Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:20][CH2:19][CH:18]([N:15]3[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]3)[CH2:23][CH2:22]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: CN1CCN(C2CCNCC2)CC1
Product: CN1CCN(C2CCN(c3cccc(Br)c3)CC2)CC1

Procedure:
1-[1-(3-Bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine was prepared from 3-bromophenylboronic acid (0.50 g, 2.5 mmol) and 1-methyl-4-piperidin-4-yl-piperazine (0.23 g, 1.2 mmol) in a manner analogous to Step 49a. The reaction product was isolated as a brown viscous oil (0.069 mg, 16%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.08 (t, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 3.72 (d, J=11.7 Hz, 2H), 2.78-2.33 (m, 11H), 2.30 (s, 3H), 1.93 (d, J=12.9 Hz, 2H), 1.69-1.57 (m, 2H). MS=338, 340 (MH)+. 58b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyri din-2-yl]-{3-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (55.0 mg, 0.191 mmol) and 1-[1-(3-bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine (69.0 mg, 0.204 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.035 g, 34%). MP=237-239° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.5 Hz, 1H), 8.25 (d, J=6.9 Hz, 2H), 8.08 (d, J=7.7 Hz, 2H), 7.65 (d, J=7.1 Hz, 1H), 7.31 (s, 1H), 7.24-7.18 (m, 1H), 7.04-6.95 (m, 2H), 6.82 (s, 1H), 6.60 (d, J=7.9 Hz, 1H), 3.81 (d, J=11.4 Hz, 2H), 3.10 (s, 3H), 2.77 (t, J=12.2 Hz, 2H), 2.72-2.33 (m, 9H), 2.30 (s, 3H), 1.96 (d, J=11.2 Hz, 2H), 1.75-1.63 (m, 2H). MS=546 (MH)+.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[C:21](/[CH3:28])=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO>[F:30][C:2]([F:1])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[C:21](/[CH3:28])=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C(=C\C(=O)O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To (E)-ethyl 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-2-enoate (C26) (1.30 g, 3.10 mmol) in methanol (10 mL) was added sodium hydroxide (2 N, 12.3 mL, 24.6 mmol) and stirred at room temperature overnight. Additional sodium hydroxide (2 N) was added and the reaction was heated to 50° C. for 3 days. The reaction was acidified with hydrogen chloride (2 N) and the white precipitate was collected by vacuum filtration to afford the title compound as a white solid (1.16 g, 95%): mp 234-238° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.43 (s, 1H), 8.14 (d, J=8.6 Hz, 2H), 8.09 (d, J=9.1 Hz, 2H), 7.73 (d, J=8.6 Hz, 2H), 7.68-7.53 (m, 2H), 6.22 (d, J=1.3 Hz, 1H), 2.54 (d, J=1.3 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 390 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[CH:5][CH:4]=1)#[N:2].N([O-])=[O:13].[Na+].S(=O)(=O)(O)O>C(O)(=O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:13])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=N[O-]
Reactant: N#Cc1ccc(C(N)=O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
p-Cyanobenzamide (1.46 g) and acetic acid (20 ml) were mixed and stirred vigorously at room temperature. To the mixture, sodium nitrite (2.07 g), and immediately thereafter, 95 wt. % sulfuric acid (3 g) was added and stirred vigorously for one hour. The acetic acid was removed under reduced pressure, and water (40 ml) was added to the residue. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 1.26 g of p-cyanobenzoic acid (yield 86%). The p-cyanobenzoic acid obtained had a purity of 95%.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([S:13]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([S:13]([NH:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(S(=O)(=O)NCCN2CCOCC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(NCCN1CCOCC1)c1cccc(O)c1
Temperature: 0 °C

