Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[S:33](Cl)(=[O:35])=[O:34]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[S:33]([C:29]2[S:28][CH:32]=[CH:31][N:30]=2)(=[O:35])=[O:34])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1nccs1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ncccn3)cc2)S(=O)(=O)c2nccs2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 1 from 3-{3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11z, and thiazole-2-sulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.80 (d, 2H), 8.30 (d, 2H), 7.96 (d, 1H), 7.59 (m, 1H), 7.24 -7.13 (m, 4H), 7.05 (d, 1H), 6.96 (d, 1H), 6.92 (s, 1H), 4.54 (s, 2H), 4.49 (s, 2H), 3.64 (s, 3H), 2.82 (t, 2H), 2.51 (t, 2H); MS 509 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Si]([O:46][CH2:47][C:48]1[S:52][C:51]([C:53](=[N:55]O)[NH2:54])=[C:50]([CH3:57])[CH:49]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.O1CCCC1.O>[CH3:57][C:50]1[CH:49]=[C:48]([CH2:47][OH:46])[S:52][C:51]=1[C:53]1[N:55]=[C:12]([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)[O:14][N:54]=1
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3)cc2)n1
Yield: 86 %

Procedure:
To a solution of 4-phenoxybenzoic acid (0.14 g, 0.63 mmol) in a mixture of acetonitrile (4 ml) and tetrahydrofuran (2 ml) were added successively 1-hydroxybenzotriazole (89 mg, 0.66 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.13 g, 0.66 mmol) and 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-N′-hydroxy-3-methylthiophene-2-carboximidamide (0.18 g, 0.60 mmol) that was obtained in Example 11 (11d) with stirring, and the resulting mixture was stirred at 50° C. for 30 minutes. After stirring, water (5 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with ethyl acetate. The extract was washed successively with 0.1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained in tetrahydrofuran (5 ml) was added a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.2 ml, 1.2 mmol) with stirring, and the resulting mixture was stirred at 50° C. for 2 hours. After stirring, the reaction mixture was poured into water (20 ml) to quench the reaction and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3 to 1:2) as the eluent to afford the title compound (0.19 g) in a yield of 86% as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:19]C1C=CC(NC2C=CC=CC=2)=CC=1.N1C=CC=CC=1C=O>>[F:19][C:7]1[CH:6]=[CH:5][C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)=[CH:3][CH:2]=1
Reactant: Fc1ccc(Nc2ccccc2)cc1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: Fc1ccc(-n2nnc(-c3ccccn3)n2)cc1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 4-fluorophenylaniline (33.3 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(4-fluorophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17]3=[N:18][C:19]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:13]2=[O:37])[CH2:8]1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl.O>[OH:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17]3=[N:18][C:19]([NH:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:13]2=[O:37])[CH2:8]1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)C3)C2=O)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@H]3CC[C@H](O)C3)C2=O)cc1
Reaction time: 0.5 h

Procedure:
(−)-(1S,3S)-1-[3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentyl]-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (445 mg, 0.82 mmol) (from Example 29g supra) was dissolved in a 25% trifluoroacetic acid in dichloromethane solution (5 mL) and water (300 μL) at 0° C. After stirring for 30 minutes the mixture was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide and the pH of the aqueous layer was adjusted to 12 via the addition of solid sodium hydroxide. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a residue that was purified by chromatography with a silica gel column and a 0–100 ethyl acetate in hexanes to 0–40% tetrahydrofuran in ethyl acetate gradient to give (−)-(1S,3S)-1-(3-hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid. (Yield 307 mg, 86%).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])(C)C)=[O:17])[C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([Cl:12])[CH:5]=1.Cl.[CH:24]1[C:36]2C(COC(ON3C(=O)CCC3=O)=O)[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1.CCOC(C)=O>O1CCOCC1.O>[NH:1]([C:16]([O:18][CH2:19][CH:22]1[C:27]2[C:28](=[CH:36][CH:24]=[CH:25][CH:26]=2)[C:29]2[C:34]1=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:17])[C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([Cl:12])[CH:5]=1
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1Cl
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1Cl
Temperature: 23 °C
Reaction time: 18 h

Procedure:
Boc-3-Cl-D-Tyr(Me)-OH (9.60 g, 29.1 mmol) was treated with 4 M HCl in dioxane (25 mL) at 23° C. for 1 h then the reaction mixture was concentrated in vacuo. The residual white solid was dissolved in 10% aqueous Na2CO3 (60 mL), dioxane (60 mL) and N-(9-Fluorenylmethoxy-carbonyloxy)succinimide (9.82 g, 29.1 mmol) were added. The reaction mixture was stirred at 23° C. for 18 h, then diluted with water (100 mL). The aqueous phase was extracted with Et2O (2×100 mL), acidified to pH 2 (conc. HCl) and extracted with EtOAc (3×100 mL). The combined EtOAc phases were washed with saturated aqueous NaCl, dried with MgSO4, filtered and concentrated. Without further purification the title compound 8 (12.65 g, 96%) was obtained as white foam. TLC Rf=0.26 (EtOAc, PMA stain); 1H NMR (CDCl3, 400 MHz) δ 9.82 (br s, 1H), 7.76 (d, J=7.6, 2H), 7.56 (t, J=7.6, 2H), 7.39 (t, J=7.6, 2H), 7.31 (d, J=7.6, 2H), 7.19 (d, J=1.6, 1H), 6.99 (dd, J=8.3, 1.6, 1H), 6.80 (d, J=8.3, 1H), 5.44 (d, J=7.8, 1H), 4.64-4.69 (m, 1H), 4.46 (dd, J=10.5, 7.0, 1H), 4.35 (dd, J=10.5, 7.0, 1H), 4.21 (t, J=7.0, 1H), 3.83 (s, 3H), 3.14 (dd, J=14.1, 5.3, 1H), 3.02 (dd, J=14.1, 6.3, 1H); 13C NMR (CDCl3, 101 MHz) δ 175.0, 155.9, 154.2, 143.7, 141.4, 131.1, 128.8, 128.8, 127.8, 127.2, 125.2, 125.1, 120.1, 112.2, 67.2, 56.1, 54.6, 47.2, 36.8; MS (ESI+) m/z 474.1 [M+Na]+ (C25H22ClNNaO5 requires 474.1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[C:10]([C:13]1[C:14]([OH:23])=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])(=[O:12])[CH3:11].CCN(C(C)C)C(C)C.O>CC#N>[C:7]([O:23][C:14]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=[CH:22][C:13]=1[C:10](=[O:12])[CH3:11])(=[O:8])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COC(=O)c1cccc(C(C)=O)c1O
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(C(C)=O)c1OC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.4 %

Procedure:
Pyridine-4-carbonyl chloride 42 (705 mg, 5 mmol) was added to a solution of methyl 3-acetyl-2-hydroxybenzoate 38 (650 mg, 3.6 mmol) and DIEA (932 mg, 7.2 mmol) in CH3CN (10 mL). The reaction mixture was stirred at room temperature for 12 h, poured into H2O (20 mL) and extracted with CH2Cl2. The combined organic extracts were dried (MgSO4) and concentrated. The residue was purified by prep HPLC to give the product as a yellow solid (855 mg, 83% yield).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12]/[C:13](=[CH:21]\[CH2:22][CH2:23][C:24](=[CH2:27])[CH:25]=[CH2:26])/[CH2:14][CH2:15][C:16]([O:18]CC)=[O:17].C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:9][CH:21]([C:13]1([CH3:12])[CH2:14][CH2:15][C:16](=[O:18])[O:17]1)[CH2:22][CH2:23][C:24](=[CH2:27])[CH:25]=[CH2:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(=C)CC/C=C(\C)CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: C=CC(=C)CCC(O)C1(C)CCC(=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
