Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH3:8])(=[O:7])[OH:6].[C:9]([O:14][CH:15]([O:17][C:18](OC1CC(=O)NC1=O)=[O:19])[CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11]>C(#N)C.O>[C:9]([O:14][CH:15]([O:17][C:18]([NH:1][CH2:2][CH2:3][CH2:4][P:5]([CH3:8])(=[O:6])[OH:7])=[O:19])[CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Reactant: CP(=O)(O)CCCN
Solvent: O
Solvent: CC#N
Product: CC(OC(=O)NCCCP(C)(=O)O)OC(=O)C(C)C

Procedure:
A solution of 3-aminopropylmethylphosphinic acid (137 mg, 1 mmol) and compound (17) (301 mg, 1 mmol) in acetonitrile (5 mL) and water (0.5 mL) was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to afford the title compound (111) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.69 (br, 1H), 6.77 (q, 1H, J=5.2 Hz), 3.27 (t, 2H, J=6 Hz), 2.53 (m, 1H), 1.83-1.73 (m, 4H), 1.45 (m, 6H), 1.15 (d, 6H, J=7.2 Hz). MS (ESI) m/z 296.1 (M+H)+, 294.1 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[N:23]=1.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1)[O:17][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:32][CH:33]=2)[N:23]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: FC(F)(F)Oc1ccc(-c2cccc(CCl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2cccc(-c3ccc(OC(F)(F)F)cc3)n2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
A solution of 39 mg (0.17 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 2.0 ml N,N-dimethylformamide was treated at 0° C. with 7 mg (0.17 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 50 mg (0.17 mmol) 2-Chloromethyl-6-(4-trifluoromethoxy-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 4 ml water, the precipitate was isolated, washed thoroughly with water, n-heptane and diisopropylether. The residue was dried at 40° C. to give 65 mg (77%) of the title compound as white powder.
Reaction SMILES: [O:1]=[S:2]1(=[O:43])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:31])(=[O:30])=[O:29])=[O:19])[C:15](C2C=C(C)C=CC=2S([O-])(=O)=O)=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.C[O-:45].[Na+]>CO.O>[O:1]=[S:2]1(=[O:43])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:31])(=[O:30])=[O:29])=[O:19])[C:15]([OH:45])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: C[O-]
Reactant: Cc1ccc(S(=O)(=O)[O-])c(-c2c(C(=O)NCc3ccccc3S(C)(=O)=O)nc(N3CCCCS3(=O)=O)c3cccnc23)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(1,1-dioxido-1,2-thiazinan-2-yl)-7-({[2-(methylsulfonyl)benzyl]amino}carbonyl)-1,6-naphthyridin-8-yl-4-methylbenzenesulfonate (220 mg, 0.34 mmol) was dissolved in methanol (10 mL) and NaOMe (55 mg, 1.02 mmol) was added. The reaction was stirred overnight at room temperature. The crude reaction was diluted with water (10 mL) and extracted with CH2Cl2 (2×10 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to afford a yellow oily solid. The material was suspended in methanol and a yellow precipitate fell out of solution. Washing with fresh methanol (2×10 mL) gave the desired product as an off-white solid.
Reaction SMILES: C[Si](OP(=O)=O)(C)C.[Br:9][C:10]1[CH:11]=[C:12]([C:26](O)=O)[C:13]([C:16]2[C:17](=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=2)[C:18](O)=O)=[CH:14][CH:15]=1.[C:29]1([NH2:36])[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35].C([O-])(O)=O.[Na+]>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:17]=2[C:18]2[NH:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:36]=2)=[C:12]([C:26]2[NH:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:36]=2)[CH:11]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1cc(Br)ccc1-c1ccc(Br)cc1C(=O)O
Agent: C[Si](C)(C)OP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Brc1ccc(-c2ccc(Br)cc2-c2nc3ccccc3[nH]2)c(-c2nc3ccccc3[nH]2)c1
Temperature: 160 °C
Yield: 53.9 %

