Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](CS([O-])(=O)=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:17][C:18]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:19]=1[NH2:20].C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:20][C:19]3[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:18]=3[CH3:17])=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: Cc1ccc(C)c(N)c1
Reactant: O=S(=O)([O-])Cc1ccc(-n2cccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1ccc(C)c(Nc2ccc(-n3cccc3)cc2)c1
Temperature: 110 °C
Yield: 105.2 %

Procedure:
Following general procedure A, a mixture of 4-(1H-pyrrol-1-yl)phenylmethanesulfonate (119 mg, 0.5 mmol), 2,5-dimethylaniline (75 μL, 0.6 mmol), K2CO3 (97 mg, 0.7 mmol), 10 (4 mg, 1 mol %), 1 (2.5 mg, 1 mol %), and t-BuOH (6 mL) was heated to 110° C. for 16 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-30% EtOAc/hexanes) to provide the title compound as a white solid (138 mg, 95%), mp 97-98° C. 1H NMR (300 MHz, CDCl3) δ: 7.31 (d, J=9.0 Hz, 2H), 7.14 (d, J=7.5 Hz, 1H), 7.04 (m, 5H), 6.82 (d, J=7.5 Hz, 1H), 6.37 (t, J=2.5 Hz, 2H), 5.40 (s, 1H), 2.33 (s, 3H), 2.27 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 142.4, 141.1, 136.9, 134.4, 131.2, 125.6, 123.3, 122.3, 119.9, 119.8, 118.5, 110.0, 21.5, 17.8 ppm. IR (neat, cm−1): 3386, 2920, 1519, 1310, 1072, 829, 726. Anal. Calcd. for C18H18N2: C, 82.41; H, 6.92. Found: C, 82.03; H, 7.03.
Reaction SMILES: [CH:1]1([C:7]2[S:19][C:10]3[N:11]=[C:12]([CH3:18])[N:13]=[C:14](/[CH:15]=[CH:16]\[OH:17])[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[BH4-].[Na+]>O>[CH:1]1([C:7]2[S:19][C:10]3[N:11]=[C:12]([CH3:18])[N:13]=[C:14]([CH2:15][CH2:16][OH:17])[C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc(/C=C\O)c2cc(C3CCCCC3)sc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc(CCO)c2cc(C3CCCCC3)sc2n1
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
To a mixture of (Z)-2-(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)ethenol (430 mg) and MeOH (10 mL) was added NaBH4 (65 mg) in small divided portions, followed by stirring for 15 minutes. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed sequentially with a saturated aqueous NH4Cl solution and brine, and dried over Na2SO4, and the residue was purified by silica gel column (hexane/EtOAc) to obtain 2-(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)ethanol (315 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]#[C:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: [H][H]
Reactant: Cc1cc(C#CCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1cc(CCCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Yield: 94.3 %

Procedure:
A mixture of 7-methyl-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.076 g, 0.17 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-methyl-5-[3-(4-methyl-piperazin-1-yl)-propyl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.074 g, 95%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.79 (m, 2H), 2.22-2.78 (m, 18H), 4.20 (s, 2H), 4.76 (s, 2H), 7.02 (d, 2H), 7.18 (d, 2H), 7.36 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH2:16])[N:9]=[CH:8][CH:7]=[C:6]2[O:17][C:18]1[C:19]([CH3:28])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.[C:29]([NH:36][C:37]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=NS(C(F)(F)F)(=O)=O)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][C:37]([NH:36][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:9]=[CH:8][CH:7]=[C:6]2[O:17][C:18]1[C:19]([CH3:28])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.9 %

