Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]([OH:42])[CH2:39][CH:40]=[O:41])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].CO.[BH4-].[Na+]>O1CCOCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]([OH:42])[CH2:39][CH2:40][OH:41])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCCCCC(O)CC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCCCCC(O)CCO)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
In a 100 mL round-bottomed flask was 12-(Cholest-5-en-3β-oxy)-3-hydroxydodecanal (1.90 g, 3.25 mmol) dissolved in 1,4-Dioxane (10 ml) to give a colorless solution. MeOH (5 ml) was added slowly and only enough was added to keep the aldehyde in solution. SODIUM BOROHYDRIDE (0.184 g, 4.87 mmol) was added to the stirring solution which was then allowed to stir for 2 hours at room temperature. The reaction mixture was quenched by addition of 1N HCl (2 mL). The mixture was diluted to 100 mL with water and extracted with ethyl acetate (3×50 mL). The organic phase was combined, washed with brine (1×50 mL), dried over Na2SO4, filtered and concentrated to give 12-(Cholest-5-en-3β-oxy)dodecan-1,3-diol (1.85 g, 3.15 mmol, 97% yield) as a colorless wax. 1H NMR (300 MHz, CDCl3) δ0.69 (3H, s); 0.83-2.07 (58H, m); 2.13-2.28 (1H, m); 2.32-2.43 (1H, m); 3.14 (1H, tt, J=11.2, 4.4 Hz); 3.46 (2H, t, J=6.8 Hz); 3.60-4.19 (3H, m); 5.36 (1H, d, J=5.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]#[N:16].[NH2:17][OH:18]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([NH:17][OH:18])=[NH:16]
Reactant: N#CCc1ccccc1-c1ccccc1Cl
Reactant: NO
Solvent: CCO
Product: N=C(Cc1ccccc1-c1ccccc1Cl)NO
Temperature: 60 °C
Yield: 91.7 %

Procedure:
To a stirred solution of (2′-chloro-biphenyl-2-yl)-acetonitrile (15) (2 g, 8.78 mmol) in ethanol (20 mL) was added aqueous hydroxylamine (50%) (1.16 g, 17.8). The mixture was heated to 60° C. for 16 h. After completion of the reaction, the reaction mixture was evaporated, extracted with ethyl acetate and concentrated to get 2-(2′-chloro-biphenyl-2-yl)-N-hydroxy-acetamidine (16) (2.1 g, 91.7%) as an off-white solid which was directly used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]=[C:8]=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14]2[S:25][C:24]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][C:15]=2[N:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:12][C:13]2[C:14]3[S:25][C:24]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][C:15]=3[N:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: CCOC(=O)n1nc(N)c2sc(C(=O)OC)cc21
Reactant: O=C=NCc1ccc(F)cc1
Solvent: ClCCl
Product: CCOC(=O)n1nc(NC(=O)NCc2ccc(F)cc2)c2sc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 59.5 %

Procedure:
4-Fluorobenzylisocyanate (0.130 ml, 1.02 mmol) was added to a solution of 1-ethyl 5-methyl 3-amino-1H-thieno[3,2-c]pyrazole-1,5-dicarboxylate (85 mg, 0.32 mmol) in anhydrous dichloromethane (5 ml). After stirring for 96 h at room temperature, the solvent was removed under reduced pressure, and the residue purified by chromatography over silica gel (eluent dichloromethane 50; methyl alcohol 0.5; 6% aqueous ammonia 0.1) to yield 80 mg of the title compound as a white solid. Chromatographic method A, Rt 6.11, [M+H]+ 621.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.[Cl:18][C:19]1[CH:30]=[C:29]([Cl:31])[C:28]([OH:32])=[CH:27][C:20]=1[O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:26][O:25][C:23](=[O:24])[CH2:22][O:21][C:20]1[CH:27]=[C:28]([O:32][CH2:4][CH:2]2[CH2:3][O:1]2)[C:29]([Cl:31])=[CH:30][C:19]=1[Cl:18]
Reactant: COC(=O)COc1cc(O)c(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(OCC2CO2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
A mixture of (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (0.4 g), methyl (2,4-dichloro-5-hydroxyphenoxy)acetate (0.39 g) and Cs2CO3 (0.58 g) in DMF (2 ml) was stirred at r.t. overnight. Water was added and (2,4-dichloro-5-oxiranylmethoxy-phenoxy)-acetic acid methyl ester (0.22 g) was isolated by filtration and dried in vacuo. 5-Chloro-3H-spiro[1-benzofuran-2,4′-piperidine] (0.16 g) in ethanol (5 ml) was added and heated at 70° C. for 2 h. The mixture was allowed to cool and water (1 ml) followed by LiOH (2 eq) was added. Stirred for 3 h. RPHPLC (Xterra, gradient 95-5%, ammonia (0.2% aq.): acetonitrile) gave the title compound (0.1 g) as a white solid.
Reaction SMILES: [C:1]([C:3]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:17]=1)([CH2:10][CH2:11][C:12]([O:14]C)=O)[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:2].[H-].[Na+].O>COCCOC>[C:6]([CH:5]1[CH2:4][C:3]([C:1]#[N:2])([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:17]=2)[CH2:10][CH2:11][C:12]1=[O:14])([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c(OC2CCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)C1CC(C#N)(c2ccc(OC)c(OC3CCCC3)c2)CCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
To a solution of dimethyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)pimelate (5.9 g, 14.6 mmol) in dry 1,2-dimethoxyethane (120 mL) under an argon atmosphere was added sodium hydride (80% suspension in mineral oil, 1.05 g, 43.8 mmol). The mixture was heated to reflux for 4.5 h, then was cooled to room temperature and was stirred for 16 h. Water was added and the reaction mixture was partitioned between ether and acidic water. The organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, to provide a white foam (4.9 g, 93%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.F[C:12]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOCCOC.CCOCC>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][C:12]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:13]=3[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: COC(=O)c1ccc(F)cc1Oc1ccc2[nH]ccc2c1
Reaction time: 24 h

