Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I:26][CH2:27][CH2:28][CH2:29][CH2:30]I.C(=O)([O-])[O-].[K+].[K+].CCOCC>CS(C)=O>[CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:17])([CH3:18])[C:9](=[O:16])[CH:10]([CH2:30][CH2:29][CH2:28][CH2:27][I:26])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Reactant: ICCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)C(CCCCI)C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O

Procedure:
A mixture of ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (0.5 g), 1,4-diiodobutane(0.23 ml) and potassium carbonate(1.0 g) was stirred in dimethylsulphoxide at 20° C. for 12 hours. The mixture was diluted (ether), washed (brine), dried (MgSO4), evaporated and the residue purified by column chromatography (ethyl acetate/hexane 1:3) to give ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-(4'-iodobutyl)-4-methyl-3-oxo-pentanoate (0.3 g), NMR 1.24(3H, t), 1.3-1.4(2H, m), 1.43((3H, s), 1.48(3H, s), 1.7-2.0(7H, m), 3.12(2H, t), 3.8-3.9(1H, m), 4.1-4.2(2H, m), 5.28(2H, d), 7.2-7.4(5H, m).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1.N1C=CC=CC=1.[F:26][C:27]([F:34])([F:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30]>ClC(Cl)C>[F:19][C:2]([F:18])([F:1])[O:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[S:29]([CH2:28][C:27]([F:34])([F:33])[F:26])(=[O:31])=[O:30])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: FC(F)(F)Oc1cccc(NCc2cccnc2)c1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: O=S(=O)(CC(F)(F)F)N(Cc1cccnc1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(3-trifluoromethoxyphenyl)pyrid-3-ylmethylamine(0.270 g, 1 mmol) and pyridine were dissolved in dichloroethane (2 ml). The solution was cooled in an ice-bath. To the solution was added 2,2,2-trifluoroethylsulfonyl chloride (0.274 g, 1.5 mmol). The mixture was stirred at room temperature overnight. Upon removing solvent, the residue was dissolved in water and extracted with EtOAc. The organic phase was washed with brine concentrated. The residue was chromatographed to afford the title compound. 1H NMR: 8.42 (d,1H,J=6.4 Hz), 8.20 (d,1H,J=2.0 Hz), 7.57 (d,1H,J=9.8 Hz), 7.40-6.85 (m,5H), 4.81 (s,2H), 3.72 (q,2H, J=7.8 Hz). MS calcd 414.1; MS (M+1) 415.1.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8](Cl)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:21][CH2:20]1>>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([NH:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH2:23][CH2:24]2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: CCCCc1nnc(Cl)c2cc(OC)ccc12
Product: CCCCc1nnc(NC2CCN(Cc3ccc4ccccc4c3)CC2)c2cc(OC)ccc12

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 4-butyl-1-chloro-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [SH:1][CH2:2][C@H:3]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([C:13]([OH:15])=[O:14])[NH:5][C:4]1=[O:16].[C:17](Cl)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([S:1][CH2:2][C@H:3]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([C:13]([OH:15])=[O:14])[NH:5][C:4]1=[O:16])(=[O:19])[CH3:18]
Reactant: O=C1N[C@@H](C(=O)O)CCCCCC[C@@H]1CS
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans 3-mercaptomethyl-2-oxo-1-azacyclodecane-10-carboxylic acid (0.75 g, 3.06 mmol) is dissolved in pyridine (20 mL). Acetyl chloride (0.26 g, 3.37 mmol) is added, and the reaction is stirred at room temperature overnight. The reaction is quenched by cooling to 0° C., adding concentrated hydrochloric acid (20 mL), diluting with water, and extracting several times with ethyl acetate. The combined organic layers are dried (MgSO4), and the solvent is evaporated to give trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid, MS: M+1=288.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[N:15][CH:16]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([O:17][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:14]=[N:15][CH:16]=1
Reactant: Oc1cncc(Cl)c1
Reactant: N#Cc1cccnc1F
Product: N#Cc1cccnc1Oc1cncc(Cl)c1