Procedure:
To the PPSE solution was added 15.0 g of 4,4'-dibromodiphenic acid, 8.11 g of o-phenylene diamine (recrystallized from methylene chloride and charcoal). This mixture was rapidly heated to 160° C. and maintained there for 20 hours. The solution was cooled, then poured into 2 1 of 10% NaHCO3 solution. The product was filtered, washed with 300 ml of hot methylene chloride, then extracted using a Soxhlet extractor using 10% NaHCO3 overnight. The product was dried then recrystallized from ethanol to give 11 g of white crystals, mp 326° C.-328° C. Analysis calculated for C26H16N4Br2 : C, 57.38; H, 2.96; N, 10.29. Found: C, 57.81; H, 3.04, N, 10.30.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][C:9]3[C:16]4([CH3:19])[CH:17]([CH3:18])[CH:3]1[CH2:4][C:5]=2[C:10]=3[CH:11]=[CH:12][CH2:13][N:14]=[CH:15]4.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>O>[CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][C:9]3[C:16]4([CH3:19])[CH:17]([CH3:18])[CH:3]1[CH2:4][C:5]=2[C:10]=3[CH:11]=[CH:12][CH2:13][NH:14][CH2:15]4
Reactant: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2C
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC1C2CC3=C(CCC4=C3C=CCNCC41C)N2C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
To a stirred solution of 2.24 g of 1,2,3,4,5,6-hexahydro-3,6,12-trimethyl-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine and 23 ml of acetic acid, cooled to 15° C. under nitrogen, was added 1.70 g of sodium cyanoborohydride. The reaction mixture was stirred for an additional 2 hr and 90 ml of water was added. The solution was made basic (pH 12) with 50% aqueous sodium hydroxide solution and extracted with dichloromethane-ether. The combined organic layers were washed with brine, dried over anhydrous potassium carbonate, filtered and concentrated. The residue was purified by flash chromatography (alumina, ether). Recrystallization from ether/pentane gave 1.55 g (69%) of product, mp 126°-128° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([C:23]([O:25]C)=[O:24])[CH:19]=[CH:18]2)([CH3:4])([CH3:3])[CH3:2].CO>C(OCC)(=O)C.CCCCCC.C(O)(=O)C>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([C:23]([OH:25])=[O:24])[CH:19]=[CH:18]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2cccc(OCCCCCC(=O)OC(C)(C)C)c2n1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)CCCCCOc1cccc2ccc(C(=O)O)nc12
Temperature: 25 °C

Procedure:
To a solution of compound 1 (540 mg, 1.45 mmol, 1 eq.) in MeOH (3 mL) NaOH (116 mg, 2.9 mmol, 2 eq.) was added as, a concentrated aqueous solution, and the mixture was stirred at room temperature. The reaction was monitored by TLC (ethyl acetate/hexane/acetic acid, 1:1:0.01). Upon completion the volatiles were removed in vacuo and ethyl acetate added. The solution was washed with NaH2PO4 buffer (pH 5, 1M) and brine, dried over Na2SO4, and concentrated in vacuo to give 446 mg of crude 2, which was used directly in the next step. MS m/z 360 [M−H]+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)[S:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)#[CH:2].C(O)=[O:27]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)[S:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)(=[O:27])[CH3:2]
Reactant: C#Cc1ccc(-c2cc3sc(N4CCN(CC)CC4)cc3cn2)cc1
Reactant: O=CO
Product: CCN1CCN(c2cc3cnc(-c4ccc(C(C)=O)cc4)cc3s2)CC1

