Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.CN(C=O)C.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:28][NH:29][O:30][CH3:31]>[Cl-].[NH4+]>[CH3:31][O:30][N:29]([CH3:28])[C:7](=[O:9])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cccs1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cc1cccs1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A 25 mL RB flask with a stirring bar was charged with 2-thiopheneacetic acid (2.84 g, 2 mmol), followed by anhydrous DMF (10 mL). 1,1′-Carbonyldiimidazole (3.24 g, 2 mmol) was added in one portion, giving rise to significant gas evolution. The mixture was warmed to 40° C. After 30 min, N,O-dimethylhydroxyamine hydrochloride (2.14 g, 2.2 mmol) was introduced in one portion. The mixture was allowed to stir at 23° C. for 30 min. before being diluted with sat. ammonium chloride solution (100 mL) and extracted twice with 1:1 ethyl acetate/hexanes (100 mL). The crude mixture was purified by column chromatography over silica gel (0-25% ethyl acetate/hexanes) to give N-methoxy-N-methyl-2-(2-thienyl)acetamide (1-1). 1H NMR (CDCl3, ppm) δ 7.20 (m, 1H), 6.96 (m, 2H), 3.91 (s, 2H), 3.70 (s, 3H), 3.25 (s, 3H).
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(O)(C)C.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[N+:28]([O-:30])=[O:29])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CS(C)=O>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]2[CH2:7][C@H:27]2[N+:28]([O-:30])=[O:29])=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)O
Agent: C[S+](C)(C)=O
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.3 %

Procedure:
Trimethylsulfoxonium iodide (0.62 g, 2.82 mmol) was added in portions to a solution of t-BuOH (0.32 g, 2.82 mmol) in dry DMSO (5 mL). After 10 min a solution of 1-(benzyloxy)-4-[(E)-2-nitrovinyl]benzene (0.60 g, 2.35 mmol) in DMSO (5 mL) was transferred via canula and the mixture was stirred at room temperature for 6 h. The reaction was poured over water (10 mL) and extracted with Et2O (3×10 mL); the organic layers were washed with brine (2×15 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residual orange oil was purified by column chromatography on silica gel (5% EtOAc/hexanes) affording 0.16 g of 1-(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene [Rf=0.5 (20% EtOAc/hexanes), white solid, 26% yield].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][C:14](F)=[CH:15][CH:16]=3)[CH:8]=[N:7][C:6]=12.[NH2:18][CH2:19][C:20]([CH3:23])([OH:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:18][CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])=[N:13][CH:12]=3)[CH:8]=[N:7][C:6]=12
Reactant: CC(C)(O)CN
Reactant: Fc1ccc(-c2cnc3c(Br)cnn3c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)CNc1ccc(-c2cnc3c(Br)cnn3c2)cn1

Procedure:
A solution of 3-bromo-6-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyrimidine (0.1 g, 0.34 mmol), 1-amino-2-methylpropan-2-ol (0.06 g, 0.68 mmol) and potassium carbonate (0.9 g, 0.68 mmol) in DMF (3 mL) was heated to 80° C. for 72 hours. The reaction was directly purified by reverse phase LC to give 1-{[5-(3-bromopyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl]amino}-2-methylpropan-2-ol. LC-MS EIMS: m/z 364.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:40])([F:39])[F:30])=[CH:33][CH:34]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(C(F)(F)F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethyl)phenol: ESMS m/e: 543.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][CH2:17][O:18]S(C1C=CC(C)=C([N+]([O-])=O)C=1)(=O)=O.[C:32]([O:36][C:37](=[O:55])[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][C:41]=1[CH2:47][NH:48][C:49]([O:51][CH:52]([CH3:54])[CH3:53])=[O:50])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:55])[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:18][CH2:17][CH2:16][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:42][C:41]=1[CH2:47][NH:48][C:49]([O:51][CH:52]([CH3:53])[CH3:54])=[O:50])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)OC(=O)NCc1cc(O)ccc1CCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc([N+](=O)[O-])cc3)oc2C)cc1[N+](=O)[O-]
Product: Cc1oc(-c2ccc([N+](=O)[O-])cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1

