Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:26]=[CH:25][C:16]4[C:17]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([CH3:20])[O:19][C:15]=4[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:33][CH:34](Br)[CH3:35]>CN(C=O)C>[Br:33][CH2:34][CH2:35][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:26]=[CH:25][C:16]4[C:17]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([CH3:20])[O:19][C:15]=4[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(Br)Br
Reactant: COC(=O)c1c(C)oc2cc(Oc3ccnc4cc(O)ccc34)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)oc2cc(Oc3ccnc4cc(OCCBr)ccc34)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a solution of methyl 6-[(7-hydroxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxylate 121-D (2.4 g, 7.2 mmol) in DMF (20 ml) was added K2CO3 (5 g, 35.8 mmol) a dibromoethane (2.7 g, 14.3 mmol). The reaction mixture was stirred at room temperature overnight. Column chromatography gave methyl 6-{[7-(2-bromoethoxy)quinolin-4-yl]oxy}-2-methyl-1-benzofuran-3-carboxylate 121-E (1.5 g). A solution of compound 121-E (750 mg) and pyrrolidine (351 mg) in DMF (3 ml) was heated to 60° C. for 45 min. The reaction mixture was extracted with EtOAc. Methyl 2-methyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy}benzofuran-3-carboxylate 121-F (110 mg) was purified by silica gel chromatography using 5-10% MeOH/CH2Cl2. Compound 121-F (110 mg) was treated with 20% NaOH (1 ml) in MeOH (1 ml) overnight. The reaction mixture was acidified with AcOH and extracted with EtOAc. The residue was purified by silica gel chromatography using 0-10% MeOH in CH2Cl2 to give 2-methyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxylic acid 121-G (100 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11](=[O:21])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([Mg]Br)[CH:26]=[CH:27][CH:28]=1.[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.CO>[Si:1]([O:8][C@H:9]([CH2:10][CH:11]([C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([F:22])[CH:28]=1)[OH:21])[CH2:13][NH:12][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Fc1cccc([Mg]Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@@H](CC(O)c1cccc(F)c1)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-oxopyrrolidine-1-carboxylate (I-1) (13.6 g, 43.2 mmol) in THF (100 mL) at 0° C. under N2 was added (3-fluorophenyl)magnesium bromide (52 mL of 1 M solution in THF, 51.84 mmol) over 1 hour. The reaction mixture was stirred at 0° C. for 1 hour. Methanol (80 mL) was added to the mixture followed by NaBH4 (2.45 g, 64.8 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour then poured into 10% aqueous NH4Cl. The mixture was extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield tert-butyl (2R)-2-(tert-butyldimethylsilyloxy)-4-(3-fluorophenyl)-4-hydroxybutylcarbamate (I-2). 1H NMR (400 MHz, CDCl3) δ 7.33-7.28 (m, 1 H), 7.13-7.09 (m, 2 H), 6.98-6.92 (m, 1 H), 4.97-4.90 (m, 1 H), 4.82 (bs, 1 H), 4.12-4.06 (m, 1 H), 3.42-3.33 (m, 1 H), 3.22-3.17 (m, 1 H), 1.88-1.84 (m, 2 H), 1.47 (s, 9 H), 0.93 (s, 9 H), 0.11 (s, 6 H). MS m/z 436.1 (M+23)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: C1COCCN1
Product: CC(C)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1

Procedure:
Prepared from the product of Example 15 and morpholine.