Procedure:
A solution of 2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethylamine (compound 354) (340 mg) in dichloromethane (1 ml) and N,N-dimethylformamide (0.5 ml) were added to 1,3-diboc-2-(trifluoromethylsulfonyl)guanidine (355 mg), and the mixture was stirred at room temperature for 4 hr. The solvent was removed from the reaction solution under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give N-{2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-N′,N″-diboc-guanidine (223 mg, yield 33%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[CH:44][C:45]([N:48]3[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]3)=[N:46][CH:47]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:42]4[CH:43]=[CH:44][C:45]([N:48]5[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]5)=[N:46][CH:47]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:25])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Yield: 69 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (150 mg, 0.286 mmol) was coupled with tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (intermediate 69C) (167 mg, 0.429 mmol) in sodium carbonate (76 mg, 0.715 mmol), Pd(PPh3)2Cl2 (10 mg, 0.014 mmol), DME/water (5/1 mL). This afforded 140 mg (69.0% yield) after purification by column chromatography (60-120 silica gel) using 2% methanol in DCM as eluent. MS: m/z=708.3 (M+1).
Reaction SMILES: Cl.[C:2]1([C:8](C2C=CC=CC=2)=[CH:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:26])[CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:35])C>>[O:35]=[C:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][CH2:12]1
Reactant: CCO
Reactant: O=C1c2ccccc2CN1C1CCN(CC=C(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Product: O=C(CCN1CCC(N2Cc3ccccc3C2=O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
To a solution of Example 2 Part A compound (1.93 g, 8.92 mmol) in dry ethanol (15 mL) at RT was added a solution of Part B compound (1.1 g, 7.43 mmol) in dry ethanol (2 mL). The reaction was stirred at RT for 4 h. The reaction was evaporated to dryness. Ethyl ether (150 mL) was added, and the solution was washed water (2×30 mL), brine (2×30 mL) and dried over MgSO4. Purification was performed by flash chromatography on silica gel (150 g), loaded and eluted with 4% methanol in dichloromethane. Pure fractions were combined and evaporated to give title compound (1.0 g, 37%) as a yellowish solid.
Reaction SMILES: CC(OC([NH:8][CH2:9][CH2:10][N:11]1[CH2:19][CH2:18][CH2:17][C@H:12]1[C:13](OC)=[O:14])=O)(C)C.C(O)(C(F)(F)F)=O>ClCCl.CO>[C:13]1(=[O:14])[NH:8][CH2:9][CH2:10][N:11]2[CH2:19][CH2:18][CH2:17][C@@H:12]12
Reactant: COC(=O)[C@@H]1CCCN1CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCN2CCC[C@@H]12

Procedure:
To a solution of methyl 1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-L-prolinate (D75, 1 g) in dichloromethane (20 ml) was added at r.t. TFA (5 ml) and the reaction mixture was stirred for 1 hr. The mixture was diluted with MeOH and it was filtered trough SCX cartridge. The fractions eluted with methanolic ammonia were evaporated in vacuo keeping the bath temperature at 40° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C[Si](C)(C)N[Si](C)(C)C.[Na].[NH2:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][O:27][C:28]2=O)=[CH:24][CH:23]=1.Cl>CN(C=O)C>[NH2:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][O:27][C:28]2=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:24][CH:23]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: Nc1ccc2c(c1)C(=O)OC2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
To a solution containing oxindole (0.5 g, 3.76 mmol) in 7.5 mL DMF was added 7.51 mL of sodium hexamethyldisilazane (1.0 M in THF) over 3 min. After stirring 10 min at room temperature, a solution of 6-aminophthalide (0.672 g, 4.51 mmol) in 4.0 mL DMF was added over 3 min. The reaction was stirred for 50 min at room temperature and then poured into 4% HCl to give a yellow solid. The solid was filtered to a wet cake and then partitioned between EtOAc and saturated NaHCO3. Then the mixture was heated to dissolve the solid. The organic phase was washed with H2O, brine and then dried with Na2SO4. The solvent was removed in vacuo and the resultant solid triturated with CHCl3 to afford the title compound (445 mg, 45%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[C:18]([CH2:19]Br)=[C:17]([F:21])[C:16]([F:22])=[C:15]([F:23])[C:14]=1[F:24]>>[F:12][C:13]1[C:18]([CH2:19][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[C:17]([F:21])[C:16]([F:22])=[C:15]([F:23])[C:14]=1[F:24]
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: O=C(O)c1cc(NCc2c(F)c(F)c(F)c(F)c2F)ccc1O
Yield: 59.8 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and pentafluorobenzyl bromide (1.02 g, 3.92 mmole), 650 mg (60% yield) of 5-(pentafluorobenzyl)aminosalicylic acid was obtained as a white solid.:mp>190° C. (decompose).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][C:19](=[O:22])[CH2:20][CH3:21])[C:12](=[O:23])[N:11]([CH3:24])[C:10]=3[N:9]=[C:8]2[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH:19]([OH:22])[CH2:20][CH3:21])[C:12](=[O:23])[N:11]([CH3:24])[C:10]=3[N:9]=[C:8]2[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:34])[F:35])[CH:27]=2)=[CH:37][CH:38]=1
Reactant: CCC(=O)CCn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(O)CCn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-1-(3-oxopentyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (150 mg, 0.273 mmol, example 20) in methanol (20 mL) was added sodium borohydride (40 mg, 1.05 mmol) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 2 h. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC to give 7-(4-chlorobenzyl)-1-(3-hydroxypentyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (50 mg, 33.5% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.63-7.58(t, 1H), 7.49(s, 1H), 7.44-7.42(m, 5H), 7.34-7.31(d, 1H), 5.44(s, 2H), 4.48-4.46(d, 1H), 4.08-4.01(m, 1H), 3.89-3.83(m, 1H), 3.42-3.37(m, 1H), 3.29(s, 3H), 1.63-1.55(m, 2H), 1.44-1.31(m, 2H), 0.87-0.84(t, 3H). LCMS retention time 3.372 min; LCMS MH+ 553.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])([F:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].Cl[C:14]1[C:18]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:17][S:16][N:15]=1>O1CCCC1>[F:3][C:4]([F:12])([F:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:14]1[C:18]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:17][S:16][N:15]=1
Reactant: OCCCCCC(F)(F)F
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)CCCCCOc1nsnc1-c1cccnc1
Yield: 31 %

