Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:19])=[N:8][N:9]2[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=2)=[CH:5][CH:4]=1)#[CH:2].[Li+].CC([N-]C(C)C)C.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34](=[O:36])[CH3:35]>C1COCC1>[NH2:18][C:14]1[N:13]=[C:12]([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[C:2][C:34]([C:30]4[N:29]([CH3:28])[CH:33]=[CH:32][N:31]=4)([OH:36])[CH3:35])[CH:11]=3)[C:7]([CH3:19])=[N:8]2)[CH:17]=[CH:16][N:15]=1
Reactant: C#Cc1ccc2c(C)nn(-c3ccnc(N)n3)c2c1
Reactant: CC(=O)c1nccn1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3nccn3C)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-(6-ethynyl-3-methylindazol-1-yl)pyrimidin-2-amine (150 mg, 0.6 mmol) in THF (2 mL) at −78° C. under nitrogen was added 2M LDA in THF (0.75 mL, 1.50 mmol). After 5 minutes, 1-(1-methyl-1H-imidazol-2-yl)ethanone (225 mg, 1.81 mmol) in THF (1.0 mL) was added, and after a further 20 minutes the mixture was allowed to warm to RT and stirred for 1.5 hours. The reaction mixture was then cooled to −78° C. and treated with additional 2M LDA in THF (0.3 mL, 0.6 mmol) and 1-(1-methyl-1H-imidazol-2-yl)ethanone (90 mg, 0.6 mmol). After stirring at RT for 4 hr, the reaction mixture was quenched by addition of saturated aqueous NH4Cl (2 mL). The volatiles were removed in vacuo and the mixture was diluted with DCM (10 ml) and washed with water (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage, 3-12% methanol gradient in DCM) to give the title compound: 1H NMR (500 MHz, DMSO) delta 2.00 (3H, s), 2.57 (3H, s), 3.92 (3H, s), 6.32 (1H, s), 6.77 (1H, s), 6.98 (2 H, s), 7.03 (1H, d, J=5.5 Hz), 7.15 (1H, s), 7.36 (1H, d, J=8.2), 7.84 (1H, d, J=8.2 Hz), 8.25 (1H, d, J=5.5 Hz), 8.84 (1H, s); LC-MS: m/z=+374.05 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Br.Br[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCN(CC)CCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CCNCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Chlorobenzylamine (1.0 mL, 8.2 mmol) was added to a solution of 2-bromo-N,N-diethylethylamine hydrobromide (2.4 g, 9.0 mmol) and triethylamine (3.4 mL, 25 mmol) in dichloromethane (16 mL). The mixture was stirred at room temperature for 5 hours. The mixture was then concentrated to give N1-(4-chlorobenzyl)-N2,N2-diethylethane-1,2-diamine as an oil which was used immediately without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@H:12]([CH2:17][NH2:18])[CH2:11]2)=[CH:4][CH:3]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[CH:33]=[C:32]([C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH:31]=[C:30]([CH2:40][CH3:41])[CH:29]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH2:40]([C:30]1[CH:29]=[C:28]([NH:27][C:26]([NH:18][CH2:17][C@H:12]2[C@H:13]([CH3:16])[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:11]2)=[O:25])[CH:33]=[C:32]([C:34]2[N:38]([CH3:39])[N:37]=[N:36][N:35]=2)[CH:31]=1)[CH3:41]
Reactant: C[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CN
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(NC(=O)NC[C@@H]2CN(CCc3ccc(F)cc3)CC[C@H]2C)cc(-c2nnnn2C)c1
Reaction time: 23 h
Yield: 86.1 %

Procedure:
A solution of trans-1-[2-(4-fluorophenyl)ethyl]-4-methyl-piperidin-3-ylmethylamine (12 mg, 46 μmol) and [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (15 mg, 46 μmol) in N,N-dimethylformamide (0.5 mL) was treated with triethylamine (13 μL, 93 μmol). After 23 hours, the mixture was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 3% methanol in dichloromethane containing 0.3% aqueous ammonium hydroxide, provided an amorphous solid (19 mg, 86%). 1H NMR (300 MHz, CDCl3) δ7.71 (s, 1H), 7.64 (s, 1H), 7.11 (m, 3H), 6.91 (t, J=9 Hz, 2H), 4.17 (s, 3H), 3.6-3.3 (m, 3H), 3.2-2.9 (m, 6H), 2.66 (q, J=7 Hz, 2H), 2.50 (m, 1H), 1.9-1.7 (m, 3H), 1.42 (m, 1H), 1.24 (t, J=7 Hz, 3H), 1.01 (d, J=7 Hz, 3H). Mass spec (ES+) m/z 480.4 (M+H+, 100%).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=O)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([NH2:27])([CH3:26])[CH3:25])=[CH:18][CH:17]=1.O>C1C=CC=CC=1>[OH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([NH:27][CH2:10][CH:8]([OH:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([CH3:25])[CH3:26])=[CH:18][CH:17]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: CC(C)(N)CCc1ccc(OCCO)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(CCc1ccc(OCCO)cc1)NCC(O)c1ccccc1
Reaction time: 0.25 h
Yield: 78 %

Procedure:
A solution of phenyl glyoxal monohydrate (3.6 g) and 3-[4-(2-hydroxyethoxy)phenyl]-1,1-dimethylpropylamine (5 g) in benzene (100 ml) was heated under reflux with removal of water by a Dean and Stark trap. When water removal was complete, the benzene was evaporated under reduced pressure, the residue dissolved in methanol and sodium borohydride (2 g) added. The solution was stirred at ice-water temperature for 15 minutes, the methanol evaporated and the residue portioned between ethyl acetate and water. The organic layer was dried MgSO4 and evaporated to give a solid (6 g) which was purified on a silica gel column eluting with 4% methanol in chloroform. The product (2.8 g) was crystallised from dichloromethane, mp 118°-120° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[C:13]1(=[O:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1.[Cl-].[NH4+]>CCCCCC.CCOCC>[N:10]1[CH:11]=[CH:12][C:7]([C:13]2([OH:23])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[CH:8][CH:9]=1
Reactant: O=C1CCCc2ccccc21
Reactant: Brc1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: OC1(c2ccncc2)CCCc2ccccc21
Reaction time: 0.5 h

Procedure:
85 ml of a 1.5M solution of n-butyllithium in hexane are added, dropwise, to a solution of 20 g of 4-bromopyridine in 73 ml of ether, cooled to −78° C. Stirring is carried out for 30 minutes at that temperature, a solution of 1-tetralone in 73 ml of ether is then poured in and, at the end of the addition, the mixture is allowed to return to ambient temperature. After stirring overnight, a saturated aqueous solution of ammonium chloride is poured in. After separation, extraction with ether is carried out. The ethereal phases are combined and extracted with 1N hydrochloric acid. The combined acid phases are adjusted to pH=8 using 20% sodium hydroxide solution and extracted with dichloromethane. After drying, the expected product is isolated, which is purified by high-speed chromatography on silica (eluant: dichloromethane/methanol 95/5) to yield the expected product.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([NH:13][C:14]1[NH:22][C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]=2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][Cl:31]>>[Cl:31][CH2:30][CH2:29][CH2:28][CH2:27][N:20]1[C:19]([O:23][CH3:24])=[N:18][C:17]2[C:21]1=[N:22][C:14]([NH:13][C@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=2[NH2:25]
Reactant: ClCCCCBr
Reactant: CCC[C@@H](C)Nc1nc(N)c2nc(OC)nc-2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Nc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from N2-[(1R)-1-methylbutyl]-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [F:1][C:2]1([F:56])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH:42]=[O:43])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:4][CH2:3]1.[CH:57]([Mg]Br)([CH3:59])[CH3:58].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[F:56][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH:42]([OH:43])[CH:57]([CH3:59])[CH3:58])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:53])([F:52])[F:54])=[CH:49][CH:50]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C=O)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C(O)C(C)C)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of 213 mg (0.273 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-formyl pyrimidin-2-yl)piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 16, in 5 ml of tetrahydrofuran, 0.5 ml (0.5 mmol) of 1.0 mol/L isopropyl magnesium bromide-tetrahydrofuran solution was added under an argon gas atmosphere, and the reaction solution was stirred at room temperature for 0.5 hour. Then, 0.5 ml (0.5 mmol) of 1.0 mol/L isopropyl magnesium bromide-tetrahydrofuran solution was further added and the reaction solution was stirred at room temperature for 0.5 hour. After completion of the reaction, the reaction solution was poured into saturated ammonium chloride aqueous solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=85/15-80/20 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 174 mg of the title compound as a white solid (yield: 77%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][C:25]([O:32][CH2:33][CH2:34][OH:35])=[C:26]([F:31])[CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.[C:36](=O)([O:46]C1C=CC([N+]([O-])=O)=CC=1)[O:37][CH2:38][C:39]1[O:40][C:41](=[O:45])[O:42][C:43]=1[CH3:44]>CN(C=O)C>[F:10][C:8]([F:9])([F:11])[C@H:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:36](=[O:46])[O:37][CH2:38][C:39]2[O:40][C:41](=[O:45])[O:42][C:43]=2[CH3:44])[CH2:3]1)[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][C:25]([O:32][CH2:33][CH2:34][OH:35])=[C:26]([F:31])[CH:27]=4)[N:22]=3)=[N:19][N:20]=2)[CH:17]=1