Reaction SMILES: O[C@@:2]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:25][N:26]([CH3:36])[C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:22])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].C(N(S(F)(F)[F:50])CC)C.C(=O)=O.CC(C)=O>C(Cl)Cl>[F:50][C:2]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:25][N:26]([CH3:36])[C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:22])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8]
Reactant: CCN(CC)S(F)(F)F
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: COCCCCC(F)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Reaction time: 0.08 h
Yield: 79.5 %

Procedure:
To a 50 mL round bottom flask were added 0.0597 g (0.097 mmol, 1.0 equiv) of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate and 5 mL of CH2Cl2. The flask was evacuated and refilled with N2. The mixture was cooled with a dry ice-acetone bath and 0.1860 g (ca. 10 equiv) of (diethylamino)sulfur trifluoride (DAST) was added. After 5 min, the dry ice-acetone bath was replaced by an ice-MeOH bath (−10° C.). After an additional hour, the reaction mixture was quenched with 10% Na2CO3 (10 mL), extracted three times with Et2O, and dried over Na2SO4. The crude product was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 15 min, flow rate 25 mL/min) to give 0.0478 g (80%) of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-(1-fluoro-5-methoxy-1-phenylpentyl)-piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate. LC-MS tR=2.59 min in 3 min chromatography, m/z 642 (M+Na+), 620 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.83 (br s, 1H), 7.36-7.19 (m, 5H), 5.42 (br s, 0.69H), 5.00 (br s, 0.31; H), 4.39-4.36 (m, 1H), 4.14-4.03 (m, 3H), 3.72-3.46 (m, 2H), 3.28-3.24 (m, 5H), 2.94-2.86 (m, 4H), 2.62-2.40 (m, 2H), 2.11-0.81 (m, 25H), 0.03 and −0.01 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.4, 157.8, 141.3, 141.0, 128.2, 128.1, 127.3, 126.9, 124.7, 124.6, 101.3, 99.5, 72.52, 72.46, 63.9, 63.8, 58.4, 58.3, 52.7, 52.6, 47.9, 47.6, 45.0, 44.82, 44.77, 44.6, 41.3, 41.1, 37.1, 36.9, 34.7, 34.6, 34.4, 34.3, 33.5, 33.4, 33.2, 29.6, 29.5, 26.4, 26.2, 26.13, 26.09, 25.1, 25.0, 24.6, 19.8, 17.7, −1.6.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH:13]([NH2:16])([CH3:15])[CH3:14]>O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:16][CH:13]([CH3:15])[CH3:14])=[O:4]
Reactant: CC(C)N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: O
Product: CC(C)NC(=O)c1ccccc1N
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A round-bottomed flask was charged with isatoic anhydride (5.0 g, 0.030 mol) and 30 mL water. Isopropylamine (4.64 mL, 0.049 mol) was added slowly to the reaction mixture. The product precipitated from the reaction mixture. After 1 h, the reaction mixture was filtered and washed with water to give 4.12 g (71% yield) of a white solid
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.ClC1C2N(C(CCC)=NN=2)C2C(N=1)=CC=CC=2.C1(N)CCCC1>>[CH:17]1([NH:23][C:2]2[C:3]3[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Reactant: NC1CCCCC1
Agent: CCCc1nnc2c(Cl)nc3ccccc3n12
Agent: NC1CCCC1
Product: CCc1nnc2c(NC3CCCCC3)nc3ccccc3n12

Procedure:
The title compound was prepared essentially as described in Example 4 substituting 4-chloro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline and cyclohexanamine for 4-chloro-1-propyl[1,2,4]triazolo [4,3-a]quinoxaline and cyclopentanamine respectively; mp 217°-220° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[N:6][N:7]=1.[Na].[NH2:10][C:11]1[NH:15][N:14]=[N:13][N:12]=1>C(#N)C>[NH:12]1[C:11]([NH:10][C:2]2[N:3]=[N:4][C:5]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[N:6][N:7]=2)=[N:15][N:14]=[N:13]1
Reactant: Nc1nnn[nH]1
Reactant: Clc1nnc(Cl)nn1
Agent: [Na]
Solvent: CC#N
Product: n1n[nH]c(Nc2nnc(Nc3nnn[nH]3)nn2)n1
Temperature: 25 °C

Procedure:
To a solution of 3,6-dichloro-1,2,4,5-tetrazine (1.51 g, 10 mmol) in acetonitrile (70 ml) was added the sodium salt of 5-amino-1H-tetrazole (2.14 g, 10 mmol). The mixture was refluxed for 24 hours then allowed to cool to room temperature. The suspension was centrifuged until the supernatant liquid was clear. The liquid was decanted and the brown solid washed successively with acetonitrile and water. With each wash the solid was separated from the solvent by centrifugation followed by decantation. The isolated crude yield was 1.5 g (60%), this material was recrystallized from DMSO/methanol yielding an orange brown powder mp 264° C. dec; 1H NMR(deuteriomethylsulfoxide) ∂ 12.5(b,r s,4H); 13 C NMR (deuteriomethylsulfoxide) ∂ 151.74, 158.25; IR (KBr) 3421, 3000, 1615, 1436, 1127 cm−1.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:15]([NH:18][C:19](=[O:22])[CH:20]=[CH2:21])[CH2:16][CH3:17].Cl>>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][N:11]([CH2:21][CH2:20][C:19]([NH:18][CH2:15][CH2:16][CH3:17])=[O:22])[CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CC1=C2CCNCC2c2ccccc21