Procedure:
4-Methyl-3-nitro-benzenesulfonic acid 2-[5-methyl-2-(4-nitro-phenyl)-oxazol-4-yl]-ethyl ester (Preparation 7) and 3-[4-hydroxy-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester were coupled by Standard procedure A to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21]>>[OH:21][CH2:20][C:19]([NH:18][C:8]([C:5]1[CH:4]=[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:23])[CH3:22]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)c(Cl)cn1
Product: CC(C)(CO)NC(=O)c1cc(-c2cccc(Cl)c2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-(3-chlorophenyl)-pyridine-2-carboxylic acid and 2-amino-2-methyl-1-propanol (CAN 124-68-5) as starting materials and isolated (13 mg, 38%) as colorless oil; MS (ESI, m/z): 339.0, 341.0 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:17])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:6]=2.[O:18]1CCOCC1>O>[F:1][C:2]1[C:3]([CH:17]=[O:18])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:6]=2
Reactant: COCCOc1ccc2cc(F)c(C)nc2c1
Reactant: C1COCCO1
Solvent: O
Product: COCCOc1ccc2cc(F)c(C=O)nc2c1
Yield: 97 %

Procedure:
A solution of 3-fluoro-7-(2-methoxyethoxy)-2-methylquinoline (0.234 g, 0.995 mmol) and SeO2 (0.132 g, 1.19 mmol) in dioxane (10 mL) and water (0.1 mL) was stirred at 102° C. (bath) for 5 hours. The solid was removed by filtration. The filtrated was concentrated under reduced pressure. The residue obtained was purified by flash chromatography (1:1 hexane/ethyl acetate) to give 3-fluoro-7-(2-methoxyethoxy)quinoline-2-carbaldehyde (0.24 g, 0.963 mmol, 97% yield) as a solid.
Reaction SMILES: [Li+].[OH-].[CH3:3][O:4][C:5]([CH:7]1[CH2:11][CH:10]([OH:12])[CH:9]=[C:8]1[C:13]([O:15]C)=[O:14])=[O:6].C1(C)C=CC=CC=1.CO>O1CCOCC1.O>[CH3:3][O:4][C:5]([C:7]1[CH:8]([C:13]([OH:15])=[O:14])[CH2:9][CH:10]([OH:12])[CH:11]=1)=[O:6]
Reactant: COC(=O)C1=CC(O)CC1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C1=CC(O)CC1C(=O)O
Temperature: 0 °C
Yield: 24.4 %

Procedure:
LiOH (0.52 g, 22 mmol) was added to an ice-cold solution of the alcohol 23b (3.4 g, 22 mmol) dissolved in dioxane and water (1:1, 110 mL). After two and a half hours the mixture was co-evaporated with toluene and methanol. Purification by flash chromatography (toluene/Ethyl acetate 3:1+1% HOAc) gave the title compound (1.0 g, 27%) as yellow-white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].FC(F)(F)[C:14]([O:16]C(=O)C(F)(F)F)=[O:15]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:14]([OH:16])=[O:15])=[CH:5][N:6]2[CH3:11]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cn1ccc2c(Br)cccc21
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c2c(Br)cccc21
Temperature: 25 °C

Procedure:
A solution of 4-bromo-1-methyl-1H-indole (D16) (7.0 g) in tetrahydrofuran (50 ml) was treated with a solution of trifluoroacetic anhydride (5.65 ml) in tetrahydrofuran (20 ml) at 0° C. The reaction mixture was allowed to warm to room temperature over 6 h, whilst stirring. The reaction mixture was concentrated in vacuo and then re-suspended in ethanol (25 ml). The solution was treated with 5N sodium hydroxide solution (50 ml) and heated under reflux for 18 h. The reaction mixture was washed with diethyl ether and the aqueous phase acidified with 5N hydrochloric acid solution. The precipitate was filtered, washed with water and concentrated in vacuo to afford the title compound (4.88 g). TLC, Silica (cyclohexane-ethyl acetate-acetic acid [3:1:0.1]), Rf=0.35.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[O:16])[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1.CCOCC>C(Cl)Cl>[O:33]1[C@H:9]2[CH2:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([CH2:13][NH:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[O:16])[CH2:12][CH2:11][C@H:10]12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CC=CCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CC[C@@H]2O[C@H]2C1