m-Chloroperbenzoic acid (36 g, 0.175 M) is added in five portions to a mixture of ethyl 4-methyl-8-methylene-(E)-4,9-decadienoate (40 g, 0.18 M) and methylene chloride (1 l), at -8° C. under nitrogen and the resulting mixture is stirred for two hours. The precipitate is filtered and the filtrate dried in vacuo to give crude ethyl 4-methyl-8-methylene-4,5-oxido-9-decenoate. This material is dissolved in methanol (200 ml) and the resulting solution is treated with saturated potassium carbonate solution (50 ml) and water (50 ml) and stirred overnight. Most of the methanol is removed in vacuo, the residue is cooled to 0° C. and slowly treated with conc. hydrochloric acid (150 ml). The resulting mixture is extracted with ether (3×350 ml). The combined organic layers are dried (Na2SO4), the solvent is removed in vacuo, and the residue (52 g) is purified by column chromatography on silica gel (400 g) with ether-petroleum ether (4:1) to give 2-(1-hydroxy-4-methylene-5-hexenyl)-2-methyl-5-oxo-tetrahydrofuran as a colorless liquid (22 g, 58%).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45](Cl)=[CH:44][C:43]=1[F:49].[CH2:51]([C:53]([C:72]1[CH:85]=[CH:84][C:75]([O:76][CH2:77][CH:78]([OH:83])[C:79]([CH3:82])([CH3:81])[CH3:80])=[C:74]([CH3:86])[CH:73]=1)([C:56]1[CH:61]=[CH:60][C:59](B2OC(C)(C)C(C)(C)O2)=[C:58]([CH3:71])[CH:57]=1)[CH2:54][CH3:55])[CH3:52]>O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:59]2[CH:60]=[CH:61][C:56]([C:53]([CH2:51][CH3:52])([C:72]3[CH:85]=[CH:84][C:75]([O:76][CH2:77][CH:78]([OH:83])[C:79]([CH3:81])([CH3:82])[CH3:80])=[C:74]([CH3:86])[CH:73]=3)[CH2:54][CH3:55])=[CH:57][C:58]=2[CH3:71])=[CH:44][C:43]=1[F:49]
Reactant: COC(=O)Cc1ccc(Cl)cc1F
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
A solution of palladium acetate (3.8 mg, 0.0169 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (13.9 mg, 0.0339 mmol) and potassium phosphate (72.0 mg, 0.33 mmol) in water (0.050 mL) and toluene (0.200 mL) was stirred for three minutes. A solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester (Example 40; 36.8 mg, 0.18 mmol) and 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol (Example 31; 60.0 mg, 0.12 mmol) in toluene (0.3 mL) was added, and the mixture was stirred in a nitrogen atmosphere at 100° C. for one hour. After filtration through cotton plug, the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (8% ethyl acetate/hexane) to give the title compound (21.1 mg, 32%).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]([CH3:17])([CH3:16])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1)=[O:7]>CO>[CH3:16][C:5]1([CH3:17])[O:7][C:6]1([O:2][CH3:1])[C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1
Reactant: CSc1ccc(C(=O)C(C)(C)Br)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC1(c2ccc(SC)cc2)OC1(C)C

Procedure:
95.1 g (1.76 mols) of sodium methylate are dissolved in 600 ml of methanol, and 437.1 g (1.60 mols) of 2-bromo-2-methyl-1-[4-(methylthio)-phenyl]-propan-1-one, dissolved in 300 ml of methanol, are added dropwise to this solution at reflux temperature. The methanol is then removed by distillation. The residue is poured into ice water, and the mixture is extracted with diethyl ether. The ether solution is washed with water, dried over Na2SO4 and concentrated. The crystals obtained are purified by vacuum distillation.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[C:12]([N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1)(=[O:14])[CH3:13].