Reactant: C=CC(=O)NCCC
Agent: Cl
Product: CCCNC(=O)CCN1CCC2=C(C)c3ccccc3C2C1

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and N-propyl acrylamide are reacted in accordance with the process described in Example 6. Reaction period 20 hours. M.P. of the hydrochloride of the title compound 196°-197° from ethanol (decomp.).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH3:16])[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][CH:11]=[O:12])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.[CH3:23][Mg]Br.C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1>[Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH3:16])[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][C:11](=[O:12])[CH3:23])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: CCN(C(=O)C(C)CC=O)c1cn(-c2cccnc2)nc1Cl
Reactant: C[Mg]Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)C(C)CC(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-4-oxobutanamide (0.390 g, 1.22 mmol) was dissolved in THF (12 mL) at −78° C. To this stirring solution was added dropwise methylmagnesium bromide (0.446 mL, 1.34 mmol). The reaction mixture was stirred at −78° C. for 30 minutes and was warmed to 0° C., at which point the reaction was quenched with a saturated aqueous NH4Cl solution. The reaction product was extracted with diethyl ether, and the combined organics were washed with brine, then dried over Na2SO4 and concentrated under vacuum to provide a yellow oil. The oil was loaded onto CELITE® and purified by flash column chromatography using 0-50% acetone/hexanes as eluent. The secondary alcohol recovered as an impure oil was used immediately. The residual oil was taken up in CH2Cl2 (10 mL) and buffered with NaHCO3 (0.153 g, 1.82 mmol). The resulting mixture was cooled to 0° C. and Dess-Martin periodinane (0.516 g, 1.22 mmol) was added in a single portion. The reaction mixture was stirred at 0° C. for 1 hour, then was warmed to room temperature. The reaction was quenched by slow addition of a saturated aqueous sodium bisulfite solution, and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and concentrated to an oil that was loaded directly onto CELITE®. Purification by flash column chromatography using 0-40% acetone/hexanes as eluent provided the title compound as a clear, colorless oil. (0.0900 g, 20% over two steps).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10]([NH2:12])=[O:11])=[C:4]([F:13])[CH:3]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH:9]([C:5]1[C:4]([F:13])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[F:8])[C:10]([NH2:12])=[O:11]
Reactant: NC(=O)Cc1c(F)cc(Br)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: NC(=O)C(Br)c1c(F)cc(Br)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
A solution of 2-(4-bromo-2,6-difluorophenyl)acetamide (0.4 g, 1.6 mmol) in carbon tetrachloride (5 mL) was degassed with nitrogen for 5 min. To this was added N-bromosuccinimide (0.28 g, 1.6 mmol) and then azobisisobutyronitrile (0.039 g, 0.24 mmol) while stirring. The reaction mixture was stirred at 80° C. overnight and then cooled to room temperature. The reaction mixture was concentrated to dryness in vacuo, and the residue was purified by flash chromatography (0-100% ethyl acetate/hexanes) to afford the title product (60 mg, 11%). MS(ES)+ m/e 328 [M+H]+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:27]=[C:26]4[C:22]([C:23](=[O:30])[N:24]([CH3:29])[N:25]4[CH3:28])=[CH:21][CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:27]=[C:26]4[C:22]([C:23](=[O:30])[N:24]([CH3:29])[N:25]4[CH3:28])=[CH:21][CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(=O)n(C)n(C)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccc4c(=O)n(C)n(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,2-dimethyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (27.2 mg, 0.047 mmol) in THF (1.0 mL) and methanol (1.0 mL) was added 1N NaOH solution (0.5 mL, excess). The reaction mixture was stirred at 50° C. for 2 h and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H29ClN3O4S: 550.2; found: 550.2. 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.96 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.93 (dd, J=8.0, 0.8 Hz, 2H), 7.55-7.49 (m, 3H), 5.33 (s, 1H), 3.50 (s, 3H), 3.39 (s, 3H), 2.60 (s, 3H), 1.01 (s, 9H).