Procedure:
A solution of boron tribromide (1M in CH2Cl2, 20 mL, 20 mmol) was added to a −78° C. solution of the product of Step 1 in CH2Cl2 (50 mL) and the resulting mixture was allowed to warm to 0° C. After 2 h at 0° C. the mixture was re-cooled to −78° C. and quenched with sat. aq. NaHCO3 solution and allowed to warm to rt. The mixture was extracted with EtOAc, and the organic layers was washed with H2O and brine, dried (MgSO4), filtered and the filtrate was concentrated to give the title compound as a crude oil (1.9 g, 66%) which was used directly in the next step. MS (ES+) m/e 287 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]([CH3:9])[C:7](=[O:10])[C:6]([CH2:11][CH2:12]O)=[C:5]([CH3:14])[N:4]=1.N1C=CC=CC=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[CH3:1][S:2][C:3]1[N:8]([CH3:9])[C:7](=[O:10])[C:6]([CH2:11][CH2:12][Cl:23])=[C:5]([CH3:14])[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1nc(C)c(CCO)c(=O)n1C
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CSc1nc(C)c(CCCl)c(=O)n1C
Reaction time: 0.25 h

Procedure:
To a solution of 2-methylthio-5-(2-hydroxyethyl)-3,6-dimethyl-3H-pyrimidin-4-one (20.3 g, 0.095 mol) in chloroform (200 ml) was added one equivalent of pyridine (7.6 ml), followed by slow addition of three equivalents of thionyl chloride (21 ml). After stirring for 15 minutes, the mixture was concentrated and water (300 ml) was added. The precipitate was collected and washed with water, isopropyl alcohol and petroleum ether. Yield 34.4 g (64%). Yield 20.3 g (92%). Mp. 135-137° C.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.OS(O)(=O)=O.[CH:21](=O)[CH2:22][CH3:23]>O>[CH2:22]([CH:23]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH:2]([C:13]([OH:15])=[O:14])[NH:1]1)[CH3:21]
Reactant: CCC=O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC1NC(C(=O)O)Cc2c1[nH]c1ccccc21
Yield: 74 %

Procedure:
L-tryptophan (5.10 g, 25 mmol), water (300 ml), H2SO4 (0.05M, 30 ml) and propionaldehyde (8 ml) were added in a 250 ml round-bottom flask, and then stirred and reacted at room temperature for 24 h. After filtration, wash with water and drying, white solids (4.5 g, 74%) were obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[C:39]([C:41]1[CH:42]=[C:43]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:44]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:46]=1)#[N:40].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:39]([C:41]1[CH:42]=[C:43]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:44]=[C:45]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:46]=1)#[N:40]
Reactant: CC1(C)OB(c2cc(C#N)cc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(C#N)cc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 88.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (138 mg, 0.23 mmol) was treated with N-(3-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (545 mg, 0.62 mmol, prepared from N-(3-bromo-5-cyanophenyl)methanesulfonamide, described at WO 2009015369 A2 20090129, and bis(pinacolato)diboron according to Preparation 119b), sodium carbonate (58 mg, 0.55 mmols) and bis(triphenylphosphine)palladium(II) dichloride (61 mg, 0.07 mmol) according to the method described in Preparation 62. The residue was purified by reverse phase chromatography using SP1® Purification System (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give 145 mg (88% yield) of the title compound. Purity 100%.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([OH:21])=O)[CH:13]=[CH:12]2)(=[O:7])[CH3:6]>CN(C)C=O>[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([Cl:3])=[O:21])[CH:13]=[CH:12]2)(=[O:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2cc(C(=O)Cl)ccc2c1

Procedure:
2.0 ml of thionyl chloride and a drop of N,N-dimethylformamide were added to 1.45 g (6.30 mM) of 6-acetoxy-2-naphthoic acid, followed by refluxing for 30 minutes under stirring. Excessive thionyl chloride was distilled off from the above mixture under reduced pressure to obtain 6-acetoxy-2-naphthoyl chloride. ##STR32##
Reaction SMILES: [CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[N:6]([C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[Li]CCCC.[Si:36]([O:43][C:44]1[C:45]([F:54])=[C:46]([CH:49]=[C:50]([CH2:52][CH3:53])[CH:51]=1)[CH:47]=[O:48])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>C1COCC1>[Si:36]([O:43][C:44]1[C:45]([F:54])=[C:46]([CH:47]([C:7]2[N:6]([C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]3[CH:28]=[C:29]([CH3:30])[C:2]([CH3:1])=[CH:3][C:4]=3[N:8]=2)[OH:48])[CH:49]=[C:50]([CH2:52][CH3:53])[CH:51]=1)([C:39]([CH3:40])([CH3:42])[CH3:41])([CH3:38])[CH3:37]
Reactant: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: Cc1cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc3cc(C)c(C)cc3n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.7 %