Procedure:
A solution of 4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)-cyclohex-1-ene (Example 192, 146.3 mg, 0.46 mmol) and mCPBA (156.8 mg, 0.92 mmol) in 8.0 mL of CH2Cl2 was stirred at rt for 18 h. The reaction mixture was poured into ether, washed with NaHCO3 (3×), dried over Na2SO4, filtered through a plug of silica gel and concentrated The residue was purified by HPLC (Waters RCM, μ Porosil, 25 mm×10 cm) using a mixture of (5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane, 1.0/8.0 mL/min) to give the separated cis and trans isomers.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[C:5]#[N:6].B.C1COCC1>C1COCC1>[NH2:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([I:10])=[C:2]([OH:1])[CH:3]=1
Reactant: N#Cc1ccc(I)c(O)c1
Agent: B
Solvent: C1CCOC1
Product: NCc1ccc(I)c(O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.7 %

Procedure:
To a solution of 3-Hydroxy-4-iodo-benzonitrile (300 mg, 1.22 mmol) in THF (5 mL) is added BH3.THF (10 mL, 1 M solution in THF, 10 mmol) under N2. The mixture is then allowed to stir at room temperature for 24 hours. The reaction is quenched with 6N HCl. THF is removed and the aqueous layer is neutralized with ammonium hydroxide to pH 9. The mixture is extracted with CHCl3/MeOH (9:1). The organic layer dried and evaporated and the residue is chromatographed to provide the desired product (60 mg, 20%). MS (ESI): 250 (M+1)−1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:31][O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][NH:35]1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH3:31][O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To a cooled (0-5° ) solution of N-benzyloxycarbonyl-L-valine (450.0 g) in dry N,N-dimethylformamide (3.0 liter) was added 1-hydroxybenzotriazole hydrate (483.3 g): and the reaction mixture was stirred for 20 min, followed by the addition of a slurry of L-proline methyl ester hydrochloride (296.4 g) and triethylamine (186.6 g) in N,N-dimethylformamide (1.5 liter). After the resulting mixture was cooled to 0°, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (377.6 g, 1.97 mol) in N,N-dimethylformamide (500 ml) was added. The reaction mixture was stirred at 0°-5° for 3 hr and then allowed to warm gradually to room temperature. Stirring was continued for 65 hr, and the mixture was filtered and evaporated. The residue was partitioned between ether and lN HCl, and the precipitate which formed was removed by filtration. The etheral layer was then separated: washed with water, saturated aqueous NaHCO3 and brine; dried (MgSO4); and evaporated. The crude ester was purified by flash chromatography using a gradient elution of methylene chloride, then methanol:methylene chloride (1:99), (2.5:79.5), and, finally, (5:95). The impure material from the first column was rechromatographed using a gradient elution of methylene chloride:hexanes (1:3), methylene chloride, and, finally, methanol:methylene chloride (2:98). The combined chromatographies afforded the ester (596.9 g, 92%) as a colorless oil; TLC, Rf =0.45-0.60, methanol:methylene chloride (5:95); MS, m/e=363(M+1, base), 319, 255, 130, 91.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C(C)=CC=CC=1.[OH-].[K+].Br[C:26]1[CH:32]=[C:31]([CH3:33])[C:29]([NH2:30])=[C:28]([CH3:34])[CH:27]=1>Cl[Cu].O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:26]2[CH:32]=[C:31]([CH3:33])[C:29]([NH2:30])=[C:28]([CH3:34])[CH:27]=2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: Cc1cc(Br)cc(C)c1N
Agent: Cl[Cu]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1cc(Oc2ccc(Cc3ccccc3)cc2)cc(C)c1N
Reaction time: 12 h