Reaction SMILES: [OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C:4]1[C:5]([CH2:22]SCC2C=CC(OC)=CC=2)=[C:6]([OH:21])[C:7]([CH2:10]SCC2C=CC(OC)=CC=2)=[CH:8][CH:9]=1>CCO>[OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C:4]1[C:5]([CH3:22])=[C:6]([OH:21])[C:7]([CH3:10])=[CH:8][CH:9]=1
Reactant: COc1ccc(CSCc2ccc(CC(C)(C)O)c(CSCc3ccc(OC)cc3)c2O)cc1
Solvent: CCO
Product: Cc1ccc(CC(C)(C)O)c(C)c1O
Yield: 83.5 %

Procedure:
Raney nickel (RaNi, ca. 20 g) is washed five times with water and twice with anhydrous EtOH. A slurry of this catalyst in EtOH is then added to a solution of bis(sulfide) 37 (3.01 g, 6.04 mmol) in EtOH (30 mL). The resulting mixture is heated at vigorous reflux under N2 for 2 h, then cooled. The supernatant is decanted, and the catalyst is washed successively with MeOH and EtOAc (2×). The decanted organic layers are combined and evaporated. The residue is purified by FC (10:1, CH2Cl2 /iPrOH) to give 33 as a pale yellow oil (0.98 g, 84%) . 1H NMR (CDCl3) 6.94 (d, 1, J=7.7), 6.72 (d, 1, J=7.7), 2.81 (s, 2), 2.24 (s, 6), 1.24 (s, 6); 13C NMR (CDCl3) 152.44, 135.06, 127.42, 123.42, 122.91, 120.95, 71.59, 45.68, 29.41, 15.87, 12.76; MS (MW=194.3, CI/CH4, eE=70 eV) m/z 195 (M+H)+, 177 (base peak), 175, 149, 136, 91, 79.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].S(OC)(O[CH3:29])(=O)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:29][O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a 1-L 3-neck round bottom flask equipped with a magnetic stirrer, nitrogen inlet and thermocouple is added (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid (I, 40 g, 0.133 moles, 1 equivalent) followed by THF (240 mL). Lithium hydroxide monohydrate (5.6 g, 0.133 moles, 1 equivalent) is added in a single portion and is allowed to stir for 30 min at which time, the contents are cooled to 0°. Once cooled, dimethyl sulfate (12.6 mL, 0.133 moles, 1 equivalent) is added dropwise via syringe and then stirred for 30 min. The mixture is then heated to about 50° and monitored (by HPLC) until 90% conversion had been achieved. At that time, the mixture is cooled to below 20° (solids form). The mixture is then poured into sodium bicarbonate (200 mL), stirred for 15 min then extracted with methyl t-butyl ether (200 mL). The phases are separated and the aqueous layer is extracted with methyl t-butyl ether (2×200 mL). The combined organic phases are washed with water (400 mL) dried over sodium sulfate, filtered and concentrated under reduced pressure to give a solid. This material is then recrystallized from hexanes to give the title compound, NMR (DMSO-d6) δ 7.51, 7.15–7.25, 4.43, 3.81, 3.00–3.26 and 1.49; CMR (DMSO-d6) δ 172.43, 163.74, 161.20, 155.67, 142.58, 112.70, 120.23, 78.69, 54.71, 52.24, 39.25 and 28.37.