Procedure:
To a mixture of sodium hydride (12.8 mmol) and 6,6,6-trifluoro-1-hexanol (3.0 g, 19.2 mmol) in tetrahydrofuran (40 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)-pyridine (1.3 g, 6.4 mmol). The mixture was refluxed for 36 h and evaporated. After evaporation the residue was dissolved in water then extracted with diethyl ether. The dried organic phases were evaporated and the residue purified by column chromatography (silica gel, eluent: ethyl acetate/hexanes) to yield 630 mg (31%) of the title compound.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[C:16]([SH:20])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([S:20][C:2]2[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH:17]=[CH:18][CH:19]=1
Reactant: Sc1cccc(Cl)c1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2cccc(Cl)c2)s1

Procedure:
Prepared according to the procedure described as in Step B for example 1 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.502 g, 2.45 mmol) and 3-chlorobenzenethiol (0.353 g, 2.45 mmol). The title compound was obtained as a yellow solid (0.476 g, 62% yield). 1H NMR (300 MHz, CDCl3) δ: 8.08 (1H, s), 7.68 (1H, m), 7.45-7.60 (3H, m), 2.49 (3H, s).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:11][O:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15]>C(O)C.C(OCC)(=O)C>[OH:16][C:14]([CH3:17])([CH3:15])[CH2:13][O:12][N:11]=[CH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CC(C)(O)CON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(O)CON=Cc1cccc(Br)n1
Temperature: 25 °C

Procedure:
A solution of 6-bromopyridine-2-carbaldehyde (334 mg, 1.80 mmol) and 1-(aminooxy)-2-methylpropan-2-ol hydrochloride salt (254.6 mg, 1.80 mmol) were stirred in ethanol (5 ml) for one hour at 10° C. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Column chromatography from 100% hexanes to 30% ethyl acetate afforded the title compound as E/Z mixture.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[NH:9][C:10](=O)[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:10]1[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:3])[CH3:1])[C:8]=2[N:9]=1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(=O)[nH]c21
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)n1ncc2c(C(=O)O)cc(Cl)nc21
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
To a 75 mL pressure vessel was added 1-(1-methylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4.12 g, 18.62 mmol), followed by phosphorous oxychloride (26.0 ml, 279 mmol). The flask was sealed and the stirring mixture heated at ca. 105° C. for ca. 18 h. After cooling to room temperature, the contents were concentrated in vacuo to remove most of volatiles. The residual contents were poured into a mixture of ice and 3M NaOH (60 mL), followed by additional 3M NaOH to ensure the pH stayed basic. The mixture was stirred for 30 min., and then cooled in an ice bath. The heterogenous mixture was slowly acidified to pH=3-4 with 6M HCl. The resulting suspension was extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford a yellow solid which was dried in a hi-vac oven overnight. The title compound was collected as 4.11 g (90%), and used without further purification. LCMS E-S (M+H)=240.2/242.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J=6.57 Hz, 6H) 5.17 (quin, J=6.63 Hz, 1H) 7.65 (s, 1H) 8.41 (s, 1H) 14.25 (br. s., 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.Cl>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC=C(C(=O)O)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CC=CC(C(=O)O)C1
Yield: 96.9 %