Procedure:
A mixture of 64,4 g (0.35 mole) of p-benzylphenol, 500 ml of xylene and 28 g (0,45 mole) of pulverised potassium hydroxide is heated for 4 hours under reflux. The water formed is removed from the reaction mixture. Then 60 g (0,3 mole) of 4-bromo-2,6-dimethylaniline and 1 g of CuCl are added and the xylene is distilled off under nitrogen until the temperature in the reaction mixture is 160°-170°. The reaction mixture is stirred at this temperature for 12 hours, allowed to cool to 70°-80° C., and then taken up in 500 ml of toluene and filtered. The filtrate is diluted with diethyl ether, washed twice with 10% potassium hydroxide solution and three times with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue is purified over a column of silica gel with a 1:3 mixture of ethyl acetate/hexane as eluant. The eluant is evaporated off to give 4-(p-benzylphenoxy)-2,6-dimethylaniline as a dark liquid which after a time forms crystals with a melting point of 61°-63° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]1[CH:9]=[C:8]([N:10]2[C:22]3[C:21]4[CH:20]=[C:19]([Br:23])[CH:18]=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[NH:12][C:11]2=[O:24])[C:7]([CH3:25])=[N:6]1.I[CH3:28]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]1[CH:9]=[C:8]([N:10]2[C:22]3[C:21]4[CH:20]=[C:19]([Br:23])[CH:18]=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[N:12]([CH3:28])[C:11]2=[O:24])[C:7]([CH3:25])=[N:6]1
Reactant: CI
Reactant: COC(=O)Cn1cc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)c(C)n1
Product: COC(=O)Cn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1

Procedure:
The title compound was synthesized in a similar manner as described for Stage 245.1.1 using [4-(8-bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid methyl ester (Stage 101.1.3, 3.43 mmol) and iodomethane to give the title compound as brown solid. (HPLC: tR 2.42 min (Method A); M+H=430, 432 MS-ES)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]=[O:10].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][OH:10]
Reactant: O=Cc1cc(O)ccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(O)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of 4-bromo-3-formylphenol (20.1 g, 100 mmol) in methanol (200 mL) was added sodium borohydride (1.90 g, 50.0 mmol) portionwise at 0° C., and the mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to a half volume, 6 M HCl (50 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-bromo-3-hydroxymethylphenol (19.4 g, 96%).
Reaction SMILES: C(OCC)(=O)C.[C:7]1([CH2:13][CH2:14][CH2:15][NH:16][C:17]([C:19]2[CH:20]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[NH:21][C:22](=[O:32])[NH:23][C:24]=2[CH2:25][O:26][CH2:27][CH2:28][N:29]=[N+]=[N-])=[O:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[H][H].[Pd]>[C:7]1([CH2:13][CH2:14][CH2:15][NH:16][C:17]([C:19]2[CH:20]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[NH:21][C:22](=[O:32])[NH:23][C:24]=2[CH2:25][O:26][CH2:27][CH2:28][NH2:29])=[O:18])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=NCCOCC1=C(C(=O)NCCCc2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCCOCC1=C(C(=O)NCCCc2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1

Procedure:
10 ml of ethyl acetate was added to a mixture of 164 mg (0.350 mmol) of 6-(2-azidoethoxymethyl)-4-(3-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (3-phenylpropyl)amide and a catalytic amount of 10% palladium/carbon, and they were stirred at room temperature in hydrogen atmosphere under normal pressure for 24 hours. The catalyst was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by the basic silica gel chromatography (dichloromethane/methanol=100/1 to 20/1) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N[CH2:34][CH2:35][CH2:36][OH:37].C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:34][CH2:35][CH2:36][OH:37])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCCCO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCCCO)C1
Yield: 60 %

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]amino}-piperidine-1-carboxylic acid tert-butyl ester and 3-amino-propan-1-ol, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in DCM) afforded the title compound as a glass (70 mg, 60%); LCMS (method B): RT=3.37 min, M+H+=504.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[S:8][C:4]=2[CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][O:11][C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]([CH2:6][C:5]3[CH:13]=[CH:14][CH:2]=[CH:3][CH:4]=3)[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=[CH:13][C:5]=2[CH:6]=1)=[O:10]
Reactant: COC(=O)c1cc2ccc(N)cc2s1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(N(Cc3ccccc3)Cc3ccccc3)cc2s1