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C.C(O)(=O)C>[C:12]([N:15]1[CH2:20][CH2:19][C:18]([OH:21])([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(=O)N1CCC(O)(C#C[Si](C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of trimethylsilylacetylene (17 ml) in tetrahydrofuran (100 ml) were added successively a solution of n-butyllithium in n-hexane (1.50M, 81 ml) and a solution of 1-acetyl-4-piperidone (11.5 g) in tetrahydrofuran (15 ml) at -78° C. After stirring at -78° C. for 30 minutes, to the mixture was added acetic acid (5.0 ml) and the resultant mixture was taken up into a mixture of aqueous ammonium chloride (300 ml) and ethyl acetate (300 ml) at 0° C. The organic layer was separated and washed with brine, dried over magnesium sulfate. Evaporation of the solvent gave a crystalline which was collected by filtration, and washed with n-hexane to give 1-acetyl-4-hydroxy-4-(2-trimethylsilylethynyl)piperidine (14.48 g).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[NH2:12][CH2:13][CH:14]1[O:19][CH2:18][CH2:17][N:16]([CH2:20][CH:21]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)[OH:22])[CH2:15]1.[BH4-].[Na+]>C(Cl)Cl.CO>[O:11]1[C:3]2[CH:2]=[CH:1][C:6]([CH2:7][NH:12][CH2:13][CH:14]3[O:19][CH2:18][CH2:17][N:16]([CH2:20][CH:21]([C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=5)[N:26]=[CH:25][CH:24]=4)[OH:22])[CH2:15]3)=[CH:5][C:4]=2[O:9][CH2:10]1
Reactant: COc1ccc2nccc(C(O)CN3CCOC(CN)C3)c2c1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2nccc(C(O)CN3CCOC(CNCc4ccc5c(c4)OCO5)C3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Activated 3A molecular sieve (3.485 g) and piperonal (0.172 g, 1.15 mmol) were added to a solution of 2-(2-aminomethyl-morpholin-4-yl)-1-(6-methoxy-quinolin-4-yl)-ethanol (0.365 g, 1.15 mmol) in DCM (10.5 ml) and methanol (3.5 ml). The mixture was stirred overnight at room temperature before sodium borohydride (0.112 g, 2.9 mmol) was added. The reaction mixture was stirred at room temperature for a further 2 hours, filtered over Hydromatrix (wetted with NaHCO3) and concentrated. The residue was purified by chromatography on silica gel (DCM:MeOH 9:1+1% NH4OH).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[C:19]([CH3:32])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.FC(F)(F)S(O[C:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=4)=[C:19]([CH3:32])[CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)(OC1=CCCCC1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCCCC1
Temperature: 60 °C
Yield: 80.6 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methyl-4-(4,4,5,5tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Step B (3.50 g, 8.17 mmol), cyclohex-1-en-1-yl trifluoromethanesulfonate (2.26 g, 9.80 mmol) and dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium (II) dichloromethane adduct (0.200 g, 0.245 mmol) were combined in N,N-dimethylformamide (40.9 mL). Aqueous sodium carbonate (2M, 20.5 mL, 40.9 mmol) was added and the reaction heated to 60° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in hot ethyl acetate/petroleum ether (1:1) and filtered. The filtrate was concentrated and the residue recrystallized from petroleum ether to afford 2.52 g of the title compound as pale brown crystals, m.p. 182-183° C.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH2:13]Br.C(=O)([O-])[O-].[Cs+].[Cs+].[BH4-].[Na+]>CN(C)C=O.C(O)C>[O:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:3]([CH2:4][OH:5])[C:2]=2[O:1][CH2:13][CH2:12]1
Reactant: O=Cc1cccc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCO
Product: OCc1cccc2c1OCCO2
Temperature: 20 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
