Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][OH:12])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[C:13](=O)(OCC)[O:14]CC.C([O-])([O-])=O.[K+].[K+]>>[OH:12][CH2:11][C@H:2]1[C@H:3]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:4][C:13](=[O:14])[NH:1]1
Reactant: CCOC(=O)OCC
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1N[C@@H](CO)[C@H](c2ccccc2)O1
Temperature: 135 °C
Reaction time: 3 h
Yield: 32.4 %

Procedure:
(1S,2S)-2-Amino-1-phenylpropane-1,3-diol (20.0 g, 120 mmol), diethyl carbonate (29.7 mL, 245 mmol), and K2CO3 (1.65 g, 12.0 mmol) were charged into a flask with mechanical stirrer and a vigreux-column. This suspension was heated in an oil bath at 135° C., to give a yellow solution. The accrued EtOH was distilled off over the vigreux column. The reaction was stirred over a period of 3 h, until no more EtOH could be distilled off. The reaction mixture was then cooled to 50° C., diluted with EtOAc and aqueous NaHCO3. The organic layers were separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (550 g SiO2) using EtOAc in heptane from 33% to 100% in order to give the title compound as a beige oil (7.50 g, 33%). 1H NMR (400 MHz, DMSO-d5): 7.87 (br s, 1H), 7.50-7.30 (m, 5H), 5.37 (d, 1H), 5.23-5.17 (m, 1H), 3.70-3.60 (m, 1H), 3.60-3.50 (m, 2H).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:16]=2[N:17]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1>>[C:1]([N:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: C1CSCCN1
Product: CCCCCCC/C=C/C(=O)N1CCSCC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and thiomorpholine as starting raw materials, to produce an intended compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.[C:26]([N:28]=[C:29](SC)[S:30][CH3:31])#[N:27].CCN(CC)CC>CC#N>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:29](=[N:28][C:26]#[N:27])[S:30][CH3:31])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Reactant: CSC(=NC#N)SC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSC(=NC#N)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 57.8 %

Procedure:
A 25 mL flask was charged with (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (3 g, 8.15 mmol) and dimethyl cyanocarbonimidodithioate (1.2 g, 8.15 mmol) dissolved in 50 mL of MeCN, and 1 mL Et3N was added and the mixture was stirred for overnight. The mixture was evaporated in vacuo and the residue was purified by chromatography to give desired (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-((cyanoimino)(methylthio)methylamino)ethoxy)methyl)-piperidine-1-carboxylate (2.2 g, 58%). 1H NMR (CDCl3, 400 MHz) δ 7.28 (m, 2H), 7.23 (m, 1H), 7.16 (m, 1H), 4.10 (m, 2H), 3.86 (m, 1H), 3.68 (m, 2H), 3.22 (m, 2H), 2.72 (m, 2H), 1.62 (m, 2H), 1.46 (s, 9H), 1.40-1.10 (m, 4H).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:34][CH3:35])=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[O:20])[S:16][CH:17]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(OCC)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:34][CH3:35])=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]([CH:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[O:20])[S:16][CH:17]=3)[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)C2CCNCC2)n1
Yield: 111.8 %

Procedure:
A solution of 1.13 g of the compound prepared in step 1.1 in 10 mL of a 4 M solution of HCl in ioxane is stirred for 30 minutes at room temperature. The medium is diluted with ethyl ether and then filtered. The solid thus obtained is rinsed with ether and then dried to give 1.01 g of a white solid.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](O)([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[CH2:18][CH2:17]1.N1CCCC[CH2:31]1.[OH-].[NH4+]>CS(O)(=O)=O>[CH3:15][N:16]1[CH2:21][CH:20]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:31])[CH:23]=2)[CH2:18][CH2:17]1
Reactant: CN1CCC(O)(c2cccc(O)c2)CC1
Reactant: C1CCNCC1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [NH4+]
Product: COc1cccc(C2=CCN(C)CC2)c1

Procedure:
To a stirred solution of 200 ml. of 50 g. of phosphorous pentoxide in methanesulfonic acid was added portionwise over four minutes 59 g. of 1-methyl-4-hydroxy-4-(3-hydroxyphenyl)piperidine. The reaction was exothermic and the temperature rose to 70° C. After complete addition of the piperidine derivative, the reaction mixture was added to 200 g. of ice, and the aqueous mixture was made alkaline by the addition of ammonium hydroxide. The alkaline mixture was extracted several times with diethyl ether, and the ethereal extracts were combined, washed with water, dried, and the solvent was removed by evaporation under reduced pressure to provide 44.7 g. of the product as an oil. The oil thus formed was distilled to provide 1-methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine, B.P. 123°-138° C. at 0.1 torr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH3:10])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19].O>CC(C)=O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([N:9]([CH3:10])[C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CNc1cccc(OC)n1
Reactant: O=C(Cl)Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(N(C)C(=O)Oc2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Yield: 62 %

