Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([NH:25][C:26](=[O:40])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]3=[O:39])=[CH:29][CH:28]=2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.C=O.[BH3-]C#N.[Na+]>C(O)(C(F)(F)F)=O.O.CC#N.CC(O)=O.CO>[CH2:18]([O:17][C:15](=[O:16])[NH:14][C@H:11]1[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][C@H:10]1[NH:25][C:26](=[O:40])[C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]2=[O:39])=[CH:31][CH:32]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)c2ccc(-n3ccccc3=O)cc2)C1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CN1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)c2ccc(-n3ccccc3=O)cc2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 54.3 %

Procedure:
Cis-4-Benzyloxycarbonylamino-3-[4-(2-oxo-2H-pyridin-1-yl)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (285 mg, 0.52 mmol) was stirred in TFA (3 mL) and CH2Cl2 (5 mL) at rt for 1.5 h. LC/MS showed completion of the reaction (447.33 (M+H), tR=2.23 min, 10–90% MeOH in H2O with 10 mM NH4OAc in a 4-min run). The solvents were evaporated. Half of the residue (0.26 mmol) was dissolved in CH3CN (2 mL). HCHO (37% wt in H2O, 0.20 mL) was added, followed by the addition of NaCNBH3 (78 mg). The resulting mixture was stirred at rt for 40 min. HOAc was added dropwise to neutralize the mixture. The resulting mixture was stirred for additional 1 h, extracted with EtOAc (3×), dried over MgSO4, filtered, and concentrated to dryness to give crude cis-{1-methyl-3-[4-(2-oxo-2H-pyridin-1-yl)-benzoylamino]-piperidin-4-yl}-carbamic acid benzyl ester (130 mg). Anal. LC/MS (ESI) 461.14 (M+H), tR=2.63 min (10%–90% MeOH in H2O with 10 mM NH4OAc in a 4-min run).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[N:29]=[C:30]([NH:37][C:38]4[CH:43]=[CH:42][C:41]([CH:44]5[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]5)=[CH:40][CH:39]=4)[C:31]4[N:32]([CH:34]=[CH:35][N:36]=4)[CH:33]=3)[C:18]=1[CH2:19][O:20]C(=O)C)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[N:29]=[C:30]([NH:37][C:38]4[CH:43]=[CH:42][C:41]([CH:44]5[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]5)=[CH:40][CH:39]=4)[C:31]4[N:32]([CH:34]=[CH:35][N:36]=4)[CH:33]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCc1c(-c2cn3ccnc3c(Nc3ccc(C4CCN(C)CC4)cc3)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3nc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn4ccnc34)cc2)CC1
Yield: 36 %

Procedure:
A solution of acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{8-[4-(1-methyl-piperidin-4-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzyl ester (150 mg, 0.22 mmol) and K2CO3 (62 mg, 0.44 mmol) in MeOH (15 mL) was stirred at room temperature for 2 hours. The reaction mixture was filtered. The filter cake was washed by MeOH (5 mL) and dried to afford 50 mg of the desired product as a yellow solid (36% yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH:6]([CH3:10])[C:7](Br)=[O:8].[Cl:11][C:12]1[CH:13]=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][CH:17]=1.Cl>ClCCCl>[Br:5][CH:6]([CH3:10])[C:7]([C:17]1[CH:16]=[CH:15][C:14]([O:18][CH3:19])=[CH:13][C:12]=1[Cl:11])=[O:8]
Reactant: COc1cccc(Cl)c1
Reactant: CC(Br)C(=O)Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)C(C)Br)c(Cl)c1
Temperature: 0 °C