Procedure:
2-Fluoro-nicotinonitrile was reacted with 5-chloro-pyridin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 232 (M)+, 234 (M+2)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[OH-].[Na+].O>CCO>[O:7]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][Br:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: BrCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: BrCCCCCCCOc1ccccc1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
Phenol (3.10 g, 33 mmol), 1,7-dibromoheptane (7.74 g, 30 mmol) and NaOH (1.34 g, 33 mmol) were refluxed in EtOH (40 mL) for 30 h. After cooling to room temperature, water (150 mL) was added and the mixture was extracted with ethyl acetate (4×50 mL). The organic phase was washed with water (50 mL) and brine (50 mL), and the mixture was dried over Na2 SO4. After evaporation of solvent, the residue was purified by Kugelrohr distillation to give 7-phenoxyheptyl bromide (2.46 g, 30%), bp 126°-130° C./0.10 torr, 1H-NMR: 1.2-1.9 (m, 10H), 3.36 (t, 2H), 3.91 (t, 2H), 6.7-7.2 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([CH2:41][CH2:42]O)=[N:9]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>C(Cl)(Cl)Cl>[F:40][C:19]1[CH:20]=[C:21]([N:24]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:25]([C:27]2([C:30]([NH2:32])=[O:31])[CH2:28][CH2:29]2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:45][CH:44]=3)[N:9]=[C:10]([CH2:41][CH2:42][N:64]3[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(CCO)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Reactant: CN1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cn2nc(CCN3CCN(C)CC3)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of N-(4-(1-(4-methoxybenzyl)-3-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100 mg, 0.16 mmol; prepared as in Example 8, Step C), DIEA (0.057 mL, 0.33 mmol), and chloroform (5 mL), cooled in an ice bath under N2 was added methanesulfonyl chloride (0.0189 mL, 0.244 mmol). The reaction was allowed to warm to room temperature slowly as the ice melted. The solution was stirred for 30 minutes at room temperature. A portion of the reaction mixture (1.25 mL) was transferred to a second flask and concentrated in vacuo. To the residue was added 1-methylpiperazine (0.023 mL, 0.20 mmol). The neat reaction mixture was heated to 100° C. for 1 hour. The crude was partitioned between DCM (2 mL) and a 1:1 saturated aqueous NaHCO3/water mixture (2 mL). The phases were separated, and the organic phase was dried (Na2SO4) and loaded directly on to a preparative TLC plate, eluting with 10% MeOH (containing 7N NH3) in CHCl3. Yield: 4 mg, 12%. 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 8.36 (s, 1H), 8.28 (d, J=6 Hz, 1H), 7.76 (m, 1H), 7.47 (m, 2H), 7.30 (d, J=9 Hz, 2H), 7.26 (m, 1H, overlaps chloroform), 7.18 (t, J=9 Hz, 1H), 7.06 (t, J=9 Hz, 2H), 6.82 (d, J=9 Hz, 2H), 6.18 (d, J=6 Hz, 1H), 5.57 (s, 2H), 3.76 (s, 3H), 3.29 (m, 2H), 2.93 (m, 2H), 2.5-2.8 (m, 8H), 2.42 (s, 3H), 1.82 (m, 2H), 1.64 (m, 2H).
Reaction SMILES: C(O[C:9]([N:11]1[C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:13]2([S:17][CH2:16][CH2:15][S:14]2)[CH2:12]1)=[O:10])C1C=CC=CC=1.S1C2(C[C@@H](C(OCC)=O)NC2)SCC1.[CH2:39]([O:46][C:47]([NH:49][CH2:50]C(O)=O)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([O:46][C:47]([NH:49][CH2:50][C:9]([N:11]1[C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:13]2([S:14][CH2:15][CH2:16][S:17]2)[CH2:12]1)=[O:10])=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)SCCS2
Agent: CCOC(=O)[C@@H]1CC2(CN1)SCCS2
Product: CCOC(=O)[C@@H]1CC2(CN1C(=O)CNC(=O)OCc1ccccc1)SCCS2

Procedure:
Convert 2.22 g of 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, ethyl ester (prepared as described in paragraph A) to 1,4-dithia-7-azaspiro-[4.4]nonane-8(S)-carboxylic acid, ethyl ester as described in Example 23 and couple this compound with 1.5 g of N-benzyloxycarbonylglycine, N-hydroxysuccinimide ester as described in Example 23 to yield 7-(N-benzyloxycarbonylglycyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, ethyl ester, a yellow oil [α]D26 -21.0°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH2:12][CH2:11][C@@:10]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[N:9]=2)[CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][N:14]1[CH2:15][CH2:16][C@:10]2([N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:24]4[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=4)[CH:7]=[CH:6][N:5]=3)[CH2:12][CH2:11]2)[C:13]1=[O:18]
Reactant: CN1CC[C@@]2(CCC(c3cc(Br)ccn3)=N2)C1=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN1CC[C@@]2(CCC(c3cc(-c4ccc(C(F)(F)F)cc4)ccn3)=N2)C1=O
Temperature: 120 °C
Yield: 89.6 %