Procedure:
Methyl 6-aminobenzothiophene-2-carboxylate (29 mg, 0.140 mmol) was dissolved in 1 mL of anhydrous DMF and reacted with benzyl bromide (40 μL, 0.38 mmol) in the presence of potassium carbonate (41 mg, 0.30 mmol) at 80° C. under a nitrogen atmosphere for 16 h. The reaction mixture was used in the next step without further purification. MS (EI): cal'd 388 (MH+), exp 388 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:4]([F:19])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].Br[C:44]1[CH:59]=[CH:58][C:47]([C:48]([C@@H:50]2[CH2:54][CH2:53][CH2:52][C@H:51]2[C:55]([OH:57])=[O:56])=[O:49])=[CH:46][CH:45]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([C:44]4[CH:45]=[CH:46][C:47]([C:48]([C@@H:50]5[CH2:54][CH2:53][CH2:52][C@H:51]5[C:55]([OH:57])=[O:56])=[O:49])=[CH:58][CH:59]=4)=[CH:3][C:4]=3[F:19])[S:10][C:11]=2[CH:17]=1
Reactant: Fc1cc(I)ccc1Nc1nc2ccc(Cl)cc2s1
Reactant: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)c(F)c2)cc1
Temperature: 85 °C
Yield: 49.5 %

Procedure:
A suspension of N-(4-iodo-2-fluorophenyl)-6-chloro-1,3-benzothiazol-2-amine (200 mg, 0.49 mmol), bis(pinacolato)diboron (130 mg, 0.52 mmol), KOAc (150 mg, 1.48 mmol), and PdCl2(dppf) (30 mg, 0.04 mmol) in DMF (5.0 mL) was degassed by bubbling a flow of nitrogen for 30 minutes. The reaction mixture was heated under nitrogen at 85° C. for 3 h. After the mixture was cooled to rt, (1R,2R)-2-(4-bromobenzoyl)cyclopentanecarboxylic acid (140 mg, 0.49 mmol, >99% ee), Cs2CO3 (400 mg, 1.23 mmol) and PdCl2(dppf) (30 mg, 0.04 mmol) were added, and the reaction mixture was heated at 85° C. under nitrogen for 3 h. TLC analysis showed little starting materials remaining. The reaction mixture was cooled to rt, and diluted with water (50 mL). After the mixture was filtered through a pad of Celite®, 1 N HCl was added to the filtrate to adjust the acidity to pH<3. The solid that formed was collected by filtration, then dissolved in EtOAc (50 mL), and the resulting solution was dried over Na2SO4. Removal of solvent and drying in vacuo provided the desired product (120 mg, 60%, >99% ee). LC-MS m/z 495.3 (MH+), retention time 4.01 min.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[C:27](=[O:28])[CH2:26][NH:25][C:24]2=[O:29])[CH:18]=1)(=O)=O.[NH2:30][CH2:31][C@@H:32]([C:34]1[CH:45]=[CH:44][C:37]2[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=2[CH:35]=1)[OH:33]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:42][C:39]1([CH3:43])[O:38][C:37]2[CH:44]=[CH:45][C:34]([C@@H:32]([OH:33])[CH2:31][NH:30][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([N:23]4[C:27](=[O:28])[CH2:26][NH:25][C:24]4=[O:29])[CH:20]=[CH:21][CH:22]=3)=[CH:35][C:36]=2[CH2:41][O:40]1
Reactant: CC1(C)OCc2cc([C@@H](O)CN)ccc2O1
Reactant: CS(=O)(=O)OCCCCCCOCCCCc1cccc(N2C(=O)CNC2=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(N4C(=O)CNC4=O)c3)ccc2O1
Temperature: 20 °C
Reaction time: 72 h
Yield: 41.9 %

Procedure:
A solution of 6-{4-[3-(2,5-dioxoimidazolidin-1-yl)phenyl]butoxy}hexyl methanesulfonate (766 mg) in DMF (8 ml) was treated with tetrabutylammonium bromide (578 mg) and (1R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (544 mg) and the mixture was stirred at 20° C. for 3 d. The solvent was removed under reduced pressure, the residue was dissolved in CH2Cl2, washed with water and purified by chromatography on Biotage (40 g) eluting with 3% 2M NH3 in MeOH:CH2Cl2 to give the title compound (417 mg). ES+ve 554 (MH)+.