Procedure:
6-(4-Ethynylphenyl)-(4-ethylpiperazin-1-yl)thieno[3,2-c]pyridine (0.59 g) was reacted in formic acid (15 ml) at 100° C. for 12 hr. The reaction solutionwas evaporated, basified with an aqueous solution of potassium carbonate, and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated. The resulting residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane system), to give 0.37 g of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([O:14][CH3:13])[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: COc1cccc(Nc2nc(Cl)nc3ccccc23)c1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline and 3-methoxyaniline by a procedure similar to example 28 (80% yield). 1H NMR (CDCl3): 7.79-7.87 (m, 3H), 7.54-7.62 (m, 3H), 7.20-7.35 (m, 3H), 6.76 (dd, J=8.4 and 2.1 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.[CH2:32]([SH:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=3[N:3]=[C:2]2[S:34][CH2:32][CH3:33])=[CH:13][CH:14]=1
Reactant: CCS
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1nc2c(c(=O)n(CCCOC3CCCCO3)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.15 g, 0.29 mmol, intermediate 14) in DMF (10 mL) was added ethanethiol (27 mg, 0.44 mmol) and potassium carbonate (81 mg, 0.58 mmol). The reaction was heated at 80° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 1.912 min; LCMS MH+-THP 409.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[C@H:16]([OH:17])[CH2:15][C@@H:14]([CH2:18][OH:19])[O:13]3)[C:6]=2[N:7]=1.N1C=CN=C1.[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27].CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[C@H:16]([OH:17])[CH2:15][C@@H:14]([CH2:18][O:19][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31])[O:13]3)[C:6]=2[N:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](CO)C[C@H]2O)c(=O)[nH]1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Yield: 62.7 %

Procedure:
To a solution of 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (compound 38b, 3.8 g, 12.7 mmol) in DMF (30 mL) was added imidazole (2.6 g, 38 mmol) and tert-butylchlorodimethylsilane (4.2 g, 28 mmol) with stirring. After being stirred at room temperature for 2 hours, the resulting solution was diluted by EtOAc (200 mL), washed with water, brine, dried over Na2SO4. The organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:5 EtOAc in petroleum ether) to afford 3.3 g of 5-amino-3-[(2R,3R,5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-hydroxy-tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (compound 38d).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:15][C:16]2[CH:17]=[N:18][N:19]([CH2:21][CH2:22][OH:23])[CH:20]=2)[C:5]([C:12]([NH2:14])=[O:13])=[N:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].[NH2:24][C:25]1[CH:26]=[CH:27][C:28]([F:32])=[C:29]([OH:31])[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+].O.O>CN1CCCC1=O>[NH2:24][C:25]1[CH:26]=[CH:27][C:28]([F:32])=[C:29]([CH:30]=1)[O:31][C:2]1[N:3]=[C:4]([NH:15][C:16]2[CH:17]=[N:18][N:19]([CH2:21][CH2:22][OH:23])[CH:20]=2)[C:5]([C:12]([NH2:14])=[O:13])=[N:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9]
Reactant: CC(C)(O)c1nc(C(N)=O)c(Nc2cnn(CCO)c2)nc1Cl
Reactant: Nc1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(O)c1nc(C(N)=O)c(Nc2cnn(CCO)c2)nc1Oc1cc(N)ccc1F
Yield: 52.3 %

Procedure:
A mixture of 5-chloro-3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-(2-hydroxypropan-2-yl)pyrazine-2-carboxamide (790 mg), 5-amino-2-fluorophenol (442 mg), potassium carbonate (641 mg), and N-methylpyrrolidone (8 mL) was reacted at 100° C. for 2 hours. To the reactant was added a mixed solution of saturated brine:water (1:1), followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=99:1-80:20) to obtain 5-(5-amino-2-fluorophenoxy)-3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-(2-hydroxypropan-2-yl)pyrazine-2-carboxamide (523 mg) as a pale brown solid.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([O:30][CH:31]([CH3:33])[CH3:32])[CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[O:20][C:21]=2[CH3:22])=[C:9]([CH3:29])[CH:8]=1)C.[OH-].[Na+].CCOC(C)=O>C1COCC1.CCO>[CH:23]1([C:19]2[O:20][C:21]([CH3:22])=[C:17]([CH2:16][CH2:15][O:14][C:10]3[C:9]([CH3:29])=[CH:8][C:7]([CH2:6][CH:5]([O:30][CH:31]([CH3:32])[CH3:33])[C:4]([OH:34])=[O:3])=[CH:12][C:11]=3[CH3:13])[N:18]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)C(Cc1cc(C)c(OCCc2nc(C3CCCCC3)oc2C)c(C)c1)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(CC(OC(C)C)C(=O)O)cc(C)c1OCCc1nc(C2CCCCC2)oc1C
Reaction time: 14 h
Yield: 87.5 %

