Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.O=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15]1([C@@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>CCCCCCC>[C:15]1([C@@H:21]([NH:23][C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: C[C@H](N)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CO
Solvent: CCCCCCC
Product: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CCCC1

Procedure:
In an additional embodiment, (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) is produced from a starting material comprising ethyl 2-oxocyclohexane carboxylate (6). This embodiment comprises reacting ethyl 2-oxocyclohexane carboxylate (6) with (S)-(−)-1-phenylethylamine (7) in the presence of a catalyst, ytterbium trifluoromethanesulfonate, and heptane to produce (S)-Ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate (8). The next step is reduction of the amine (8) with sodium acetoxyborohydride in the presence of a acetonitrile produce (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate (9), as illustrated in FIG. 1. The production of the cis-cyclohexane derivative (9) is followed by epimerization of the chiral center adjacent to the ethyl ester functionality using sodium t-butoxide to afford trans-cyclohexane derivative (10) as a major diastereomer. Reduction of the ester functionality in compound (10), using lithium borohydride yields (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) in good overall yield, which is subsequently purified by chromatography.
Reaction SMILES: C[O-].[Na+].C[C:5](C)(C([O-])=O)[C:6]([O-])=[O:7].[C:13]1(=[C:19](C#N)[C:20]([NH2:22])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+]>CO>[O:7]=[C:6]1[NH:22][C:20](=[O:21])[CH2:19][C:13]2([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:5]1
Reactant: N#CC(C(N)=O)=C1CCCCC1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC2(CCCCC2)CC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
204 ml of a 5.4 M solution of sodium methylate in methanol, 550 ml methanol and 145.5 g of dimethylmalonate are placed in a 2 litre flask equipped with a mechanical stirrer, thermometer and condenser, under nitrogen flow. After 30 minutes, 148 g of cyclohexylidenecyanoacetamide are added over a period of 30 minutes. The mixture is left under agitation for 1.5 hours at 30° C., after which 626 g of 15% NaOH are added, then heated under reflux for 1.5 hours. 400 ml of methanol are distilled and the mixture is acidified with 36% HCl to pH 3 then heated under reflux for 3 hours. By cooling to 25° C. a precipitate is formed which is filtered off, washed with water until the washing waters are neutral and dried under vacuum at 45° C. 69 g of 2,4-dioxo-3-azaspiro[5,5]undecane are obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:30][CH2:31][N:32]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:20])=[CH:8][C:9]=2[S:16]([CH3:19])(=[O:18])=[O:17])=[O:13])[CH2:33][CH2:34]1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
4-(1,1-Dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (335 mg) described in Preparation Example 22, 1-(2,4-dimethylphenyl)piperazine (199 mg), 1-hydroxybenzotriazole 1 hydrate (142 mg) were dissolved in N,N-dimethylformamide (5 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (202 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (436 mg).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][CH:16]([OH:20])[CH2:17][NH:18][CH3:19])=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH:26]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][CH:16]([OH:20])[CH2:17][N:18]([CH2:26][C:25]2[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH3:19])=[CH:3][CH:2]=1
Reactant: CNCC(O)COc1cccc2[nH]c3ccccc3c12
Reactant: COc1cc(C=O)cc(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(CN(C)CC(O)COc2cccc3[nH]c4ccccc4c23)cc(OC)c1
Yield: 13 %

Procedure:
The reaction of 1-(9H-carbazol-4-yloxy)-3-(methylamino)propan-2-ol (0.20 g, 0.74 mmol) with 3,5-dimethoxybenzaldehyde (0.185 g, 1.11 mmol) in the presence of 2-3 drops of glacial acetic acid and Na(OAc)3BH (0.157 g, 0.578 mmol) following the procedure similar to the one described in example 26, afforded the title compound as a brown colored paste (0.045 g, 13% yield) with 1H NMR (400 MHz, DMSO): δ 2.25(s, 3H), 3.40-3.60 (m, 2H), 3.51 (s, 2H), 3.65 (s, 6H), 4.10-4.13 (m, 1H), 4.15-4.25 (m, 2H), 5.00 (s, 1H), 6.31 (s, 1H), 6.49 (d, 2H, J=1.6 Hz), 6.67 (d, 1H, J=8.0 Hz), 7.05-7.12 (m, 2H), 7.25-7.35 (m, 2H), 7.43 (d, 1H, J=8 Hz), 8.17 (d, 1H, J=8.0 Hz), 11.23 (s, 1H). MS m/z: 421.0 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([CH3:8])=[CH:6][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1.[C-:15]#[N:16].[K+].O>CS(C)=O>[CH3:8][C:7]1[C:3]([CH2:2][C:15]#[N:16])=[N:4][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=1
