Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@:3]1([CH3:11])[C:7]([O:9][CH3:10])=[O:8].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C@@H:2]2[CH2:6][CH2:5][CH2:4][C@:3]2([CH3:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)[C@@]1(C)CCC[C@H]1N
Product: COC(=O)[C@@]1(C)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
According to the procedure of Example 47, Step 4, using methyl (1S,2R)-2-amino-1-methylcyclopentanecarboxylate (480 mg, 2.48 mmol) and 4-(benzyloxy)benzene-1-sulfonyl chloride (0.692 g, 2.45 mmol), methyl (1S,2R)-2-({[4-(benzyloxy)phenyl]sulfonyl}amino)-1-methylcyclopentanecarboxylate was obtained (811 mg, 82%) as a colorless solid after purification via column chromatography on silica gel eluting with 25% ethyl acetate/hexane. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.20 (s, 3H) 1.45-1.56 (m, 3H) 1.68-1.77 (m, 1H) 2.10 (ddd, J=12.57, 8.53, 3.66 Hz, 1H) 3.27-3.36 (m, 1H) 3.64-3.67 (m, 3H) 5.10 (s, 2H) 5.61 (d, J=10.11 Hz, 1H) 7.00-7.05 (m, 2H) 7.31-7.43 (m, 5H) 7.78-7.83 (m, 2H).
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[C:6](/[C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26])\[CH3:7])C.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>CCOCC>[C:18]([C:10]1[C:9]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:8]([CH:6]([CH3:7])/[CH:5]=[CH:4]\[OH:3])[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[CH:11]=1)([CH3:19])([CH3:20])[CH3:21]
Reactant: CCCCOc1c(/C(C)=C/C(=O)OCC)cc(C(C)(C)C)cc1C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CCOCC
Product: CCCCOc1c(C(C)/C=C\O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
0.9 g of (E)-3-(3,5-di-tert.-butyl-2-butyloxyphenyl)-butenoic acid ethyl ester was dissolved in 20 ml of dry ether. This was cooled to −78° C. and treated with 6.0 ml of diisobutylaluminum hydride (1.0M in hexane). The temperature was allowed to warm to 0° C. and was then treated with 20% aqueous Rochelle salt. This was stirred at 25° C. for 1 hr. The organic fraction was separated, washed with water, dried (Na2SO4), and had solvent removed to give 0.78 g of (Z)-3-(3,5-di-tert.-butyl-2-butyloxyphenyl)-buten-1-ol. 1H NMR (CDCl3) δ 7.08 (dd, 4H, aromatics), 5.90 (t, 1H, CH—OH), 3.80 (t, 2H, —OCH2—), 2.49 (t, 1H, —OH), 2.21 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:12].[CH3:13][O:14][C:15](=[O:19])[CH2:16][CH2:17][NH2:18].[BH4-].[Na+].Cl>CO.C(N(CC)CC)C>[ClH:12].[CH3:13][O:14][C:15](=[O:19])[CH2:16][CH2:17][NH:18][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)CCN
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CCNCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 71 %