Procedure:
To a solution of (5S)-2-(4-bromo-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 3) (640 mg, 2.0768 mmol) in MeCN (8 mL) and water (1 mL) in a Smith microwave vessel was added [4-(trifluoromethyl)-phenyl]boronic acid (394.44 mg, 2.0768 mmol), bis(triphenylphosphine)palladium (II) dichloride (60 mg, 0.0855 mmol) and sodium carbonate (484.26 mg, 4.5689 mmol). The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated by microwave at 120° C. for 25 min. The reaction mixture was treated with water and was extracted with DCM twice and the organic layers were collected by passing down a PhaseSep cartridge, and evaporated. The crude residue was purified by silica gel chromatography (50 g, SiO2) eluting with ethyl acetate in iso-hexane (10-100%). Evaporation of desired fractions gave (5S)-7-methyl-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one (D118) (695 mg, 1.8614 mmol, 89.6% yield);
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH2:30][CH2:31][NH:32][CH2:33][CH:34]3[CH2:36][CH2:35]3)[CH:25]=[CH:24]4)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH2:30][CH2:31][N:32]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:33][CH:34]3[CH2:35][CH2:36]3)[CH:25]=[CH:24]4)=[N:17][CH:18]=2)=[CH:11][CH:12]=1
Reactant: O=CC1CC1
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc4c(ccn4CCNCC4CC4)c3)nc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1ccc(-c2ccc(C#Cc3ccc4c(ccn4CCN(CC4CC4)CC4CC4)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
36 μL (0.47 mmol) cyclopropanecarbaldehyde are added to a solution of 100 mg (0.24 mmol) (2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-cyclopropylmethyl-amine in 20 mL MeOH at RT and 15 min later 59 mg (0.94 mmol) NaBH4 and one drop of glacial acetic acid are added. The mixture is stirred for 1 h at RT, evaporated down i.vac., the residue is taken up in dilute K2CO3 solution, extracted exhaustively with EtOAc and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is triturated with PE, suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH2:13]([O:20][CH2:21]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:20][CH2:21][N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]2[CH:10]=[CH:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccnc2c1ccn2COCc1ccccc1
Yield: 95.2 %

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine (20 g, 131 mmol) was dissolved in hydrous DMF (200 mL), and sodium hydride (60%, 6.0 g, 150 mmol) was added thereto. The resulting mixture was stirred under ice-cooling for 30 minutes, and then benzyloxymethyl chloride (26.8 g, 171 mmol) was added thereto. The resulting mixture was stirred under ice-cooling for 1 hour and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (300 mL) and saturated brine (200 mL). The aqueous layer was further extracted with ethyl acetate (300 mL). The combined organic layer was washed with saturated brine, dried, and concentrated. The residue was purified by silica-gel column chromatography (manufactured by Fuji Silysia, BW300 1500CC, n-hexane:EtOAc=4:1) to give 34 g of 1-benzyloxymethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine as a light-yellow syrup (yield: 95%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:20])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Cl)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-bromo-3-methylbenzoic acid (8.6 g, 40.0 mmol) in CH2Cl2 was added DMF (0.4 mL), followed by oxalyl chloride (3.7 mL, 42 mmol) slowly over 10 minutes by syringe. The reaction was stirred for 1 hour at room temperature, and then concentrated to give the title compound.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH2:23][OH:24])[CH:17]=[CH:16]2.C(OCC)C>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH:23]=[O:24])[CH:17]=[CH:16]2
Reactant: OCc1ccc2cc(Br)ccc2c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a suspension of pyridinium chlorochromate (2.4 gr, 11 mmol) in anhydrous CH2Cl2 (60 mL) was added a solution of the above alcohol in anh. CH2Cl2 and the reaction was heated under reflux for 5 hours. Upon completion, it was cooled to room temperature and poured into diethyl ether. The solution was then filtered through a pad of silica and concentrated under reduced pressure to yield 21 (2.4 gr, 95%). 20: white solid; 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.31 (bs, 1H), 8.08 (bs, 1H), 7.98 (dd, 1H, J=1.5 Hz, J=8.5 Hz), 7.86 (m, 2H), 7.67 (dd, 1H, J=1.5 Hz, J=8.5 Hz); 13C NMR (100 MHz, CDCl3) δ 191.8, 137.3, 134.3, 134.1, 131.0, 131.0, 130.6, 130.2, 128.2, 124.0, 123.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]#[N:10])[C@@H:4]([CH2:11][OH:12])[CH2:3]1.C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C>>[OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[NH:10][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[C@@H:4]([CH2:11][OH:12])[CH2:3]1
Reactant: N#CCCN1C[C@@H](O)C[C@@H]1CO
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3C[C@@H](O)C[C@@H]3CO)cc12
Yield: 16.8 %