Procedure:
To a cooled (0° C.) stirring suspension of aluminum chloride (10.89 g, 82 mmol) in DCE (700 ml) is added 2-bromopropionyl bromide (8.66 ml, 82 mmol) followed by 3-chloroanisol (10 ml, 82 mmol) dropwise (rapidly) maintaining the temperature below 5° C. The reaction mixture is stirred at 0° C. for 10 min and RT for 3 hours. The mixture is poured into ice/water (1000 ml) containing 90 ml of 5M HCl. The organic phase is separated and the aqueous portion is washed with DCM (500 ml). The organic extracts are combined, washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 2.5% incraesing to 5% TBME/Hex increasing up to 5% affords the title product. MS: m/z 278.9 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].C1COCC1.[O:33](C(OC(C)(C)C)=O)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=O>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][N:15]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:33])[C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][CH:21]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc2c(CNc3ccc(N4CCOCC4)cc3)c[nH]c2c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(CN(C(=O)OC(C)(C)C)c3ccc(N4CCOCC4)cc3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 123 (689 mg, 1.89 mmol) in THF (100 ml) Et3N (289 μl, 2.08 mmol) was added dropwise. (BOC)2O was added slowly and the mixture was stirred at room temperature overnight under nitrogen, THF was evaporated off and the residue was partitioned between water and CH2Cl2. Organic layer was separated, dried over MgSO4, evaporated to form another residue which was purified by flash column chromatography (EtOAc/hexane, 7:3) to afford the title compound 124 (692 mg, 79%). 1H-NMR (CDCl3) δ: 8.24 (m, 1H), 8.09 (m, 1H); 7.76 (dd, J=8.2, 1.4 Hz, 1H); 7.55 (d, J=8.8 Hz, 1H); 7.13 (d, J=2.5 Hz, 1H); 6.93 (m, 3H); 4.97 (s, 2H); 3.94 (s, 3H); 3.89 (m, 4H); 3.16 (m, 4H); 1.47 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]#[C:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:24][C:25]#[C:26][CH3:27])=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 89.1 %

Procedure:
A commercially available reagent of ethyl (S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionate (4.84 g, 15.6 mmol) was dissolved in N,N-dimethylformamide (39 mL), and 1-bromo-2-butyne (1.65 mL, 18.8 mmol) and potassium carbonate (3.25 g, 23.5 mmol) were then added at room temperature. After stirring at 60° C. for 6 hours, and the reaction solution was cooled to room temperature. 1-Bromo-2-butyne (0.55 mL, 6.28 mmol) was added at room temperature, and the mixture was then stirred at 60° C. for 5 hours. The reaction solution was cooled to room temperature, and potassium carbonate (0.433 g, 3.13 mmol) was then added. After stirring at 60° C. for 4.5 hours, the reaction solution was cooled to room temperature. Water (70 mL) was added, and the mixture was then extracted twice with ethyl acetate (70 mL). The organic layer was washed with saturated aqueous solution (30 mL) of sodium chloride, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 5.02 g (13.9 mmol, yield 89%) of ethyl (S)-2-tert-butoxycarbonylamino-3-(4-but-2-ynyloxy-phenyl)-propionate.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)(C)C>Cl.O>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(C)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 2-chloro-9-cyclopentyl-7-fluoro-5,7-dimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (obtained above), 4-amino-3-methoxybenzoic acid (585 mg, 3.5 mmol), isopropanol (10 ml), water (5 mL) and concentrated hydrochloric acid (10 drops) was stirred at 100° C. for 20 h. Solid was filtered to give the product as white solid (396 mg). [M+H] calc'd for C22H26FN5O4, 444; found 444.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:15])[N:6]=1)=[O:4].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:34])([CH3:33])[CH2:24][C:25]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH:26]=O)=[C:19]([O:35][CH3:36])[CH:18]=1.C(O)(=O)C.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:15]=[CH:26][C:25]([OH:32])([C:28]([F:29])([F:31])[F:30])[CH2:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[O:35][CH3:36])([CH3:33])[CH3:34])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3ccc(Cl)cc3OC)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 1, 250 mg (1.24 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester is reacted with 484 mg (1.49 mmol) of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 1.40 ml of concentrated acetic acid in 20 ml of toluene. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 500 mg (79% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:12]([C:13]([N:15]2[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:16]2[CH2:21][OH:22])=[O:14])=[C:11]([N+:27]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.CCOC(C)=O>CO>[NH2:27][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:24]([O:25][CH3:26])=[CH:23][C:12]=1[C:13]([N:15]1[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:16]1[CH2:21][OH:22])=[O:14]
Reactant: COc1cc(C(=O)N2C[C@H](O)C[C@H]2CO)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2C[C@H](O)C[C@H]2CO)c(N)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of diol 20 (26 g, 64.6 mmol, 1.0 equiv.) and SnCl2.2H2O (72.9 g, 323 mmol, 5.0 equiv.) in MeOH (300 mL), was heated at reflux and the progress of the reaction monitored by TLC (EtOAc). After 3 h, the MeOH was evaporated in vacuo and the resulting residue was cooled and treated carefully with saturated NaHCO3 (400 mL). The mixture was diluted with EtOAc (800 mL), and after 12 h stirring at room temperature the inorganic precipitate was removed by filtration through celite. The organic layer was separated, washed with brine (100 mL), dried (MgSO4), filtered and evaporated in vacuo to give a brown solid 21 which was used in the next reaction without further purification: [α]29D=−69° (c=0.13, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.70-1.82 (m, 1H, 1-H), 2.06-2.19 (m, 1H, 1-H), 3.52-3.85 (m, 9H, 3-H, 11-H, 7-OMe, 2×OH), 4.26-4.72 (m, 1H, 11a-H), 4.47-4.60 (m, 1H, 2-H), 5.10 (s, 2H, OCH2Ph), 6.26 (s, 1H, 9-H), 6.78 (s, 1H, 6-H), 7.29-7.36 (m, 7H, Ph, NH2); 13C NMR (CDCl3, 100 MHz): δ 37.0, 57.1, 58.5, 59.0, 66.2, 69.4, 70.7, 103.4, 112.4, 112.9, 127.1, 128.0, 128.6, 136.5, 140.0, 141.9, 151.0, 172.8; IR (neat): 3358, 2939, 1619, 1589, 1512, 1455, 1432, 1408, 1263, 1231, 1171, 1113, 1012, 787, 735, 698, 644 cm−1; MS (ES+) m/z (relative intensity) 395 ([M+Na]+., 4), 373 ([M+H]+., 70), 374 ([M+2H]+., 40), 256 (100), 257 (45).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:14]2[C:7]([NH:8][CH:9]=[C:10]2[CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:16](=O)[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].[OH-].[K+].[BH4-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:15]=[C:14]2[C:7](=[CH:6][CH:5]=1)[NH:8][CH:9]=[C:10]2[CH2:11][CH2:12][NH:13][CH2:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[OH:19])([O-:3])=[O:2]
Reactant: NCCc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: O=Cc1ccccc1O
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]cc(CCNCc3ccccc3O)c2c1