Procedure:
A mixture of p-nitrobenzaldehyde (1.51 g), β-alanine methyl ester hydrochloride (1.40 g), triethylamine (1.6 ml) and methanol (20 ml) is stirred at room temperature for 25 minutes. The mixture is ice-cooled, and sodium borohydride (807 mg) is added thereto. The mixture is stirred at the same temperature for 10 minutes. The mixture is acidified with 10% HCl, and extracted with ethyl acetate. The aqueous layer is neutralized with 10% NaOH, and extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent. The residue is dissolved in ether, and a HCl-ether solution is added thereto. The precipitates are collected and recrystallized from methanol to give N-(p-nitrobenzyl)-β-alanine methyl ester hydrochloride (1.95 g, 71.1%) as pale yellow plates, m.p. 219.5°-220° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:34])=[CH:28][CH:27]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)Cc1ccc(OC)cc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (4-methoxy-phenyl)-acetic acid to yield (3aR,4S,7aR)-methyl 4-(2-(4-methoxyphenyl)acetoxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT==7.889 min; LCMS Method III
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1([CH3:45])[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:11](=[O:21])[CH2:10][N:9]1[CH2:22][C@H:23]([NH:32]S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C@@H:24]1[CH2:28][C@@H:27]([CH2:29][CH3:30])[C:26](=[O:31])[O:25]1.C1(S)C=CC=CC=1.C(=O)(O)[O-].[Na+].[C:58](OC(OC(C)(C)C)=O)([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59].N[C@H]([C@@H]1C[C@@H](CC)C(=O)O1)CN1C(C)(C)CN(C2C=CC=CC=2C)C(=O)C1>C(#N)C.[Cl-].[Na+].O.C(OCC)(=O)C.O>[C:61]([O:60][C:58](=[O:59])[NH:32][C@H:23]([C@@H:24]1[CH2:28][C@@H:27]([CH2:29][CH3:30])[C:26](=[O:31])[O:25]1)[CH2:22][N:9]1[CH2:10][C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:13][C:8]1([CH3:45])[CH3:7])([CH3:64])([CH3:63])[CH3:62]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3C)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CC[C@@H]1C[C@@H]([C@@H](N)CN2CC(=O)N(c3ccccc3C)CC2(C)C)OC1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3C)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reaction time: 1 h
Yield: 88.6 %

Procedure:
854 mg of cesium carbonate (2.62 mmol) was added to a solution of 1.22 g of N-{(S)-2-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (110a) (2.18 mmol) and 0.45 ml of thiophenol (content: 95%) (4.37 mmol) in acetonitrile (22 ml) under a nitrogen atmosphere at room temperature, and the mixture was stirred at the same temperature for one hour. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=19/1-9/1). 197 mg of sodium bicarbonate (2.34 mmol) and 510 mg of di-t-butyl dicarbonate (2.34 mmol) were added to a solution of 4-{(S)-2-amino-2-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]ethyl}-5,5-dimethyl-1-(2-methylphenyl)piperazin-2-one obtained above in ethyl acetate (10 ml)-water (10 ml), and the mixture was stirred at room temperature for 15 hours. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=3/7) to obtain 915 mg of the title compound (yield: 88%).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([NH:12][C@H:13]([CH3:17])[CH2:14][CH2:15][CH3:16])[N:5]=2.C[C@H](NC1N=C2C(N=CN2C2CCCCO2)=C(N)N=1)CCC>>[Br:1][C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([NH:12][C@@H:13]([CH3:17])[CH2:14][CH2:15][CH3:16])[N:5]=2
Reactant: CCC[C@@H](C)Nc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: CCC[C@H](C)Nc1nc(N)c2ncn(C3CCCCO3)c2n1
Product: CCC[C@H](C)Nc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 71 from N2-[(1S)-1-methylbutyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1CCCCC1.[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30](C=O)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>C(O)C>[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30]([CH:11]=[CH:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1ccc(N2CCC(O)CC2)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(N3CCC(O)CC3)cc2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A one liter three necked flask fitted with a dropping funnel, mechanical stirrer and condenser is charged with 34.35 g of 4-nitrophenylacetic acid. Piperidine (16.2 g) is added dropwise over a period of 30 minutes. At the end of the addition, 38.4 g of 4-(4-hydroxypiperidyl)benzaldehyde is added. The reaction mixture is heated at 100° C. for three hours, and at 130° C. for three hours. After cooling, the semi-solid product mass is ground in ethanol in a blender, then filtered, washed, and vacuum dried. The crude product is recrystallized from chlorobenzene, m.p. 248°-250° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(S(C)(=O)=O)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)cc(S(C)(=O)=O)c1