Procedure:
A mixture of 5-hydroxyindole (8.5 g), methyl 2,4-difluorobenzoate (7.05 g), and K3PO4 (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24 hours. The reaction was cooled, diluted with ether (600 mL), and washed twice with water, and brine, and concentrated. The crude product was chromatographed on silica gel with 2-50% ethyl acetate/hexanes.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([CH2:14][CH2:15][CH:16]=O)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]1([CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][N:26]3[CH2:25][CH2:24][N:23]([CH2:22][C:21]4[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=4[C:19]([F:33])([F:34])[F:18])[CH2:28][CH2:27]3)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCc1cc(C=Cc2ccccc2)no1
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1CN1CCN(CCCc2cc(C=Cc3ccccc3)no2)CC1
Yield: 76.8 %

Procedure:
About 2 min after dissolving 3-[3-(2-phenylvinyl)isoxazol-5-yl]propanal (10 mg, 0.05 mmol) and 1-[2-(trifluoromethyl)benyl]piperazine (9.2, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (28 mg, 0.13 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 16.4 hr and followed the same processes as in Example 1 to obtain 14 mg (69.8%) of the target compound.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[Cl:10])#[N:2].[O:11]1[CH2:13][C@@H:12]1[CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25]>CC(O)C>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:13][C@@H:12]([OH:11])[CH2:14][N:15]2[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]2=[O:24])=[CH:5][C:4]=1[Cl:10])#[N:2]
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: N#Cc1ccc(N)cc1Cl
Solvent: CC(C)O
Product: N#Cc1ccc(NC[C@@H](O)CN2C(=O)c3ccccc3C2=O)cc1Cl
Yield: 42.9 %

Procedure:
According to the same procedure as Preparation Example 1, 4-cyano-3-chloroaniline (VI-d) (3.00 g, 19.66 mmol) and 2-(((S)-oxiran-2-yl)methyl)isoindoline-1,3-dione (III) (4.66 g, 20.64 mmol) were stirred under reflux in 2-propylalcohol to obtain the title compound (VII-d) (3.00 g, 8.43 mmol, 43%) as yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:32][O:31][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:37]1[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCN1CCN(C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (50 mg), 4-methylpiperazine (33 mg), and potassium carbonate (76 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (29 mg, yield 52%).
Reaction SMILES: [CH3:1][C:2]([CH3:32])=[CH:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=3[CH:19]=2)=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8]C)=[O:7].[OH-].[Na+]>O.CCO>[CH3:1][C:2]([CH3:32])=[CH:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=3[CH:19]=2)=[CH:12][CH:11]=1)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)C[C@H](C=C(C)C)c1ccc(OCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)=C[C@@H](CC(=O)O)c1ccc(OCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of compound 33.2 (0.15 mmol) and sodium hydroxide (0.8 mmol) in water (1 mL) and EtOH (3 mL) is stirred at room temperature overnight. EtOH is removed under reduced pressure, and the remaining solution acidified with 1N HCl to pH 3-5 and then diluted with EtOAc (70 mL), washed with saturated brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography (silica gel; 1:9 MeOH/DCM) to yield compound 33.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[CH2:12][OH:13].[CH3:14][N:15](CCN(C)C)C>CN(C=O)C.[C-]#N.[C-]#N.[Zn+2]>[OH:13][CH2:12][CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([C:14]#[N:15])[C:3]=2[CH2:4][CH2:5][O:6]1
Reactant: CN(C)CCN(C)C
Reactant: OCC1OCCc2c(Br)cccc21
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1CCOC2CO