Procedure:
5-Nitrotryptamine (6 mmol) and salicylaldehyde (7 mmol) are dissolved in ethanol (35 mL) buffered with potassium hydroxide (0.15 g) and treated with sodium borohydride (18 mmol) 8 h at 24° C. The ethanol is removed in vacuo and the residue partitioned between ether and water, the ether phase dried, evaporated and the oil chromatographed on silica gel with ethyl acetate-hexane to afford 2-{[2-(5-nitro-1H-indol-3-yl)-ethylamino]-methyl}-phenol. After hydrogenation over Pd/C as above, the residue is dissolved in pyridine (12 mL) and treated with methyl chloroformate (9 mmol). A brownish precipitate forms immediately upon addition of the chloroformate, which dissolves during 20 min. After a short time silica gel TLC (5% methanol-chloroform eluent) is performed to judge completion of the reaction. The mixture is evaporated to dryness and maintained at a vacuum of <0.1 mmHg at least 2 h. It is then dissolved in a small amount of methanol, and purified by reverse-phase HPLC with a gradient of water to methanol.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH2:10][CH:11]([OH:20])[CH2:12][O:13]2)=[CH:8][CH:7]=1)=[O:4]>C(Cl)Cl>[CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH2:10][C:11](=[O:20])[CH2:12][O:13]2)=[CH:8][CH:7]=1)=[O:4]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC(O)C2
Solvent: ClCCl
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC(=O)C2
Yield: 66.7 %