Procedure:
To the mixture of 1.38 g of 2-methoxy-6-methylaminopyridine and 1.38 g of anhydrous potassium carbonate in 20 ml of acetone was added dropwise the solution of 2.25 g of 4-trifluoromethylphenyl chloroformate in 20 ml of acetone under stirring at room temperature. The mixture was stirred for 30 minutes and then was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into water and the product was extracted with benzene. The benzene solution, successively washed with water and brine, was dried over anhydrous magnesium sulfate. The residue obtained by the removal of benzene under reduced pressure was chromatographed through silica gel column using benzene as an eluent to give 2.02 g of pure 4-trifluoromethylphenyl N-(6-methoxy-2-pyridyl)-N-methylcarbamate as solid in the yield of 62%. A part of the solid was recrystallized from hexane and crystalls having melting point of 85° to 86° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.C([Li])CCC.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:25]2[C:37](=[O:38])[N:36]([CH2:39][CH3:40])[C:28]3[N:29]=[C:30](S(C)=O)[N:31]=[CH:32][C:27]=3[CH:26]=2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1.C(OCC)(=O)C.O>C1COCC1.CO.C(Cl)(Cl)Cl>[CH3:24][O:23][C:21]1[CH:20]=[C:19]([C:25]2[C:37](=[O:38])[N:36]([CH2:39][CH3:40])[C:28]3[N:29]=[C:30]([NH:1][C:2]4[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=4)[N:31]=[CH:32][C:27]=3[CH:26]=2)[CH:18]=[C:17]([O:16][CH3:15])[CH:22]=1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(S(C)=O)nc21
Reactant: Cc1cc(N)cc(C)n1
Agent: [Li]CCCC
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3cc(C)nc(C)c3)nc21
Temperature: -10 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a −78° C. solution of 3.9 g (32.1 mmol) of 4-amino-2,6-dimethylpyridine in 120 mL of THF was added dropwise 17.5 mL (30.5 mmol) of 1.6 M n-butyllithium in hexanes. The reaction solution was stirred for 15 minutes at which time 3.0 g (8.0 mmol) of the product of Example 7, 6-(3,5-dimethoxy-phenyl)-8-ethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one, was added in small portions as a solid. The reaction mixture was allowed to warm slowly to −10° C. then remain at −10° C. overnight. The reaction. mixture was poured into ethyl acetate/water/5 mL 6N HCl. The mixture was shaken and separated. The organic phase was washed with a saturated solution of sodium bicarbonate, twice with water, and brine, then dried over magnesium sulfate, filtered, and concentrated to a solid residue. The residue was triturated under ethyl acetate/dichloromethane. The resulting material was further purified by column chromatography eluting with 5:50:50 methanol/ethyl acetate/dichloromethane to give an orange crystalline material. This material was dissolved in 150 mL of hot 1:9 methanol/chloroform and filtered. The addition of 60 mL of hexane results in the precipitation of 0.99 g (28%) of the title compound as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([C@H:23]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:24]([O:26]CC3C=CC(OC)=CC=3)=[O:25])[CH2:13]2)[CH2:7][CH2:6]1>C(O)=O>[O:1]=[C:2]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C@@H:12]2[C@@H:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][N:14]([C@H:23]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:24]([OH:26])=[O:25])[CH2:13]2)[CH2:7][CH2:6]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(CCC(=O)c4ccccc4)CC3)[C@@H](c3ccccc3)C2)cc1
Solvent: O=CO
Product: O=C(CCC1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1)c1ccccc1
Reaction time: 2 h
Yield: 71.5 %