Procedure:
0.181 g of the above prepared 3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-3,5-dimethyl-phenyl}-2-isopropoxy-propionic acid ethyl ester (0.384 mmol) was dissolved in 6 ml of THF/EtOH=1/1, treated with 0.959 ml of 2N NaOH (5 eq.), and kept at ambient temperature for 14 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase reextracted once more with AcOEt, the combined organic layers washed with water, dried over magnesium sulfate, and evaporated to dryness. Boiling up in hexane, followed by decantation after cooling, yielded 0.149 g of the title compound as pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[N:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CC1(C)C(C)(C)OB([C:52]2[CH:53]=[C:54]([CH2:58][CH:59]3[CH2:64][CH2:63][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:61][CH2:60]3)[CH:55]=[CH:56][CH:57]=2)O1.O1CCOCC1.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.O>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:22][C:20]([C:16]3[N:15]=[C:14]([C:12]([NH:11][CH2:10][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([C:56]5[CH:57]=[CH:52][CH:53]=[C:54]([CH2:58][CH:59]6[CH2:60][CH2:61][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:63][CH2:64]6)[CH:55]=5)[CH:3]=4)=[O:13])[CH:19]=[CH:18][CH:17]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(Br)c2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
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
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(-c3cccc(CC4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)n1
Temperature: 100 °C
Yield: 113.2 %

Procedure:
To N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (40.46 g, 62.2 mmol) in a 2 L 3-neck flask was added 1,1-dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylate (24.96 g, 62.2 mmol) and 1,4-dioxane (700 mL). Then potassium carbonate (25.8 g, 187 mmol) and water (233 mL) were added followed by tetrakis(triphenylphosphine)palladium(0) (3.59 g, 3.11 mmol) and the mixture was then stirred at 100° C. under nitrogen with conventional heating. After 2 h the reaction was cooled and the mixture was partitioned between ethyl acetate and water and the aqueous layer extracted well with ethyl acetate. The combined organics were washed with water, brine, dried (MgSO4), filtered and evaporated to give 59.49 g (113%) of a brown foam. The crude product was purified on a 750 g Companion XL silica cartridge, eluting with 0-100% of {1% MeOH in ethyl acetate} in dichloromethane over 14 column volumes. This gave 25.38 g (48%) of a pale beige foam that the lab HPLC showed to be 97.23% pure with a retention time of 2.60 min. LC-MS m/z 845 (M+H)+, 3.02 min (ret time).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C:4]2=[O:22])[CH3:2].[H][H]>O1CCOCC1.[Ni]>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])[CH3:2]
Reactant: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)C1=CCC2=O
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCO1
Product: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC2=O
Yield: 59.6 %