Procedure:
3-(Methylsulfonyl)-5-nitro-benzoic acid methyl ester (32 g; 0.12 mol) was dissolved in methanol (300 ml), 4 g Pd/C (5%) were added and the mixture was hydrogenated at 5 bar. The mixture was filtered and the filtrate concentrated. 26 g (0.11 mmol; 94% yield) were obtained as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:11][CH2:12][CH2:13][N:14](CC2C=CC=CC=2)[CH2:15][CH:16]([OH:30])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:21][CH:20]=2)[CH:7]=[CH:8][C:9]=1[OH:10])(=[O:3])[NH2:2].[ClH:38]>CO>[C:1]([C:4]1[CH:5]=[C:6]([CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:30])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:23][CH:24]=2)[CH:7]=[CH:8][C:9]=1[OH:10])(=[O:3])[NH2:2].[ClH:38]
Reactant: COCCOc1ccc(OCC(O)CN(CCCc2ccc(O)c(C(N)=O)c2)Cc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: COCCOc1ccc(OCC(O)CNCCCc2ccc(O)c(C(N)=O)c2)cc1

Procedure:
A solution of 16 g of crude 1-[N-[3-(3-carbamoyl-4-hydroxyphenyl)propyl]benzylamino]-3-[4-(2-methoxyethoxy)phenoxy]propan-2-ol is hydrogenated analogously to Example 1. The hydrogenating solution is neutralised with a solution of hydrochloric acid gas in methanol, concentrated by evaporation and crystallised from acetone. In this manner 1-[3-(3-carbamoyl-4-hydroxyphenyl)propylamino]-3-[4-(2-methoxyethoxy)phenoxy]propan-2-ol is obtained as a hydrochloride having a melting point of 194°-200°.
Reaction SMILES: [NH2:1][C@H:2]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[CH2:33]([O:40][C:41](Cl)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCOC(C)=O>C1COCC1>[C:13]([O:12][C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C@H:2]([NH:1][C:41](=[O:42])[O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:5][CH:6]=1)=[O:17])([CH3:14])([CH3:15])[CH3:16]
Reactant: CON(C)C(=O)[C@@H](N)Cc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
To a solution of amine 62 (0.79 g, 2.43 mmol) in THF (20 mL) was added DiPEA (1.2 eq., 2.91 mmol, 482 μL), and benzylchloroformate (1.1 eq., 2.67 mmol, 392 μL) and the mixture was stirred for 4 hours in which a colorless solid precipitated. EtOAc was added and the mixture was extracted with 1 M aq. HCl (2×), sat. aq. NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure. The title compound was obtained after column chromatography (10%->75% EtOAc/PE) as a colorless foam (yield: 0.95 g, 2.06 mmol, 85%). 1H NMR (400 MHz, CDCl3): δ=7.33-7.23 (m, 7H), 7.14 (s, 1H), 7.05 (d, J=8.21 Hz, 2H), 5.80 (d, J=8.71 Hz, 1H), 5.04 (dd, J=26.77, 12.39 Hz, 2H), 4.98-4.94 (m, 1H), 3.62 (s, 3H), 3.13 (s, 3H), 3.01 (dd, J=13.65, 5.91 Hz, 1H), 2.85 (dd, J=13.58, 7.35 Hz, 1H), 1.49 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ=171.72, 155.64, 152.64, 137.21, 136.07, 130.35, 129.52, 128.13, 127.69, 127.64, 118.18, 79.88, 66.41, 61.21, 51.95, 37.53, 31.73, 28.05 ppm. [α]D23=+8.1 (c=1, CHCl3). HRMS: calcd. for C24H31N3O6 458.22856 [M+H]+. found 458.22845.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(N3CCCCC3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(N3CCCCC3)cc2)cc1)C(=O)O
Yield: 93 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(4-piperidine-1-ylbenzoylamino)ethoxy]phenyl]propionate (370 mg), which is the product of Example 63, was reacted with aqueous sodium hydroxide solution (1N, 2.30 ml) and the reaction mixture was treated to give the title compound (324 mg) as a white powder.
Reaction SMILES: [NH2:1][C@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([NH:5][CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37])([O-:29])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[C:14]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][NH:5][C:3](=[O:4])[C@H:2]([NH:1][S:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N+:27]([O-:29])=[O:28])(=[O:37])=[O:38])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)NCC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(c1ccccc1)c1ccccc1)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 74.3 %