Procedure:
1,1,1-Tris-(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess Martin periodinane, 5.65 g) was added to a stirred solution of methyl 7-(2,2-dimethylpropionylamino)-3-hydroxychroman-8-carboxylate (Intermediate 11, 3.41 g) in DCM (50 mL) and the resultant mixture was stirred at room temperature for 5 hours. The resulting solution was washed with a 10% solution of sodium thiosulphate in saturated sodium bicarbonate solution, dried (Na2SO4) and filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-30% to give methyl 7-(2,2-dimethylpropionylamino)-3-oxochroman-8-carboxylate (2.26 g) as an off-white solid.
Reaction SMILES: CC([O:4][C:5]([C:7]1[N:40]=[CH:39][C:10]2[N:11]([CH2:26][C:27]([N:29]([CH3:38])[CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:28])[C:12]3[C:17]([C:9]=2[C:8]=1[CH2:41][O:42][CH3:43])=[CH:16][C:15]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14][CH:13]=3)=[O:6])C.[OH-].[Na+].Cl>CO>[CH2:19]([O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:26][C:27]([N:29]([CH3:38])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:28])[C:10]1[CH:39]=[N:40][C:7]([C:5]([OH:6])=[O:4])=[C:8]([CH2:41][O:42][CH3:43])[C:9]2=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COCc1c(C(=O)OC(C)C)ncc2c1c1cc(OCc3ccccc3)ccc1n2CC(=O)N(C)CCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCc1c(C(=O)O)ncc2c1c1cc(OCc3ccccc3)ccc1n2CC(=O)N(C)CCc1ccccc1
Yield: 76.7 %

Procedure:
211 mg of 6-benzyloxy-4-methoxymethyl-9-{2-[N-methyl-N-(2-phenylethyl)-amino]-2-oxoethyl}-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is mixed in 1 ml of methanol with 0.5 ml of aqueous 2N sodium hydroxide solution and held at 40° C. until the reaction is completed. Then, the reaction mixture is acidified with dilute hydrochloric acid, the precipitated yellow reaction product is suctioned off, washed with water and diethyl ether and dried in a vacuum. 150 mg of 6-benzyloxy-4-methoxymethyl-9-{2-[N-methyl-N-(2-phenylethyl)-amino]-2-oxoethyl}-9H-pyrido[3,4-b]indole-3-carboxylic acid is obtained.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[N:9]=[CH:8][C:7]=1[C:17]#[N:18]>C1COCC1>[CH:1]([O:4][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[N:9]=[CH:8][C:7]=1[C:17]#[N:18])([CH3:3])[CH3:2]
Reactant: Cc1ccc2ncc(C#N)c(Cl)c2n1
Reactant: CC(C)O
Solvent: C1CCOC1
Product: Cc1ccc2ncc(C#N)c(OC(C)C)c2n1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a 50 mL flask placed with KH (30%, 685 mg, 6.0 mmol, pre-washed with nHex) was added a solution of anhydrous isopropanol (0.76 mL, 10.0 mmol) in anhydrous THF (5 mL) at room temperature under argon. The reaction mixture was cooled to −20° C. 4-chloro-6-methyl-[1,5]naphthyridine-3-carbonitrile (407.0 mg, 2.0 mmol) in THF (8 mL) was added dropwise and the reaction mixture was stirred at −20° C. to r.t for 30 min. The reaction mixture was quenched with sat.NH4Cl and extracted with AcOEt (100 mL×3). The combined organic layers was dried over Na2SO4 and concentrated to give the crude product which was purified by flash column (AcOEt/Hex=1/3˜3/2) to give 4-Isopropoxy-6-methyl-[1,5]naphthyridine-3-carbonitrile as white solid (240.0, 52.8%) which was used in the next step without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][C@@H:15]1[CH3:22])[CH2:10][CH2:9]3.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:22][C@@H:15]1[C@@:16]2([CH:17]=[O:18])[C:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:19]2[CH2:20][CH2:21][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C:2]2=[O:1])=[CH:12][C:13](=[O:23])[CH2:14]1
Reactant: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C=O