Procedure:
To a solution of intermediate 415.1 (100 mg, 0.257 mmol) in 2 mL THF at 0° C., was added BuLi (1.6 M in hexanes, 193 μL, 0.309 mmol). The mixture was stirred at 0° C. for 20 min, then a solution of 3-(tert-butyldimethylsilyloxy)-5-ethyl-2-fluorobenzaldehyde (188.3) (72.6 mg, 0.257 mmol) in 0.6 mL THF was added. The mixture was removed from the ice bath and stirred 70 min, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 115 mg of intermediate 415.2. LCMS (2 min gradient) RT=2.24 min, 671.13 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5](OC)=[O:6].[BH4-].[Li+]>COCCOCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:5][OH:6]
Reactant: COC(=O)c1ccc(C)c(N)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: COCCOCCOC
Product: Cc1ccc(CO)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
Methyl 3-amino-4-methylbenzoate (16.52 g, 0.1 mol) was dissolved in diglyme (150 ml), lithium borohydride (2.18 g, 0.1 mol) added, and the solution stirred at room temperature overnight. A further portion of lithium borohydride (2.18 g, 0.1 mol) was added, and the mixture heated at reflux for 20 minutes. The reaction was quenched with water, the solvent evaporated, the residue dissolved in water, the solution adjusted to pH 5 with hydrochloric acid, and the product extracted into dichloromethane. Drying, evaporation and trituration with ether gave 3-amino-4-methylbenzyl alcohol (7.3 g, 54%), m.p. 105°-107°.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14]C[NH:12]2)[CH:6]=[N:7][CH:8]=1)=[CH2:2].[ClH:16].CO>CCOCC>[ClH:16].[ClH:16].[NH:12]1[CH2:14][CH2:15][C@H:11]1[CH2:10][O:9][C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH:1]=[CH2:2])[CH:4]=1
Reactant: C=Cc1cncc(OC[C@@H]2CCCN2)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C=Cc1cncc(OC[C@@H]2CCN2)c1

Procedure:
To a solution of 5-ethenyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine in Et2O was added hydrogen chloride (1.0 M in Et2O) carefully to afford the tittle compound: mp 88-90° C. 1H NMR (D2O) δ 2.64-2.78 (m, 2H), 4.04-4.22 (m, 2H), 4.50 (d, 1H, J=4.0 Hz), 4.80 (m, 1H), 4.96 (m, 1H), 5.58 (dd, 1H, J=11.0 Hz), 6.04 (d, 1H, J=18.0 Hz), 6.83 (dd, 1H, J=11.0, 18.0 Hz), 7.85 (t, 1H, J=2.0 Hz), 8.31 (br s, 1H), 8.36 (br s, 1H); MS (CI/NH3) m/z 191 (M+H)+. Anal. Calcd for C11H14N2O.1.8 HCl: C, 51.64; H, 6.22; N, 10.95. Found: C, 51.59; H, 5.92; N, 10.75. [α]25D +2.58 (c 0.62, MeOH
Reaction SMILES: N(OC(C)(C)C)=O.NC1C=C([C@@H]2CNC(=O)C2)C=CC=1[Cl:15].Cl.[NH2:23][CH2:24][C@@H:25]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32](Br)[CH:31]=1)[CH2:26][C:27]([OH:29])=[O:28]>C(#N)C.C(OCC)(=O)C.[Cu](Cl)Cl>[ClH:15].[NH2:23][CH2:24][C@@H:25]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:15])[CH:31]=1)[CH2:26][C:27]([OH:29])=[O:28]
Reactant: NC[C@H](CC(=O)O)c1ccc(Cl)c(Br)c1
Reactant: Nc1cc([C@@H]2CNC(=O)C2)ccc1Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC[C@H](CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Copper(II) chloride (0.183 g, 1.37 mmol) and tert-butyl nitrite (0.2 mL, 1.71 mmol) was stirred in acetonitrile (1 mL) at 0° C. (4R)-4-(3-Amino-4-chlorophenyl)pyrrolidin-2-one (0.24 g, 1.14 mmol) in acetonitrile (1 mL) was added dropwise. The mixture was warmed to 60° C. and stirred for 1 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and washed with a 10% aqueous HCl solution, brine, and the ethyl acetate layers were concentrated. Hydrolysis of the resulting lactam with aqueous HCl as described for the preparation of (3R)-4-amino-3-(3-bromo-4-chlorophenyl)butanoic acid hydrochloride provided the title compound. 1H-NMR (400 MHz, CD3OD): δ 7.53-7.54 (m, 1H), 7.51 (s, 1H), 7.26 (m, 1H), 3.28-3.41 (m, 2H), 3.15-3.21 (m, 1H), 2.77-2.83 (dd, J=16.4, 6.4 Hz, 1H) 2.63-2.69 (dd, J=16.8, 8.0 Hz, 1H); MS (ESI) m/z 247.99 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[CH2:11][CH:10]([C:14](OC)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCN(Cc2ccccc2)C1
Temperature: 60 °C