Procedure:
To a stirred solution of the product of step 1 (12.3 g, 35.6 mmol) in methylene chloride (200 mL) was added 2-nitrobenzenesulfonyl chloride (9.00 g, 40.6 mmol) followed by triethylamine (6.4 mL, 46 mmol). After 30 minutes the reaction was concentrated and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated. The resulting amber foam was purified by flash chromatography over silica (hexane/ethyl acetate) to afford 14.0 g (74%) of product as a colorless foam: 1H NMR (CDCl3) δ 7.95–7.87 (m, 1H), 7.76–7.62 (m, 3H), 7.35–7.15 (m, 10H), 7.06–6.94 (m, 3H), 6.90–6.83 (m, 2H), 6.42 (t, J=5.6, 1H), 5.80 (d, J=5.8, 1H), 4.12 (t, J=8.1, 1H), 4.01–3.82 (m, 3H), 3.18–3.08 (m, 1H), 2.68–3.57 (m, 1H) ppm.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].N1C=CC=CC=1.[Br:16][CH2:17][C:18](Br)=[O:19].Cl>C(Cl)Cl>[Br:16][CH2:17][C:18]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:19]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)CNC(=O)CBr
Reaction time: 3 h
Yield: 153.1 %

Procedure:
To a solution of 4 g (0.02 mol) of t-butyl glycinate and 4 ml of pyridine in 100 ml of methylene dichloride at 0° under nitrogen was added a solution of 2.01 ml (0.024 mol) of bromoacetyl bromide in 10 ml of methylene dichloride. After the addition, the mixture was stirred for 3 hrs and poured into 1 N aqueous hydrochloride. The organic layer was separated and then washed successively with 1 N HCl, water and brine. After drying over anhydrous sodium sulfate, the mixture was evaporated to dryness in vacuo to yield 6 g of a light brown product, which upon recrystallization from hexane-ethyl acetate, yielded a product with mp 90°-91°.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]([C:11]([OH:13])=O)=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[O:3][C:4]([C:11]([Cl:17])=[O:13])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: O=C(O)c1oc(Br)nc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1oc(Br)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.4 %

Procedure:
To a solution of 2-bromo-4-trifluoromethyloxazole-5-carboxylic acid (A-38) (1.30 g, 5.0 mmol) in CH2Cl2 (25 mL) was added oxalyl chloride (8.5 mL, 10.0 mmol) and DMF (0.019 mL), respectively, at RT under a nitrogen atmosphere. The reaction was stirred for 6 h at RT. The solvent was concentrated, and the residue was dried in vacuo to yield 2-bromo-4-trifluoromethyloxazole-5-carbonyl chloride (A-39) as yellow oil (1.30 g, 96% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[F:22])[CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[CH2:30][OH:31].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:22][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]=1[C:4]1[CH:3]=[C:2]([NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[CH2:30][OH:31])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Fc1ccc(C(F)(F)F)cc1-c1cc(Cl)c2cccnc2n1
Reactant: Nc1ccncc1CO
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: OCc1cnccc1Nc1cc(-c2cc(C(F)(F)F)ccc2F)nc2ncccc12
Yield: 31 %

Procedure:
150 mg 4-chloro-2-(2-fluoro-5-trifluoromethyl-phenyl)-[1,8]naphthyridine and 57 mg 4-amino-3-hydroxymethylpyridine in 6 ml dioxane containing 299 mg Cs2CO3, 8 mg Pd2 (dba)3 and 10 mg xantphos were incubated under argon gas at 90° C. for 18 hrs. After evaporation to dryness the crude sample was flashed on SiO2 with a MeOH gradient in DCM. A pooled fraction was evaporated to give 59 mg product {4-[2-(2-fluoro-5-trifluoromethyl-phenyl)-[1,8]naphthyridin-4-ylamino]-pyridin-3-yl}-methanol with Rt˜1.48 min and correct mass found M+H˜415.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(C)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2c(Br)cccc21
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)C1CC2(CCNCC2)c2c(Br)cccc21
Temperature: 25 °C
Yield: 0.1 %