Procedure:
A solution of 2-(R)-(3-(S)-(4-(3-oxo-3-phenylpropyl)piperidin-1-yl)methyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid 4-(methoxy)benzyl ester (29 mg, 0.046 mmol, from Step E) in 96% formic acid (2.0 mL) was stirred at rt. After 2 h, the formic acid was evaporated at reduced pressure. Toluene was added and evaporated, and this was repeated with two additional portions of toluene. The crude product was purified by flash column chromatography on silica gel packed in CH2Cl2. Elution with 5% CH3OH/1% conc. aq. NH4OH/CH2Cl2 followed by 10% CH3OH/2% conc. aq. NH4OH/CH2Cl2 gave 17 mg of the title compound as a colorless glass. ESI-MS: 517 (M+H).
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([O:14][CH3:15])[C:3]=1[CH:4]=[O:5].[CH3:16][O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC(O)=O.CC(O)=O.[Pd]>[CH:4]([C:3]1[C:6]([O:14][CH3:15])=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:2]=1[C:23]1[CH:24]=[CH:25][C:20]([C:18]([O:17][CH3:16])=[O:19])=[CH:21][CH:22]=1)=[O:5]
Reactant: COc1cc(C(F)(F)F)cc(Cl)c1C=O
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OC)c2C=O)cc1
Temperature: 80 °C

Procedure:
2-Chloro-6-methoxy-4-(trifluoromethyl)benzaldehyde (224 mg, 0.94 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (219 mg, 1.22 mmol), S-PHOS (115 mg, 0.28 mmol), Pd(Oac)2 (32 mg, 0.14 mmol) and K3PO4 (597 mg, 2.81 mmol) were dissolved in wet PhMe (8 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:20]=4[CH3:19])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Cc1cccc(B(O)O)c1C
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cccc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)c1C
Yield: 25.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2,3-dimethylphenylboronic acid (117 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×50 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 55 mg (25%) of the title compound as an amorphous solid. mp 133°-140°. FDMS: m/e=333. α[D]589 =+61.90 (c=1.05, methanol).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8]C)=O)[CH2:2]1.O.[NH2:11][NH2:12]>>[O:1]1[CH2:5][CH2:4][CH:3]([C:6]([NH:11][NH2:12])=[O:8])[CH2:2]1
Reactant: COC(=O)C1CCOC1
Reactant: NN
Solvent: O
Product: NNC(=O)C1CCOC1
Reaction time: 3 h
Yield: 74 %

Procedure:
Into around-bottom flask, was placed hydrazine hydrate (20 mL). To this was added methyl tetrahydrofuran-3-carboxylate (compound 38.1, 390 mg, 3.00 mmol, 1.00 equiv) dropwise with stirring. The resulting mixture was stirred at 50° C. in an oil bath. After 3 h, the reaction mixture was concentrated and dried under reduced pressure to yield 0.29 g (74%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.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]>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH:34]=[C:35]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([Cl:11])[CH:10]=2)[C:7](=[O:12])[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=2)[CH2:5]3)[CH2:36][CH2:37]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(Cl)c3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)CC1
Temperature: 110 °C
Yield: 23.3 %

Procedure:
5-Bromo-7-chloro-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one (190.0 mg, 0.452 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert butyl ester (140.0 mg, 0.452 mmol), potassium carbonate (187.0 mg, 1.36 mmol), and PdCl2(dppf) (37.0 mg, 0.045 mmol) were suspended in anhydrous dimethyl formamide (2 mL) and the mixture was heated to 110° C. After nineteen hours, the heating was stopped and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The product was purified by column chromatography (30% EtOAc/Hexanes) to provide the title compound as a colourless solid (55.0 mg, 23%.) 1H NMR (300 MHz, CDCl3): δ 7.38 (m, 3H), 7.26 (s, 1H), 7.18 (d, 2H), 6.18 (broad s, 1H), 4.79 (s, 2H), 4.25 (s, 2H), 4.11 (broad s, 2H), 3.65 (t, 2H), 2.5 (broad s, 2H), 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2.[CH3:13][S:14]([CH:17]=[CH2:18])(=[O:16])=[O:15]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][CH2:17][S:14]([CH3:13])(=[O:16])=[O:15])[C:6]([CH2:11][OH:12])=[CH:5]2
Reactant: OCc1cc2cc(Cl)ccc2[nH]1
Reactant: C=CS(C)(=O)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCn1c(CO)cc2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of (5-chloro-1H-indol-2-yl)-methanol (3.6 g, 0.02 mol), Ce2CO3 (13 g, 0.04 mol) in 100 mL of DMF which was cooled to 0° C., was added methanesulfonyl-ethene (2.1 g, 0.02 mol) in portions. The reaction mixture was stirred at a temperature between 30° C. and 50° C. overnight. Ice-water was then added to the mixture, the precipitate was filtered and dried to give [5-chloro-1-(2-methanesulfonyl-ethyl)-1H-indol-2-yl]-methanol (2 g, yield: 34.7%).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].N1CCCCC1.CCOC(C)=O>C1COCC1.O.[Cu]I>[CH3:12][C:4]1[CH:3]=[C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][OH:9]
Reactant: Cc1cc(I)ccc1OCCO
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C#C[Si](C)(C)C)ccc1OCCO