Dissolve 2,3-dihydroxybenzaldehyde (25 g, 181 mmol) and 1,2-dibromoethane (34 g, 181 mmol) in N,N-dimethylformamide (500 mL). Add cesium carbonate (118 g, 362 mmol), stir and reflux under nitrogen for 2 hours. Cool the reaction to 20° C., dilute with absolute ethanol (250 mL) and add sodium borohydride (6.8 g, 181 mmol). Stir at 20° C. for 1 hour and concentrate under high vacuum to remove the ethanol and dimethylformamide. Dilute the residue with diethyl ether and wash with distilled water, 0.25 molar aqueous sodium hydroxide, and aqueous saturated sodium chloride. Dry the organic phase over anhydrous magnesium sulfate, filter and concentrate under reduced pressure. Chromatograph on flash silica using a gradient from 75% hexane, 25% ethyl acetate to 25% hexane, 75% ethyl acetate to obtain 8.1 g (27%) of the desired compound as a white solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2([OH:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]2=[O:25])=[CH:11][C:10]=1[CH3:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:28][C:29]([F:41])([F:40])[O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][C:9]1[C:10]([CH3:27])=[CH:11][C:12]([C:16]2([OH:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:29]([F:28])([F:40])[F:41])[CH:32]=3)[C:17]2=[O:25])=[CH:13][C:14]=1[CH3:15])([CH3:6])([CH3:5])[CH3:7]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Cc1cc(C2(O)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(C2(O)C(=O)N(c3cccc(OC(F)(F)F)c3)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Temperature: 32 °C
Yield: 80.2 %

Procedure:
Using a method similar to Preparation 38, with 3-[4-(tert-Butyl-dimethylsilanyloxy)-3,5-dimethyl-phenyl]-3-hydroxy-1,3-dihydro-indol-2-one (15.34 g, 40 mmol), 3-(trifluoromethoxy)phenylboronic acid (16.47 g, 80 mmol), copper (II) acetate (7.27 g, 40 mmol), pyridine (6.5 ml, 80 mmol) and powdered 4A sieves (25 g) in dichloromethane (130 mL) and heat at 32° C. for 1 day stirring mechanically. Add more 3-(trifluoromethoxy)phenylboronic acid (8.24 g, 40 mmol), copper (II) acetate (3.64 g, 20 mmol), pyridine (6.5 ml, 80 mmol) and powdered 4A sieves (25 g) and continue heating for 1 day. Dilute with ethyl acetate (150 mL) and filter slowly through a pads of Celite and silica gel. After the filtration is complete stir the pads in additional ethyl acetate and refilter. Evaporate the organics in vacuo and apply the resulting residue to a silica pad with dichloromethane/acetone. Elute with 2% ethyl acetate/dichloromethane and concentrate in vacuo to obtain 17.45 g of a yellow solid. Titurate the solid in diethyl ether, filter, and dry to obtain 9.47 g (44%) of a white solid. MS (ES): m/z=526 (M+1−H2O); 1H NMR (DMSO-d6): δ7.71 (t, 1H), 7.58-7.52 (m, 3H), 7.32-7.25 (m, 2H), 7.13 (t, 1H), 7.01 (s, 2H), 6.87 (d, 1H), 6.76 (s, 1H), 2.14 (s, 6H), 0.99 (s, 9H), 0.17 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C@@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:23]>C(Cl)Cl.O1CCOCC1.CCOCC>[ClH:23].[CH2:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C@@H:12]([NH2:15])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](COCc2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N[C@@H]1CC[C@H](COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To a solution of 1.52 g (5 mmol) of tert-butyl {(1R,3S)-3-[(benzyloxy)methyl]-cyclopentyl}carbamate in 20 mL of DCM are added, at 0° C., 5 mL (20 mmol) of a 4N solution of HCl in dioxane. The medium is then stirred for 12 hours at room temperature, and then concentrated under reduced pressure. The residue obtained is solidified in 20 mL of Et2O, filtered and dried under vacuum. 1 g of (1R,3S)-3-[(benzyloxy)methyl]cyclopentanamine hydrochloride is obtained in the form of a powder.