Reactant: Cc1cn(-c2ccccc2)nc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn(-c2ccccc2)nc1CC#N
Temperature: 60 °C
Yield: 113.2 %

Procedure:
A mixture of 3-(bromomethyl)-4-methyl-1-phenyl-1H-pyrazole (112 mg, 446 μmol) and potassium cyanide (33.3 mg, 491 μmol) in DMSO (2 mL) was heated to 60° C. for 2 h. The reaction mixture was cooled to RT, poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The organic phases were washed with water (3×25 mL) and brine 1×25 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 99.6 mg crude material. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow oil (58 mg, 294 μmol, 65.9%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)[CH2:15][Br:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1

Procedure:
3,5-Di-t-butyltoluene (5 g), N-bromosuccinimide (4.79 g) and azobisisobutyronitrile (20 mg) were dissolved in carbon tetrachloride (30 ml) and the solution was heated at reflux for 3 h. When cool, a white solid was removed by filtration, and the filtrate was concentrated yielding a yellow oil, which was used without further purification. 1H NMR (360 MHz, CDCl3) δ1.30 (18H, s, CH3), 4.45 (2H, s, CH2), 7.2 (2H, d, J=1.75 Hz, ArH), 7.4 (1H, s, ArH).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]1[C:47]([C:51](O)=[O:52])=[N:48][NH:49][N:50]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:51]([C:47]2[C:46]([CH3:45])=[N:50][NH:49][N:48]=2)=[O:52])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: Cc1n[nH]nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1n[nH]nc1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reaction time: 8 h
Yield: 28.2 %

Procedure:
HATU (0.092 g, 0.241 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), 5-methyl-2H-1,2,3-triazole-4-carboxylic acid (0.022 g, 0.177 mmol) and DIPEA (0.042 mL, 0.241 mmol) in DMF (2 mL). The resulting solution was stirred overnight. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4 and evaporated to a residue. Purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.0191 g, 28%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.51 (s, 1H), 7.79 (d, 1H), 7.69 (t, 1H), 7.46-7.51 (m, 2H), 7.44 (d, 1H), 7.30 (t, 1H), 4.36 (d, 2H), 2.15 (s, 3H). LCMS: m/z 420.0 (M+1).
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16](=[O:43])[N:17]=[C:18]([S:22][CH:23]2[C:28]([CH3:29])=[C:27]([C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])[N:26]3[C:36](=[O:40])[C@H:37]([O:38][CH3:39])[C@H:25]3[S:24]2(=[O:42])=[O:41])[N:19]([CH3:21])[N:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH2:46](N(CC)CC)C>CS(C)=O.ClCCl>[CH:1]([O:14][C:15]1[C:16](=[O:43])[N:17]=[C:18]([S:22][C:23]2([CH3:46])[C:28]([CH3:29])=[C:27]([C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])[N:26]3[C:36](=[O:40])[C@H:37]([O:38][CH3:39])[C@H:25]3[S:24]2(=[O:41])=[O:42])[N:19]([CH3:21])[N:20]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(C)C(Sc3nc(=O)c(OC(c4ccccc4)c4ccccc4)nn3C)S(=O)(=O)[C@H]12
Reactant: CCN(CC)CC
Solvent: CI
Solvent: ClCCl
Solvent: CS(C)=O
Product: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(C)C(C)(Sc3nc(=O)c(OC(c4ccccc4)c4ccccc4)nn3C)S(=O)(=O)[C@H]12

Procedure:
A solution of 2-(6-benzhydryloxy-2-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)thio-4-tert-butylcarbonyl-7α-methoxy-3-methyl-3-cephem 1,1-dioxide (550 mg), prepared as described in PTC EP 90/02189 in dimethyl sulphoxide (4 ml) was treated with methyl iodide (0.170 ml) and triethylamine (0.147 ml). After 2 hrs the reaction was diluted with dichloromethane, washed in sequence with hydrochloric acid and brine, and dried Na2SO4. Removal of the solvent and flash chromatography of the crude residue gave the title compound (300 mg) as a yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])C=CC=1C#N.[CH3:11][Mg]Cl.[O:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:15]=[CH:16][C:17]=1[C:18](=[O:14])[CH3:11]
Reactant: N#Cc1ccc(Cl)cc1N
Reactant: C[Mg]Cl
Reactant: C1CCOC1
Product: CC(=O)c1ccc(Cl)cc1N
Temperature: 15 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