Procedure:
In the same manner as in Example 1b (e) and using 3-[(2R,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile (0.47 g) and N,N-diethyl-2,3-dimethylbenzamide (2.1 g), 3-{2-[(2R,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]ethyl}-5-methyl-2H-isoquinolin-1-one (0.14 g) was obtained.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH3:9][C:10](=[CH:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:11]>C(Cl)Cl>[CH3:8][CH2:7][O:6][C:4]([CH:3]1[C:14]([CH3:16])([CH3:15])[CH:13]1[CH:12]=[C:10]([CH3:11])[CH3:9])=[O:5]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)=CC=C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1C(C=C(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl diazoacetate (5.0 g) in methylene chloride (50 mL) was added dropwise to a slurry of the Cu,K-PFIEP[SO3H] catalyst described above (2.0 g) in methylene chloride (100 mL) and 2,5-dimethyl-2,4-hexadiene (8.33 g). After stirring for about 18 h at ambient temperature, the reaction product was isolated by filtering off the catalyst, evaporating the solvent and chromatographing the resulting residue on silica with 10% ethyl acetate and 90% hexane as eluant. The isolated chrysanthemumate had an identical 1H nmr spectrum to a commercial sample. Anal. Calcd. for C12H20O2 : C, 73.43; H, 10.27; Found: C, 74.08; H, 10.58.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:26]([O:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[O:34][C:35](=[O:37])[CH3:36])=[O:27]>ClCCl>[C:35]([O:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[O:28][C:26]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:27])(=[O:37])[CH3:36]
Reactant: CC(=O)O[C@@H]1CCC[C@H]1OC(=O)Cl
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CCC[C@H]1OC(=O)NCC1(CC(=O)O)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
In a separate reaction flask, to a stirred solution of gabapentin (1.8 g, 10 mmol) and triethylamine (4.3 mL, 31 mmol) in dichloromethane (100 mL) at 0° C. under nitrogen atmosphere, was added dropwise a solution of chlorotrimethylsilane (2.6 mL, 21 mmol) in dichloromethane (10 mL). After stirring for 30 min at 0° C., 2(R)-acetoxycyclopent-1(R)-yl chloroformate was added dropwise into the reaction mixture. The resulting mixture was stirred at 0° C. for 2 h and then at room temperature for 2 h (monitored by TLC). The reaction mixture was then concentrated in vacuo and the resulting residue was poured into cold water (50 mL), acidified to about pH 5.0 using 0.1 N HCl, then extracted using ethyl acetate (2×50 mL). The combined extracts were washed with brine (40 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified using flash chromatography on silica gel using hexane/ethyl acetate (2:1) as eluant to afford 2.0 g (84%) of compound 48 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ1.31-1.78 (14H, m); 2.03-2.04 (5H, m); 2.31 (2H, s); 3.20 (2H, t, J=6.4 Hz); 5.07-4.97 (2H, m), 5.20 (1H, broad s). MS (ESI): m/z=340.25 (M−H−).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[CH:36]=[CH:37][C:38]=4[CH3:39])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:50]1(C(OC(C)(C)C)=O)[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:50]6[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]6)[CH:41]=5)[CH:36]=[CH:37][C:38]=4[CH3:39])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCCNCC4)c3)ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-4-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.15 mmol) in DCM (2 mL) was added tert-butyl 1-homopiperazine carboxylate (0.04 mL, 0.23 mmol), AcOH (0.01 mL, 0.18 mmol) followed by NaBH(OAc)3 (64.3 mg, 0.30 mmol). The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. LC-MS m/z 844 (M+H)+.
Reaction SMILES: [CH2:1]([S:5]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16](Cl)=[O:17])[CH:13]=[CH2:14].O1CCCC1>C(N(CC)CC)C>[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[O:6])=[N:8]1)=[O:17])[CH:13]=[CH2:14]
Reactant: CCCCS(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)CCCC)n1
Temperature: 100 °C

Procedure:
A mixture of 5.2 g. 3-butylsulphinyl-1,2,4-triazole, 6.0 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate distilled under reduced pressure to remove solvent. Finally the residue was maintained at 100° C./0.5 mm. for 30 minutes in order to remove all traces of volatile material from the product. The product, 1-diallylcarbamoyl-3-n-butylsulphinyl-1,2,4-triazole, was obtained as an oil, nD26 1.5277. Elemental analysis satisfactory.