Reactant: N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Reactant: Cc1oc(=O)oc1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
To a solution of 2-((2-(6-((R)-1-((S)-3-aminopyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro quinolin-7-yl)oxy)ethanol (125 mg, 0.255 mmol) in DMF (1.5 mL) was added a solution of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-nitrophenyl carbonate (prepared according to procedures described in J. Med. Chem. 1999, 42, 3994-4000, 71.2 mg, 0.255 mmol) in DMF (1 mL). The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (DCM:MeOH, 70:1 to 40:1) to give (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ((S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-(2-hydroxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-yl)carbamate (131 mg, 80%). LCMS APCI (+) m/z 647 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:3]([NH:5][C@H:6]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[N:8]([CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)[C:7]1=[O:29])=[O:4].C(N(CC)CC)C.[C:44]1([N:50]=[C:51]=[S:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[C:44]1([NH:50][C:51](=[S:52])[NH:1][C@@H:2]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:3]([NH:5][C@H:6]2[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=3[N:8]([CH2:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)[C:7]2=[O:29])=[O:4])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O
Reactant: S=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O)[C@H](Cc1ccccc1)NC(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of (3S)-3-[((2S)-2-amino-3-phenylpropanoyl)amino]-1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (12 g) and triethylamine (3.83 ml) in tetrahydrofuran (240 ml) was added phenyl isothiocyanate (2.99 ml) at room temperature. After stirring for 4 hours at room temperature, the solvent of the reaction mixture was evaporated under reduced pressure. Hydrochloric acid was added to the residue, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from ether to give (3S)-3-[[(2S)-2-[N'-(phenyl)thioureido]-3-phenylpropanoyl]amino]-1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (14.26 g).
Reaction SMILES: C([S:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[O:9][C:10]=1[CH3:11])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:11][C:10]1[O:9][C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)=[N:7][C:6]=1[CH2:5][SH:4]
Reactant: COC(=O)c1ccc(-c2nc(CSC(C)=O)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(CS)c(C)o2)cc1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A mixture of methyl 4-[4-[(acetylsulfanyl)methyl]-5-methyl-1,3-oxazol-2-yl]benzoate (10.5 g, 34.39 mmol, 1.00 equiv) and potassium carbonate (12.3 g, 89.00 mmol, 2.59 equiv) in methanol (200 mL) was stirred at 35° C. under an inert atmosphere of nitrogen for 30 min. Water (200 mL) was added and the resulting solution was extracted with 3×100 mL of dichloromethane. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. To afford 8.4 g (93%) of methyl 4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate as a white solid. LC-MS-: (ES, m/z): 305 [M+CH3CN+H]+, 264 [M+H]+, 230.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([OH:22])[N:5]([C:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:6]2=[O:12].CN(CCN(C)C)C.[I:31]I>C1COCC1>[OH:22][CH:4]1[C:3]2[C:7](=[C:8]([I:31])[CH:9]=[C:10]([F:11])[C:2]=2[Cl:1])[C:6](=[O:12])[N:5]1[C:13]([CH3:14])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:21]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2ccc(F)c(Cl)c2C1O
Reactant: II
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2c(I)cc(F)c(Cl)c2C1O