A three-necked flask equipped with an addition funnel, a thermometer, and an overhead mechanical stirrer was charged with 2-amino-4-chlorobenzonitrile (150 g, 983 mmol) and tetrahydrofuran (3.0 L). The reaction flask was cooled to 15° C. and then was treated with methyl magnesium chloride (825 mL, 2.48 mol). Upon completion of addition of the methyl magnesium chloride, the cold bath was removed. The reaction was stirred at 25° C. overnight. At this time, the reaction mixture was cooled to 5° C. and then was treated slowly with a solution of water (500 mL) and concentrated hydrochloric acid (300 mL) while maintaining the reaction temperature under 25° C. The resulting thick suspension was stirred at 25° C. for 3 h. At this time, the mixture was cooled to 5° C. and treated with solid sodium hydroxide (300 g) in small portions. The reaction was stirred at 25° C. overnight. At this time, the organics were decanted off. The remaining thick paste was partitioned between water (2 L) and methyl tert-butyl ether (2 L). The organic layers were combined, concentrated in vacuo and then absorbed onto silica. Flash chromatography (4″×16″ silica gel column; 1-3% ethyl acetate/hexanes) followed by concentration of the appropriate fractions, slurrying with hexanes, filtration and drying afforded 1-(2-amino-4-chlorophenyl)ethanone (81 g, 48.6%) as a yellow solid. This material was used without further purification.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[C:8]([C:13](=[O:29])[CH2:14][C:15]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)(O)[C:16]([F:19])([F:18])[F:17])[CH:9]=[CH:10][C:11]=1[F:12].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[Br:5][C:6]1[CH:7]=[C:8]([C:13](=[O:29])[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=2)[C:16]([F:17])([F:18])[F:19])[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(F)c(Br)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(F)c(Br)c1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a solution of thionyl chloride (0.618 g, 5.52 mmol) in toluene (1 mL) was added to a mixture of the product from Step A (1.2 g, 2.60 mmol) and pyridine (0.41 g, 5.18 mmol) in toluene (15 mL) at 60-65° C. When the addition was complete, pyridine (0.2 g, 2.53 mmol) was added incrementally to the reaction mixture. When the addition was complete, the mixture was allowed to cool to ambient temperature and then poured into 1N hydrochloric acid (100 mL). The resulting mixture was extracted with ethyl acetate (2×50 mL) and the combined extracts dried and evaporated to give the title product as an oil (1.12 g, 97% yield).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].[CH3:9][O:10][C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14](B(O)O)=[CH:13][N:12]=1.C(=O)(O)[O-].[Na+]>COCCOC.C(Cl)Cl.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>[CH3:8][C:4]1[S:5][C:6]([CH3:7])=[C:2]([C:14]2[C:15]([O:17][CH3:18])=[N:16][C:11]([O:10][CH3:9])=[N:12][CH:13]=2)[N:3]=1
Reactant: Cc1nc(Br)c(C)s1
Reactant: COc1ncc(B(O)O)c(OC)n1
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: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ncc(-c2nc(C)sc2C)c(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-2,5-dimethyl-1,3-thiazole (commercially available from Apollo Scientific Ltd, 410 mg, 2.135 mmol) in 1,2-Dimethoxyethane (DME) (6.5 mL), Tetrakis(triphenylphosphine)palladium (123 mg, 0.107 mmol) was added and the mixture was stirred at rt for 30 minutes. Then [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (commercially available from Aldrich, 916 mg, 4.48 mmol) and 1M Sodium bicarbonate aqueous solution (5.83 mL, 5.83 mmol) were added. The reaction mixture was then stirred at 90° C. for 2.5 h and left stirring at rt overnight. The day after the mixture was diluted with DCM and washed with water. Organic layer was dried and concentrated under vacuum. Crude product was first purified by flash chromatography (eluent: Cy/AcOEt 65:35) and further purified by SCX cartridge affording 5-(2,5-dimethyl-1,3-thiazol-4-yl)-2,4-bis(methyloxy)pyrimidine with minor unknown impurities that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[S:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH2:22](O)[C:23]#[C:24][CH3:25].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([S:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:22][C:23]#[C:24][CH3:25])=[CH:11][CH:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[CH3:2]
Reactant: CCOC(=O)C(Sc1ccc(O)cc1)c1cccc(Cl)c1
Reactant: CC#CCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC#CCOc1ccc(SC(C(=O)OCC)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
The ethyl(3-chlorophenyl)[(4-hydroxyphenyl)sulfanyl]acetate (4.2 g, 13 mmol) was stirred with THF (100 ml) in a dried two-necked flask under inert conditions. The 2-butyn-1-ol (0.97 ml, 13 mmol) and 1,1′(azodicarbonyl)dipiperidine (3.94 g, 15.6 mmol). Tributylphosphine (3.90 ml, 15.6 mmol) was added dropwise at 0° C. The reaction mixture was allowed to stir at room temperature under nitrogen for 2 hours before it was concentrated. The residue was triturated with ether and the filtrate was concentrated, Ethyl{[4-(2-butynyloxy)phenyl]sulfanyl}(3-chlorophenyl)acetate was isolated as a yellow oil (4.08 g) after silica-gel column chromatography, using methylene chloride as the mobile phase. Yield 84%; MS(EI): 375 (M+H)+