Procedure:
In accordance with the technique of “Bioorganic and Medicinal Chemistry Letters”, 1991, vol. 1, no. 12, p. 757-760, methyl 1-benzyl-5-oxopyrrolidine-3-carboxylate (mfd. by Aldrich, USA) was added to a THF solution of lithium aluminum hydride in an ice bath, and then stirred at 60° C. for 1.5Hours. Thereafter, its work-up and purification were carried out in the standard method to obtain (1-benzylpyrrolidin-3-yl)methanol. FP: 192.
Reaction SMILES: [I-].[Sm+2].[I-].[C:4]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][O:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29]([C:33]([C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH2:47][C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)[CH:41]=3)=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:28]=[CH:27]4)[N:19]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].CN(C)P(N(C)C)(N(C)C)=O.CO.[Cl-].[NH4+]>C(O)C>[C:4]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][O:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29]([CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH2:47][C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)[CH:41]=3)[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:28]=[CH:27]4)[N:19]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10])([CH3:5])([CH3:6])[CH3:7]
Reactant: CCOC(=O)C=C(c1cccc(OCc2ccccc2)c1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CC(c1cccc(OCc2ccccc2)c1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 493.2 %

Procedure:
Samarium (II) iodide [0.1 M in THF] (14.8 mL, 14.8 mmol) was added to a solution of 7-(2-{1-[1-(3-benzyloxy-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (0.10 g, 0.15 mmol), hexamethylphosphoramide (0.39 mL, 2.22 mmol) and either ethanol or methanol (10 equivalents) and stirred at room temperature overnight. Saturated ammonium chloride (20 mL) was added to the reaction and the crude product was extracted with ethyl acetate (3×20 mL). The crude mixture was then purified via column chromatography in silica gel (20% ethyl acetate in hexane) to give the title compound (0.50 g, 50% yield). 1H NMR (CDCl3) δ 7.28–7.22 (m, 5H), 7.13 (m, 4H), 7.08 (d, 1H, J=3.2 Hz), 6.86 (m, 1H), 6.79–6.69 (m, 4H), 6.35 (d, 1H, J=3.2 Hz), 5.99 (t, 1H, J=7.5 Hz), 4.98 (s, 2H), 4.29 (t, 2H, J=6.9 Hz), 3.96 (q, 2H, J=7.1 Hz), 3.68 (m, 2H), 3.18–3.10 (m, 4H), 2.66 (m, 2H), 1.85 (m, 2H), 1.45 (s, 9H), 1.01 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[CH3:10][C:11]1([CH3:20])[CH2:16][CH2:15][C:14](B(O)O)=[CH:13][CH2:12]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:14]2[CH2:15][CH2:16][C:11]([CH3:20])([CH3:10])[CH2:12][CH:13]=2)[CH:3]=1
Reactant: Nc1ccc(Br)cc1I
Reactant: CC1(C)CC=C(B(O)O)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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(c2cc(Br)ccc2N)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 93.8 %