Procedure:
A mixture of (5-bromo-3,4-dihydro-1H-isochromen-1-yl)methanol (390 mg, 1.6 mmol), Zn(CN)2 (113 mg, 0.960 mmol), TMEDA (0.37 mg), xantphose (4.6 mg) and Pd(dba)3 (2.6 mg) in anhydrous DMF was microwaved 10 min at 100° C. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was purified with prep-HPLC to give 1-(hydroxymethyl)-3,4-dihydro-1H-isochromene-5-carbonitrile. 1H-NMR (400 MHz, CDCl3) δ: 7.49˜7.50 (m, 1H), 7.24˜7.48 (m, 2H), 4.76˜14.78 (m, 1H), 4.17˜4.22 (m, 1H), 3.76˜3.95 (m, 3H), 3.01˜3.09 (m, 1H), 2.89˜2.95 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[N:9]=2)=[CH:4][CH:3]=1.B.CSC>O1CCCC1>[NH2:15][CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[N:9]=1
Reactant: N#Cc1cccc(-c2ccc(Br)cc2)n1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: NCc1cccc(-c2ccc(Br)cc2)n1

Procedure:
To a refluxing solution of 1.6 g of 2-(p-bromophenyl)-6-cyano pyridine in 8 ml of tetrahydrofuran is added slowly a solution of 0.92 ml of borane-dimethylsulfide in 6 ml. of tetrahydrofuran. Dimethyl sulfide is simultaneously removed by distillation through a 10 cm vigreux column. The mixture is refluxed for 15 minutes after the addition is complete, cooled to 30°, and 6 ml of 6N hydrochloric acid is added. After hydrogen evolution has ceased, the reaction is refluxed for 30 minutes, cooled to 0°, saturated with solid sodium carbonate and extracted with 4×50 ml aliquots of methylene chloride. The methylene chloride solution is evaporated and the residue is chromatographed through 10.0 g of silica gel with 1:1 methanol-ethyl acetate as eluent to yield 2-aminomethyl-6-(p-bromophenyl)pyridine melting at 71°-75°.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[NH:33][CH:34]=[CH:35][C:28]=12.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]3[NH:33][CH:34]=[CH:35][C:28]=23)[C:5]([C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: Brc1ccnc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.5 mmol), 4-bromo-1H-pyrrolo[2,3-b]pyridine (Ref. Org. Lett. 5(26), 5023-5024, 2003) (6.3 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.25 mmol) in a 1:1 solution of 1,4-dioxane (12 mL):2M potassium carbonate (12 mL) was stirred for 18 h at 100° C. in a sealed tube. Upon cooling to room temperature, product precipitated out of solution which was filtered and dried to provide the title product as a light yellow powder (80%). ESMS [M+H]+: 334.2
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:36][C:37]([NH:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])=[O:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:43][N:42]([CH3:44])[CH2:41][CH2:40][NH:39][C:37](=[O:38])[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCNC(=O)CCl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Reaction time: 16 h

Procedure:
A suspension of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (80 mg, 0.18 mmol), 2-chloro-N-(2-(dimethylamino)-ethyl)acetamide (40 mg, 0.25 mmol), K2CO3 (162 mg, 1.17 mmol), in DMF (5 mL). Stirred at RT for 4 h upon which 2 equivalents each of 2-chloro-N-(2-(dimethylamino)-ethyl)acetamide and K2CO3 were added. Continued to stir for 16 h. Concentrated in vacuo to afford the crude tert-butyl 5-(2-(3-(2-(2-(dimethylamino)-ethylamino)-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.18 mmol).
Reaction SMILES: Cl[CH:2]([SiH:4]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:5])[CH3:3].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>>[CH2:8]([CH2:7][CH2:6][SiH:4]([CH3:5])[CH:2]([N:19]1[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25])[CH3:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(Cl)[SiH](C)CCCc1ccccc1
Agent: [K]
Product: CC(N1C(=O)c2ccccc2C1=O)[SiH](C)CCCc1ccccc1