Procedure:
Tert-butyl 7-bromo-3-(1-ethoxy-1-oxopropan-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (300 mg, 0.645 mol) was dissolved in 20% TFA at 0° C. The reaction mixture was stirred for 1′ h at rt. The solvent was removed under reduced pressure to give ethyl 2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoate (235 mg, 100%). 1H NMR: (400 MHz, CDCl3): δ=0.98 (d, 3H), 1.23 (t, 3H), 1.61-1.73 (m, 4H), 2.42 (m, 1H), 2.73 (m, 1H), 3.01 (m, 1H), 3.23 (m, 3H), 3.48 (m, 3H), 3.68 (d, 1H), 4.21 (q, 2H), 7.03 (m, 2H), 7.38 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(c1ccncc1)C(c1ccc(F)cc1)c1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
21.5 g (100 mmoles) of 2-(4-fluorophenyl)-1-(pyridine-4-yl)ethanone (prepared as described in scheme 1) and 34.9 g of 2-chloro-3-nitropyridine are dissolved in 270 mL of dimethylformamide. 8.8 g of sodium hydride (60% in oil (220 mmoles) is slowly added to the reaction mixture which is kept between 0 and 5° C. After stirring for 1 hour at room temperature, the reaction mixture is poured into 1 L of ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. The oily residue is purified by chromatography on silica gel (ethylacetate/hexane 1/1) to give 26.7 g of 2-(4-Fluoro-phenyl)-2-(3-nitro-pyridin-2-yl)-1-pyridin-4-yl-ethanone.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][C:7](=O)[CH3:8].S(O)(O)(=O)=O.[NH2:19][OH:20].C(=O)([O-])O.[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][C:7](=[N:19][OH:20])[CH3:8]
Reactant: NO
Reactant: CC(=O)COc1cc(C)cc(C)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(COc1cc(C)cc(C)c1)=NO
Yield: 155.2 %

Procedure:
10.0 Grams (56 mmol) of 1-(3,5-dimethylphenoxy)-2-propanone was dissolved in 50 ml of ethanol, and 5.53 g (34 mmol) of hydroxylamine sulfate and 5.66 g (67 mmol) of sodium hydrogencarbonate were added. And, the resultant mixture was stirred at room temperature for 4 hours, and 50 ml of water was added. Ethanol was distilled off under reduced pressure, and the resultant solid precipitate was recovered by filtration, washed with water and dried to give 10.2 g of 1-(3,5-dimethylphenoxy)-2-propanone oxime (yield 92%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20]3)[N:13]=4)=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(N(C(C)C)CC)(C)C.Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>C(Cl)Cl>[C:22]1([C:19]2([C:14]3[N:13]=[C:12]4[S:11][C:10]([C:6]5[CH:5]=[C:4]6[C:9](=[CH:8][CH:7]=5)[CH2:1][N:2]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:3]6)=[N:18][C:17]4=[CH:16][CH:15]=3)[CH2:20][CH2:21]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6c(c5)CNC6)sc4n3)CC2)cc1
Reactant: COC(=O)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(Isoindolin-5-yl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (97 mg, 0.263 mmol) was dissolved in DCM (2.625 mL) and diisopropylethylamine (91 μL, 0.525 mmol) before methyl bromoacetate (48.5 μL, 0.525 mmol) was added and stirred at ambient temperature for 3 h. Methyl 2-(5-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)isoindolin-2-yl)acetate was obtained after purification via flash chromatograpy. MS (ESI) m/z: Calculated: 441.2; Observed: 442.4 (M++H).