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[S:8][CH:9]=[C:10]([CH3:12])[CH:11]=1)=O.O.[NH2:15]N>C(O)C>[CH3:12][C:10]1[CH:11]=[C:7]([C:5]2[CH:4]=[CH:3][NH:2][N:15]=2)[S:8][CH:9]=1
Reactant: Cc1csc(C(=O)C=CN(C)C)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1csc(-c2cc[nH]n2)c1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A mixture of 3-(dimethylamino)-1-(4-methyl-2-thienyl)prop-2-en-1-one (72 mmol) and hydrazine hydrate (144 mmol) in 80 mL ethanol was refluxed for 18 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was successively washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and brine, dried over MgSO4, filtered and concentrated to afford 11.58 g (98% yield) 3-(4-methyl-2-thienyl)-1H-pyrazole which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:23][C:24]1[CH:25]=[C:26]([CH3:49])[C:27]2[O:31][C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][CH:34]=3)=[N:29][C:28]=2[CH:48]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:9]=[C:10]([C:36]3[CH:35]=[CH:34][C:33]([NH:32][C:30]4[O:31][C:27]5[C:26]([CH3:49])=[CH:25][C:24]([CH3:23])=[CH:48][C:28]=5[N:29]=4)=[CH:38][CH:37]=3)[C:3]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: CC(C)(C)OC(=O)N1CC(n2nc(I)c3c(N)ncnc32)C1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
A mixture of tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-azetanecarboxylate (0.15 g, 0.00036 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.16 g, 0.00045 mol), tetrakis(triphenylphosphine)palladium (0.021 g, 0.000018 mol) and sodium carbonate (0.095 g, 0.0009 mol) in ethylene glycol dimethyl ether (5 mL) and water (2 mL) was heated at 80° C. for 16 hours under an atmosphere of nitrogen. The reaction was cooled to room temperature. Additional tetrakis(triphenylphosphine)palladium (0.021 g, 0.000018 mol) was added to the mixture. The reaction was stirred at 80° C. for 3 hours. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish solid which was purified by flash column chromatography on silica using 5%-50% methanol/dichloromethane as a mobile phase to give tert-butyl 3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-azetanecarboxylate (0.033 g, 0.00006 mol). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.6 min. MS: MH+ 527
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[N:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[CH2:10]([NH:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][NH:1][C:27]([C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:17]=[CH:18][CH:19]=[CH:20]2)=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: NCc1cccc(NCc2ccccc2)c1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(NCc2ccccc2)c1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
(3-Aminomethyl-phenyl)-benzylamine (62 mg, 0.29 mmol), quinoline-6-carboxylic acid (52 mg, 0.30 mmol), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (182 mg, 0.41 mmol) and triethylamine (114 μl, 0.81 mmol) were dissolved in N,N-dimethylformamide (0.5 mL), and the solution was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1), and the title compound (73 mg, 0.198 mmol, 73%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C@H:7]1[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)=[O:5])[CH3:2].[C:28]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.C(O)(=O)C>ClC(Cl)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C@H:7]1[C:21]1[CH:22]=[CH:23][C:24]([NH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:25][CH:26]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)c2ccccc2C)[C@H]1c1ccc(N)cc1
Reactant: O=C1CCCC1
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCCN(C(=O)c2ccccc2C)[C@H]1c1ccc(NC2CCCC2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
Na(OAC)3BH (495 mg, 2.33 mmol) was added to a solution of the (2R,3S)-2-(4-aminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester (612 mg, 1.67 mmol), cyclopentanone (140 mg, 1.67 mmol) and acetic acid (100 mg, 1.67 mmol) in dry dichloroethane at r.t and the reaction mixture was heated to 50° C. for 4 h, cooled to r.t and stirred for 48 h. It was then diluted with CH2Cl2 (30 mL), washed with saturated aqueous NaHCO3 solution, dried and concentrated in vacuo. The residue was purified by ISCO flash column using ethyl acete and hexanes as mobile phase (40 g column, 0-40% gradient) to afford (2R,3S)-2-(4-Cyclopentylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester (450 mg).