Procedure:
A solution of 1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid (6.5 g, 28.6 mmol) in dry tetrahydrofuran (150 ml) was added dropwise to a mixture of 2.5 M butyllithium in hexane (25 ml, 62.5 mmol) and diisopropylamine (6.37 g, 63.1 mmol) in dry tetrahydrofuran (150 ml) at <-65° C. Stirring was continued for 20 min. -10°C. The mixture was poured into 1 M aqueous HCl (100 ml) while cooling with ice. The resulting mixture was extracted several times with ethyl acetate (a total of 500 ml). The organic layer was dried over magnesium sulphate and evaporated to dryness in vacuo to give 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid (Yield: 6.3 g, 97%).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:19]2[O:20][CH2:21][C:22](=[O:24])[NH:23][C:18]=2[CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:37]=[CH:38][C:39]([CH2:42][NH2:43])=[N:40][CH:41]=1>C(Cl)Cl>[O:24]=[C:22]1[NH:23][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:13][C:5]([NH:43][CH2:42][C:39]3[CH:38]=[CH:37][C:36]([C:35]([F:45])([F:34])[F:44])=[CH:41][N:40]=3)=[O:11])[C:19]=2[O:20][CH2:21]1
Reactant: NCc1ccc(C(F)(F)F)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccc2c1OCC(=O)N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1COc2c(cccc2NC(=O)NCc2ccc(C(F)(F)F)cn2)N1
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a solution of triphosgene (0.07 g, 0.37 mol eq) in anh. CH2Cl2 (10 mL) was slowly added the amine 1f (0.2 g, 1 mmol) solubilized in CH2Cl2 (10 mL) and DIEA (2.2 mol eq, 0.4 mL). After the addition was completed, the reaction mixture was stirred at room temp. for 15 min. Then the [5-(trifluoromethyl)-2-pyridyl]methanamine (1 mol eq, 0.18 g) solubilized in CH2Cl2 (10 mL) and DIEA (2.2 mol eq, 0.4 mL) was added in one portion. The mixture obtained was stirred at room temp. for 12 h. The solvent was removed at reduced pressure, water was added and the mixture was extracted with EtOAc (3×20 mL). The recombined organic phases were anhydrified over sodium sulfate and evaporated to dryness. The residue was purified by crystallization from EtOAc to obtain the product as yellow solid (0.132 g, 37% Yield). 1HNMR (DMSO, 400 MHz) δ 4.47 (d, 2H, J=6), 4.63 (s, 2H), 6.46 (dd, 1H, J=2), 6.80 (t, 1H, J=8), 7.57 m, 2H), 7.72 (dd, 1H, J=2), 8.18 (dd, 1H, J=2), 8.22 (s, 1H), 8.90 (m, 1H), 10.66 (s, 1H). [M+1] 366.94 (C16H13F3N4O3 requires 366.29).
Reaction SMILES: C([S:8][C:9]1(SCC2C=CC=CC=2)[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C@H:20]([OH:28])[CH2:21][CH2:22]1)[CH2:17][CH2:16]3)C1C=CC=CC=1.N>C1COCC1.CCOCC>[OH:28][C@@H:20]1[CH2:21][CH2:22][C@@:23]2([CH3:24])[C@@H:18]([CH2:17][CH2:16][C@@H:15]3[C@@H:25]2[CH2:26][CH2:27][C@@:10]2([CH3:11])[C@H:12]3[CH2:13][CH2:14][C:9]2=[S:8])[CH2:19]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC2(SCc1ccccc1)SCc1ccccc1
Agent: N
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=S)CC[C@@H]12
Temperature: -78 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
17,17-Bisbenzylthio-5α-androstane-3α-ol (3.76 g, 7.22 mmol) in THF/Et2O (40:100 mL) was added in a dropwise manner to a suspension of Na (3.32 g, 144.4 mmol) in liquid NH3 at −78° C. under N2. The blue suspension was allowed to stir at −78° C. for 3 h. The reaction was then quenched by the addition of saturated NH4Cl (50 mL) and H2O (150 mL). The resulting biphasic mixture was extracted with CH2Cl2 (3×200 mL). The extracts were combined, dried (MgSO4), and concentrated to provide an orange semisolid. The semisolid was purified on silica using medium pressure column chromatography (petroleum ether/acetone, 8:2). The resulting solid was recrystallized from EtOAc/hexane to provide a salmon colored solid (1.06 g, 48%). mp. 172-173° C. 1H-NMR (300 MHz, CDCl3) δ 0.82 (s, 3H), 0.89 (s, 3H), 0.90-1.68 (m, 21H), 1.99-2.03 (m, 2H), 2.59-2.69 (ddd, J=9, 9, 21 Hz, 1H), 2.90-3.00 (dd, J=9, 9 Hz, 1H), 4.06 (m, 1H). Elemental Anal. for C19H30OS Calcd. C, 74.45; H, 9.87; S, 10.46. Found. C, 74.33; H, 10.01; S, 10.47.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N.Cl>N1CCCCC1.O.N1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5](/[CH:7]=[CH:10]/[C:11]([OH:13])=[O:12])[CH:4]=[N:3]1
Reactant: Cn1cc(C=O)cn1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: N
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: Cn1cc(/C=C/C(=O)O)cn1
Temperature: 110 °C
Yield: 41.8 %

Procedure:
A mixture of 1-methyl-1H-pyrazole-4-carbaldehyde (13 g, 118 mmol), malonic acid (12.29 g, 118 mmol), pyridine (65 ml) and piperidine (0.234 ml, 2.361 mmol) was heated to 110° C. under argon for 4 h. After cooling, water (100 ml) was added, followed by aqueous ammonia (12 ml) to obtain a clear solution, which was acidified to pH˜1 with hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to obtain the title compound (7.5 g, 40.5% yield). LCMS: rt=0.92 min, [M+H+]=153