Procedure:
A mixture of 4-bromo-2-iodo-phenylamine (873 mg, 2.93 mmol), 4,4-dimethylcyclohexen-1-ylboronic acid (496 mg, 3.22 mmol), Pd(PPh3)4 (169 mg, 0.147 mmol) and 2.0 M aq Na2CO3 (11.7 mL, 23.4 mmol) in 20 mL of 1,4-dioxane was stirred at 80° C. for 12 h under Ar. After cooling to RT, the reaction was treated with EtOAc (50 mL) and washed with H2O (25 mL) and brine (20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5% EtOAc/hexane) to afford 770 mg (91%) of the title compound as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C14H18BrN, 280.1 (M+H). found 280.1.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(Cl)Cl.O>C(Cl)Cl>[C:1]1([CH3:15])[CH:2]=[CH:3][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(Oc2ccc(N)cc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(NS(C)(=O)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-p-tolyloxy-phenylamine (0.87 g, 4.38 mmol) and pyridine (0.52 mL, 6.53 mmol) in dried CH2Cl2 (10 mL) under N2 at 0° C. was added methanesulfonyl chloride (0.41 mL, 5.26 mmol) dropwise. The mixture was stirred at 0° C. for 1 h and was then poured into CH2Cl2/H2O (10 mL/10 mL). The organic layer was washed with 2N HCl (aq) (3 mL), H2O, brine, dried (Na2SO4), and filtered through Celite. After removal of solvent, the crude product was purified by chromatography (silica gel, 45% EtOAc/hexanes) to give the titled compound. MS (EI) 278 (M+H)+.
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27])[CH3:21])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[O:27]=[C:23]1[CH2:24][CH2:25][CH2:26][N:22]1[C@@H:20]([CH3:21])[CH2:19][OH:18]
Reactant: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1CCCC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO)N1CCCC1=O
Temperature: 25 °C
Yield: 199.5 %

Procedure:
A 0° C. solution of 11.20 g (29.4 mmol) of (S)-2-(2-oxopyrrolidin-1-yl)propyl tert-butyldiphenylsilyl ether (Part B) in 100 mL of THF was treated with 36.0 mL (36 mmol) of tetrabutylammonium fluoride (1 M in THF). The reaction was stirred at ambient temperature until tic analysis indicated the complete disappearance of starting material (30 min). The reaction was poured into 300 mL of H2O and the mixture extracted with CH2Cl2 (3×300 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 8.40 g of the corresponding (S)-2-(2-oxopyrrolidin-1-yl)propyl alcohol which was used without purification.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10]O)/[CH3:8])[CH3:3].[C:12]1([OH:24])[CH:23]=[C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:16]=[C:14]([OH:15])[CH:13]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:8]/[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1])=[CH:9]\[CH2:10][C:13]1[C:12]([OH:24])=[CH:23][C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:16][C:14]=1[OH:15]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CCCCCc1cc(O)cc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCc1cc(O)c(C/C=C(\C)CCC=C(C)C)c(O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Geraniol (3 g, 0.0194 mol) and olivetol (2 g, 0.0111 mol) were dissolved in 400 mL of chloroform containing 80 mg of p-toluenesulfonic acid as catalyst and the reaction mixture was stirred at room temperature for 12 h in the dark. After 12 hours, the reaction mixture was washed with saturated sodium bicarbonate (400 mL) and then with H2O (400 mL). The chloroform layer was concentrated at 40 C under reduced pressure, and the residue obtained was chromatographed on a 2.0 cm×25 cm silica gel column using benzene (1000 mL) as the eluent to give 1.4 g (0.00442 mol)(39.9%) CBG as product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:36])[C:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[N:31](C(C)(C)C)[N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:7]=2[N:8]=1.CS(O)(=O)=O>C1(C)C=CC=CC=1>[OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:36])[C:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:7]=2[N:8]=1
Reactant: Cc1nc(CO)nc2c1CCC(=O)N2Cc1ccc(-c2ccccc2-c2nnnn2C(C)(C)C)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1nc(CO)nc2c1CCC(=O)N2Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 102.9 %

Procedure:
A mixture of 2-hydroxymethyl-4-methyl-8-[2'-(1-tert-butyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (1.2 g, 2.50 mmol), methanesulfonic acid (2.40 g, 25.0 mmol), and toluene (14 mL) was heated under reflux for 20 h. The mixture was concentrated, taken up in water, and the pH was adjusted to 7-8 with 1 N NaOH. The aqueous mixture was extracted with EtOAc (discarded), acidified to pH 4 with 1N HCl, and extracted with CHCl3. The CHCl3 layers were dried (MgSO4) and concentrated to give 1.10 g of a foam. Trituration with EtOAc/acetone and recrystallization from EtOH gave 0.45 g (46%) of product as a white solid, mp 218°-220° C.