Procedure:
The title compound was prepared from (α-chloroethyl)benzylethylmethylsilane and potassium phthalimide by a procedure similar to the one described in Example 1, Step A.
Reaction SMILES: C([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][CH2:16][CH:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:11]([F:32])[CH2:10]1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[Si:19]([O:18][CH:17]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:16][O:15][CH:12]1[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH:11]1[F:32])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OC(COC1CCC(OCc2ccccc2)CC1F)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(COC1CCC(O)CC1F)c1ccccc1
Yield: 92.9 %

Procedure:
To a solution of (2-{[4-(Benzyloxy)-2-fluorocyclohexyl]oxy}-1-phenylethoxy)(tert-butyl)dimethylsilane (11.3 g, 24.7 mmol) in ethyl acetate (200 mL) was added 10% Pd/C (1.0 g) at room temperature. The reaction mixture was stirred under balloon pressure hydrogen for 4 h, filtered and concentrated. Purification by silica gel chromatography (hexane: ethyl acetate 60:40) gave 4-(2-{[tert-Butyl(dimethyl)silyl]oxy}-2-phenylethoxy)-3-fluorocyclohexanol (8.46 g, 93% yield) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@:28]4([CH3:35])[CH2:32][O:31]C(C)(C)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:36]>CCO>[ClH:36].[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@:28]([OH:29])([CH3:35])[CH2:32][OH:31])[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@]2(C)COC(C)(C)O2)ns1
Agent: Cl
Solvent: CCO
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@](C)(O)CO)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
(R)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,4-trimethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine (65 mg, 0.128 mmol) was dissolved in EtOH (3 mL) and 1M HCl (0.3 mL) was added. The mixture was stirred at ambient temperature for 24 hours. Additional 1M HCl (0.3 mL) was added and the mixture was stirred overnight. The mixture was partitioned between saturated aqueous sodium bicarbonate and CH2Cl2, and the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (15% methanol in EtOAc) to afford (R)-2-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol hydrochloride (42.6 mg, 0.0844 mmol, 66.0% yield) as a white solid after HCl salt formation. Mass Spectrum (apci) m/z=469.1 (M+H—HCl).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH:11]=[O:12])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22]=1)#[N:20].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:11]([C:9]1[N:10]=[C:6]2[C:5]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:4][CH:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[N:22][CH:23]=3)[N:7]2[CH:8]=1)=[O:12]
Reactant: O=Cc1cn2c(Br)cnc(N3CCOCC3)c2n1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(C=O)cn23)cn1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Compound 2a (156 mg, 0.500 mmol), 2-cyanopyridine-5-boronic acid pinacol ester (230 mg, 1.00 mmol), and PdCl2(dppf).DCM (40.8 mg, 0.0500 mmol), were placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with Argon gas. Dry DME (4 mL) and 2M Na2CO3 (2 mL) were added sequentially and then the reaction was stirred at 90° C. for 3 h. The reaction was cooled to rt and diluted with DCM (10 mL). The mixture was dried through a Na2SO4 pre-packed cartridge and then the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (40-g SiO2 pre-packed column, 0-100% EtOAc/DCM) to afford compound 75a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 10.08 (s, 1H), 8.93 (s, 1H), 8.17 (s, 1H), 8.02-8.10 (m, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.49 (s, 1H), 4.47 (br. s., 4H), 3.90 (t, J=4.6 Hz, 4H). LCMS calcd for C17H14N6O2: 335.1 (M+H). found: 335.1.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C([N-]C(C)C)(C)C.[Li+].[C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])[CH:28]=[CH2:29]>O1CCCC1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]([F:18])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:29][CH2:28][C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(F)N1C(=O)c2ccccc2C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(CCC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of ethyl 2-(1,3-dioxoisoindolin-2-yl)-2-fluoroacetate (0.80 g, 3.2 mmol) in tetrahydrofuran (30 mL) is added lithium diisopropylamide (1.7 mL, 3.4 mmol, 2 M) at -78° C. After 30 minutes, t-butyl acrylate (0.42 g, 3.2 mmol) is added to the mixture which is allowed to reach room temperature. The solvent is removed in vacuo and the residue stirred with methylene chloride (50 mL) and water (30 mL) for 10 min. The organic layer is washed with brine (30 mL), and dried over sodium sulfate. The solvent is removed in vacuo to give tert-butyl 4-(1,3-dioxoisoindolin-2-yl)-4-fluoro-4-ethoxycarbonylbutanoate which is further purified by column chromatography.