Procedure:
31 mg (0.160 mmol) of CuI was added under argon to a degassed solution of 2:225 g (8.000 mmol) of 2-(4-iodo-2-methylphenoxy)ethanol, 1.22 mL (8.80 mmol) of trimethylsilylacetylene, 185 mg (0.160 mmol) of tetrakis(triphenylphosphane)palladium, and 2.38 mL (24.00 mmol) of piperidine in 50 mL of THF and the mixture was stirred for 1 hour at RT. The reaction mixture was diluted with water and the aqueous phase was exhaustively extracted with EtOAc. The combined organic phases were washed with saturated aqueous NaCl solution, dried over sodium sulfate, and evaporated down in vacuo. Purification of the crude product by column chromatography (silica gel, cyc/EtOAc 2:1) yielded light brown crystals. Yield: 1.70 g (86% of theoretical); C14H20O2Si (M=248.393); calc.: molpeak (M+H)+: 249; found: molpeak (M+H)+: 249; Rf value: 0.24 (silica gel, cyc/EtOAc 2:1).
Reaction SMILES: [CH3:1][Si:2]([CH3:54])([CH3:53])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([N:29]2[CH2:35][CH:34]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:9]=1Br.C([Sn](CCCC)(CCCC)[C:60]([O:62][CH2:63][CH3:64])=[CH2:61])CCC>O1CCOCC1.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>[CH3:1][Si:2]([CH3:54])([CH3:53])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([N:29]2[CH2:35][CH:34]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:9]=1[C:60]([O:62][CH2:63][CH3:64])=[CH2:61]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1c(N2CC3CCC(C2)N3C(=O)OC(C)(C)C)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C

Procedure:
A degassed mixture of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (256 mg, 0.31 mmol), Pd(PPh3)4 (35 mg, 0.031 mmol), tributyl(1-ethoxyvinyl)stannane (221 mg, 0.61 mmol) in dioxane (6 mL) was heated at 100° C. overnight. The reaction mixture was cooled to room temperature, filtered through a 9:1 SiO2:KF plug and concentrated in vacuo. Purification by column chromatography afforded tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, LCMS tR=3.58 Min (10 min run, UV254nm). Mass calculated for M+H 828.45, observed LC/MS m/z 828.07 (M+H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Zn](CC)CC.CN([C@@H](C1C2C(=CC=CC=2)C=CC=1)C1C2C(=CC=CC=2)C=CC=1O)[C@H](C1C=CC=CC=1)C.[Cl:47][C:48]1[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=1[CH:50]=[O:51]>C1(C)C=CC=CC=1>[Cl:47][C:48]1[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=1[C@@H:50]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:51]
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccccc1Cl
Agent: CC[Zn]CC
Agent: C[C@@H](c1ccccc1)N(C)[C@@H](c1cccc2ccccc12)c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Product: O[C@H](c1ccccc1)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 10 h
Yield: 91.1 %

Procedure:
PhB(OH)2 (122 mg, 1.0 mmol) and ZnEt2 (334 μL, 3.25 mmol) in toluene (1 mL) is charged to a 10 mL flask under a nitrogin atmosphere. This mixture is heated to 60° C. and stirred for 10 h with a magnetic stirrer. Then the mixture is cooled to 0° C. and the title compound of Example 1, 1-{(S)-[methyl-((S)-1-phenyl-ethyl)-amino]-naphthalen-1-yl-methyl}-naphthalen-2-ol (16.7 mg, 0.04 mmol) in toluene (0.5 mL) and DiMPEG (100 mg, 0.05 mmol) in toluene (0.5 mL) are added. After stirring for additional 15 min, the solution is cooled to −15° C. and 2-chlorobenzaldehyde (70.0 mg, 0.5 mmol) in toluene (1 mL) is added. After stirring 15 h at −15° C., the reaction is quenched with 1 N hydrochloric acid (HCl, 2 mL) and the mixture is extracted with ethyl acetate (EtOAc, 5 mL), dried over anhydrous sodium sulfate (Na2SO4) and the solvent is removed in vacuo. The purification of the residue by flash chromatography (EtOAc/hexane, 1:10) gives (R)-(2-chlorophenyl)phenylmethanol in about 96.9% ee and about 91.1% yield (the ee value is determined by HPLC using a Chiralcel OB-H column).