)c2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(-c2ccnc(C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-chloro-4-(4-methoxyphenyl)pyridine (660 mg) and bis(triphenyl-phosphine)nickeldichloride (200 mg) in anhydrous tetrahydrofuran (7.5 mL) is cooled to a temperature close to 0° C. A solution of methylmagnesiumbromide in tetrahydrofuran (2.6 M, 2 mL) is added slowly. The mixture is stirred at room temperature for two hours, concentrated under reduced pressure and dissolved in methyl tert-butyl ether (10 mL). Alkaloids are extracted with a 3N aqueous solution of hydrochloric acid (3 times 10 mL). Extracts are pooled, alkalinised and back extracted with methyl tert-butyl ether (3 times 20 mL) and dichloromethane (30 mL). Organic phases are dried over magnesium sulphate, concentrated under reduced pressure and purified over silica gel (eluent dichloromethane/methanol from 100/0 to 95/5). Fraction containing the expected product are pooled and concentrated under reduced pressure to give 385 mg of 4-(4-methoxyphenyl)-2-methylpyridine as a clear brown powder used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1OC(=O)[S:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:23]>ClC1C=CC=CC=1Cl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:18][N:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C#N
Reactant: O=c1oc(-c2ccc(Cl)cc2OCc2ccccc2)ns1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2OCc2ccccc2)ns1
Temperature: 150 °C
Yield: 11.4 %

Procedure:
To a solution of 5-(2-(benzyloxy)-4-chlorophenyl)-1,3,4-oxathiazol-2-one (0.15 g, 0.47 mmol) in 1,2-dichlorobenzene (1 ml) was added ethyl cyanoformate (185 μL, 1.88 mmol). The resulting reaction mixture was refluxed for 3 h at 150° C. After the completion of the reaction (TLC monitoring), the reaction mass was as such (direct loading) purified through flash chromatography (100-200 M silica, 2% EtOAc-Hexane) to get the desired product (0.02 g, 12%). MS: 375.18 (M+H)+.