Procedure:
To a solution of 17β,19-dihydroxy-1α-methyl-4-androsten-3-one in acetone at 20° C. is added 2 equivalents of Jones Reagent with stirring. After 15 minutes the upper acetone layer is decanted and poured onto ice water and stirred for an additional 30 minutes. The precipitate which forms is filtered, washed with water and dissolved in ether. The ether solution is dried over magnesium sulfate and concentrated under reduced pressure. The residue is crystallized from acetone-hexane to yield 1α-methyl-4-androstene-3,17,19-trione.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[C:11]([CH3:22])[C:10]=2[CH3:23])=[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:4][N:3]=1.[Li+].[OH-]>O.O1CCCC1>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:11]([CH3:22])[C:10]=2[CH3:23])=[C:5]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[S:4][N:3]=1
Reactant: CCOC(=O)CCc1ccc(OCc2c(Cl)nsc2-c2ccccc2)c(C)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CCC(=O)O)ccc(OCc2c(Cl)nsc2-c2ccccc2)c1C
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 3-[4-[(3-chloro-5-phenyl-1,2-thiazol-4-yl)methoxy]-2,3-dimethylphenyl]propanoate (105 mg, 0.22 mmol, 1.00 equiv, 90%), a solution of LiOH (105 mg, 4.38 mmol, 19.95 equiv) in water (1 mL), tetrahydrofuran (1 mL). The resulting solution was stirred overnight at 20° C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5 with hydrogen chloride (2 mol/L). The solids were collected by filtration. The resulting mixture was concentrated under vacuum, washed with n-hexane. This resulted in 37 mg (41%) of 3-[4-[(3-chloro-5-phenyl-1,2-thiazol-4-yl)methoxy]-2,3-dimethylphenyl]propanoic acid as a white solid. 1H-NMR (300 MHz, CD3OD) δ 7.52-7.56 (m, 5H), 6.94 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 4.98 (s, 2H), 2.91 (t, J=8.4 Hz, 2H), 2.50 (t, J=7.5 Hz, 2H), 2.22 (s, 3H), 2.07 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H20ClNO3S, 402.0 (M+H). found 402.0.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:17])([F:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]([NH2:15])[CH3:14])=[N:11][CH:12]=1.[CH3:18][C:19]1(C)C(C)(C)OB(C2C=CC(CC(O)=O)=CC=2)[O:20]1.C(Cl)CCl.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:17][C:4]([F:3])([F:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]([NH:15][C:19](=[O:20])[CH3:18])[CH3:14])=[N:11][CH:12]=1
Reactant: C[C@@H](N)c1ccc(OCC(F)(F)F)cn1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)N[C@H](C)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 112.9 %

Procedure:
To a suspension of (R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethylamine bis-HCl (0.75 g, 2.6 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylacetic acid (0.67 g, 2.6 mmol), EDC (0.59 g, 3.1 mmol), and 1-hydroxy-7-azabenzotriazole (0.42 g, 3.1 mmol) in DMF (5 mL) was added diisopropylethylamine (1.8 mL, 10.2 mmol). After stirring for 90 min at room temperature, the reaction mixture was loaded directly onto a silica gel column and purified by normal phase chromatography (20-80% EtOAc/hexanes) to give 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (0.77 g, 65%) as a viscous oil that slowly solidified to a white solid. MS (Electrospray): m/z 465.1 (M+H). To a microwave vial containing 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (50 mg, 0.11 mmol), 8-bromoquinazoline (25 mg, 0.12 mmol), and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.01 mmol) in acetonitrile (1 mL) was added aqueous 1M sodium carbonate (1 mL, 1.0 mmol) and the mixture was heated in a microwave at 150° C. for 10 min. The top organic layer was removed, loaded onto a silica gel column and purified by normal phase chromatography (30-100% EtOAc/hexanes) to give 2-(4-quinazolin-8-ylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (21 mg, 38%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 9.37 (s, 1H), 8.25 (d, J=2.4 Hz, 1H), 7.96 (m, 2H), 7.75 (m, 1H), 7.69 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.22 (m, 2H), 6.79 (d, J=7.2 Hz, 1H), 5.16 (m, 1H), 4.37 (q, J=8.0 Hz, 2H), 3.68 (s, 2H), 1.44 (d, J=6.8 Hz, 3H); MS (Electrospray): m/z 467.1 (M+H). FLIPR alpha1I IP=19 nM.
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14].[Cl-].[NH4+]>O1CCCC1>[C:13]([Si:17]([CH3:20])([CH3:19])[O:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1cccc2[nH]nnc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]nnc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 4-hydroxybenzotriazole (5.000 g) in tetrahydrofuran (250 mL) was added sodium hydride (60%, 0.932 g). The solution was stirred at room temperature for 20 minutes, cooled to 0° C., tert-butyldimethylchlorosilane (5.860 g) was added, the solution was allowed to warm to room temperature, and stirred for 16 hours. Additional sodium hydride (60%, 0.500 g) was added, the solution stirred for 15 minutes, additional tert-butyldimethylchlorosilane (3.000 g) was added, and the solution stirred for three hours at room temperature. The solution was then added to saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography on silica gel using 20-30% ethyl acetate in hexanes.