Procedure:
Dissolve 13β-ethyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (2 g) in dioxan (50 cc) containing Raney nickel (ca. 0.5 g) of moderate activity and shake with hydrogen until 160 cc., the amount corresponding to one molecular proportion has been absorbed. Recrystallize the isolated product from methanol to obtain the title product (1.2 g), m.p. 110°-125°; ultraviolet absorption peak at 280 mμ (ε13,200).
Reaction SMILES: O1CCCC1.[N:6]([CH2:9][C:10]1[N:11]([CH3:27])[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.C(OCC)(=O)C>O>[NH2:6][CH2:9][C:10]1[N:11]([CH3:27])[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:16])[CH3:17])[N:14]=1
Reactant: CC(C)c1nc(CN=[N+]=[N-])n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1nc(CN)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
To dry tetrahydrofuran solution (60 ml) of 24.2 g of 2-azidomethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazole (29a) was added 19.6 g of tripenylphosphine under ice-cooling, and the mixture was stirred at room temperature for 4 hours. After the reaction completion was confirmed (the disappearance of 29a) by TLC (silica gel, methylene chloride-ethyl acetate=10:1), 50 ml of water was added, and the mixture was stirred at room temperature for 1.5 hours, and left overnight. Tetrahydrofuran was distilled off under reduced pressure, and to the residue, 400 ml of 3N-hydrochloric acid was added. When the mixture was washed with diethyl ether, crystals were precipitated from the hydrochloric acid layer. The crystals were collected by filtration, and neutralized with a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with diethyl ether. The aqueous layer was also neutralized with a saturated aqueous sodium hydrogen carbonate solution, and was extracted with diethyl ether. These ether extracts were combined and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and 20.6 g of 2-aminomethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazole (30a) was obtained (yield 92%). mp 86-87° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[CH:14]=[C:13]([Cl:18])[N:12]=1>CS(C)=O>[Cl:10][C:11]1[CH:16]=[C:15]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:14]=[C:13]([Cl:18])[N:12]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: CN1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCN(c2cc(Cl)nc(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A mixture of N-methyl piperazine (0.604 g, 6.04 mmol) in dry DMSO (6 mL) was prepared and NaH (0.2637 g, 10.98 mmol) was added. The resulting mixture was stirred for 30 minutes at 0° C., after which time 2,4,6-trichloropyridine (1.0 g) was added. The reaction mixture was stirred at 20 to 40° C. for 4 hours. In the reaction mixture ice cold water was added and extracted with ethyl acetate giving 3-4 times water washing. The organic layer was dried and concentrated. The residue was purified by column chromatography using 100-200 mesh silica gel. Elution of the column with 20% acetone in hexanes gave the pure product as a colorless solid. Yield: 26%.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[C:8](=[O:19])[N:9]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11][N:10]2[C:17]=1[NH2:18].[NH2:20][C:21]1[C:22]([Cl:29])=[C:23]([OH:28])[C:24]([CH3:27])=[CH:25][CH:26]=1.N.OO>O.C(O)C>[NH2:18][C:17]1[N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][N:9]2[C:8](=[O:19])[C:7]=1[N:6]=[C:26]1[CH:25]=[C:24]([CH3:27])[C:23](=[O:28])[C:22]([Cl:29])=[C:21]1[NH2:20]
Reactant: Cc1ccc(N)c(Cl)c1O
Reactant: CN1CCn2c(N)c(N)c(=O)n2CC1
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: O
Solvent: CCO
Product: CC1=CC(=Nc2c(N)n3n(c2=O)CCN(C)CC3)C(N)=C(Cl)C1=O

Procedure:
0.32 mmol of 8,9-diamino-3-methyl-2,3,4,5-tetrahydro-1H,7H-pyrazolo[1,2-a][1,2,5]triazepin-7-one methanesulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.32 mmol of 3-amino-2-chloro-6-methylphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C@@H:16]2[OH:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29]>O1CCOCC1>[ClH:29].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][NH:18][CH2:17][C@@H:16]2[OH:28])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCc3ccccc3)cc2)[C@@H](O)C1
Agent: Cl
Solvent: C1COCCO1
Product: O[C@H]1CNCC[C@@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3R,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (750 mg, 2 mmol), dioxane (4 mL) and 4.9 mL of 4 M HCl in dioxane was stirred at rt for 2 h. The reaction was then evaporated to dryness to yield 550 mg of (3R,4R)-4-(4-(Benzyloxy)phenyl)piperidin-3-ol hydrochloride which was used without further purification. LCMS (method J) RT 0.70 min, m/z 284 (M+H+).