Reaction SMILES: C(O[C:4](=[O:10])[CH2:5][CH2:6][O:7][CH2:8][CH3:9])C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:21]1([NH:26][C:27]2[C:32]([CH:33]=O)=[CH:31][N:30]=[C:29]([S:35][CH3:36])[N:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1.C(OCC)(=O)C.O>[CH:21]1([N:26]2[C:27]3[N:28]=[C:29]([S:35][CH3:36])[N:30]=[CH:31][C:32]=3[CH:33]=[C:5]([CH2:6][O:7][CH2:8][CH3:9])[C:4]2=[O:10])[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCOCCC(=O)OCC
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 34.9 %

Procedure:
3-Ethoxy-propionic acid ethyl ester (12.31 g, 84.2 mmol) was dissolved in tetrahydrofuran (40 mL) to which LiHMDS (89 mL, 88.9 mmol, 1.0 M in THF) was slowly added. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (10.0 g, 42.2 mmol) was then added neat and the reaction mixture was stirred at ambient temperature for 17 hours then brought to reflux for 7 hours. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the organic layer dried over MgSO4 and the solvent evaporated to give a crude oil. The crude product was dissolved in ethyl acetate and diluted with hexanes to give a precipitate, which was collected by filtration to give 8-cyclopentyl-6-ethoxymethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid (4.70 g, 34.9%).1H NMR δ(400 MHz, CDCl3) 8.47 (s, 1H), 7.52 (t, J=1.5 Hz, 1H), 5.82 (m, 1H), 4.32 (d, J=1.7 Hz, 1H), 3.53 (q, J=7.1 Hz, 2H), 2.47 (s, 3H), 2.17 (m, 2H), 1.93 (m, 2H), 1.73 (m, 2H), 1.54 (m, 2H), 1.15 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:14][C:15]1([CH3:31])[CH2:24][CH2:23][C:22]2[N:21]=[CH:20][C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18](O)[C:17]=2[CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[CH2:7]([O:14][C:15]1([CH3:31])[CH2:24][CH2:23][C:22]2[N:21]=[CH:20][C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]([Cl:4])[C:17]=2[CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cnc2c(c1O)CC(C)(OCc1ccccc1)CC2
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(c1Cl)CC(C)(OCc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (5.2 g) is added to 200 mL of DMF dropwise under stirring and cooling keeping the temperature below -20°. Stirring is continued for 0.5 hour at the same temperature. To the mixture 7.0 g of ethyl 6-benzyloxy-4-hydroxy-6-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate is added in small portions and stirring is continued for 2 hours at -30° to -20°, then at room temperature overnight. The mixture is evaporated to dryness and the residue is taken up in CH2Cl2, washed with sat. NaHCO3, dried (MgSO4) and evaporated to dryness to an oil which is chromatographed on silica gel to yield ethyl 6-benzyloxy-4-chloro-6-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate.
Reaction SMILES: [C:1]1([OH:9])[CH:8]=[C:6]([CH3:7])[CH:5]=[C:3]([OH:4])[CH:2]=1.C(N(CC)C(C)C)(C)C.[C:19]1([CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)C.ClCCl>C(OCC)C>[CH3:7][C:6]1[CH:8]=[C:1]([O:9][S:26]([CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:28])=[O:27])[CH:2]=[C:3]([OH:4])[CH:5]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1cc(O)cc(O)c1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(O)cc(OS(=O)(=O)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of 2.0 g (16.1 mmol) of orcinol in diethyl ether (100 mL) containing 10 mL of N,N-diisopropylethylamine was added in a slow steady stream 3.05 g (16 mmol) of α-toluenesulfonyl chloride in a solution of 1:1 diethyl ether/dichloromethane (ca. 30 mL). The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was quenched with 10% hydrochloric acid, extracted into diethyl ether, dried (MgSO4), and purified by flash chromatography (dichloromethane/diethyl ether (100:0 to 95:5 to 90:10)) to give 848 mg of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.37-7.48 (m, 5H), 6.56-6.57 (m, 1H), 6.51-6.52 (m, 1H), 6.43 (t, 1H, J=2 Hz), 5.21 (s, 1H), 4.50 (s, 2H), 2.26 (s, 3H).