Yield: 49.7 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-chloro-3-hydroxy-5-fluoro-2-(1-methyl-1-phenylethyl)isoindolinone (1.20 g, 3.75 mmol) was dissolved in THF (48 mL), and the solution was treated with TMEDA (2.30 mL, 15.0 mmol), sec-butyl lithium-hexane solution (1.01 mol/L, 15.0 mL, 15.0 mmol) and iodine (1.430 g, 5.63 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=80/20 to 70/30) to obtain 3-hydroxy-4-chloro-5-fluoro-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (830 mg, yield 50%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][CH:7]([CH2:24][O:25][C:26]1[C:31]2[C:32](=[O:39])[CH:33]=[C:34]([C:36]([NH2:38])=O)[O:35][C:30]=2[CH:29]=[CH:28][CH:27]=1)[CH2:8][O:9][C:10]1[C:15]2[C:16](=[O:23])[CH:17]=[C:18]([C:20]([NH2:22])=O)[O:19][C:14]=2[CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[Cl:6][CH:7]([CH2:8][O:9][C:10]1[C:15]2[C:16](=[O:23])[CH:17]=[C:18]([C:20]#[N:22])[O:19][C:14]=2[CH:13]=[CH:12][CH:11]=1)[CH2:24][O:25][C:26]1[C:31]2[C:32](=[O:39])[CH:33]=[C:34]([C:36]#[N:38])[O:35][C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: NC(=O)c1cc(=O)c2c(OCC(Cl)COc3cccc4oc(C(N)=O)cc(=O)c34)cccc2o1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(=O)c2c(OCC(Cl)COc3cccc4oc(C#N)cc(=O)c34)cccc2o1
Temperature: 0 °C

Procedure:
To 120 parts of N,N-dimethylformamide was slowly added 5 parts of phosphorous oxychloride with stirring and ice-cooling. Then 10 parts of 5,5'-[(2-chlorotrimethylene) dioxy]bis[4-oxo-4H-1-benzopyran-2-carboxamide] were added to the solution, in small quantities, and the reaction mixture was stirred at room temperature for 60 hours. The resulting dark solution was poured into 500 parts of ice/water and the precipitated solid was filtered, washed with water and dried to give 6.8 parts of a brown powder. Crystalisation of this product from a mixture of ethanol and N,N-dimethylformamide gave 4.6 parts of 5,5'-[(2-chlorotrimethylene)dioxy]bis[4-oxo-4H-1-benzopyran-2-carbonitrile] as white crystals, m.p. 185° C. (decomp.), giving a positive Beilstein's halogen test.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:16]=1>CCO>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH:21][CH2:2][CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)=[CH:17][CH:16]=1
Reactant: BrCC1CCc2ccccc2C1
Reactant: COc1ccc(CCN)cc1
Solvent: CCO
Product: COc1ccc(CCNCC2CCc3ccccc3C2)cc1
Yield: 59 %

Procedure:
A solution of 2-bromomethyl-1,2,3,4-tetrahydronaphthalene (1.33 g, 5.91 mmol) and 4-methoxyphenethylamine (1.79 g, 11.8 mmol) in 50 ml of EtOH was refluxed for 48 hours. After removal of EtOH in vacuo, the residue was dissolved in 100 ml of CHCl3, washed with 10% K2CO3, H2O, sat'd brine, and then dried over Na2SO4. Filtration followed by evaporation of solvent gave a yellow oil, which was purified by chromatography (SiO2, MeOH:CHCl3, 5:95) to a give a yellowish oil (1.03 g, 58.9%). The product was converted to HCl salt, crystallization with MeOH/Et2O gave a white powder. mp 274-275° C.; Calcd for C20H25NO.HCl: C 72.37, H 7.91, N 4.22; Found C 72.40, H 7.76, N 4.13.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:15]3[CH:16]=[CH:17][O:18][C:14]=3[CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]3[CH:16]=[CH:17][O:18][C:14]=3[CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC=C(c2nccc3occc23)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(=O)N1CCC(c2nccc3occc23)CC1

Procedure:
0.7 g of Pd/C (10%) is added to a solution of 3.4 g of the product obtained in Step C and 4.4 g of ammonium formate in 150 ml of anhydrous methanol under a stream of argon. After refluxing for 45 minutes, the reaction mixture is cooled, 4.4 g of ammonium formate 5 and 0.2 g of Pd/C (10%) are added, and the reaction mixture is then heated at reflux for 30 minutes. After returning to ambient temperature, filtration over Celite and concentration under reduced pressure, the residue is taken up in water and then extracted with dichloromethane. The expected product is isolated by extraction, drying, filtration and concentration under reduced pressure.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH2:11]>C(OCC)C>[CH3:3][C@H:4]([CH2:5][CH:6]=[CH2:7])[CH2:9][O:11][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: C=CC[C@@H](C)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A 250-mL round-bottomed flask, equipped with a magnetic stirring bar and a thermometer was fitted with a septum and a nitrogen inlet. The apparatus was charged with 1.60 g (40.0 mmol) of a 60% dispersion of sodium hydride in mineral oil. The sodium hydride was washed with 3×20 mL of dry hexane and then suspended in 40 mL of dry N,N-dimethylformamide and cooled to 0° C. To the stirred suspension was added 4.32 mL (6.21 g, 36.3 mmol) of benzyl bromide followed by dropwise addition of 3.47 g (34.6 mmol) of ketone 2 (via cannula) dissolved in 10 mL of diethyl ether over 15 min maintaining the reaction temperature at 6° C. or less. The reaction mixture was stirred for 20 minutes at 0° C., then warmed to room temperature. After 12 hours, 10 mL of water was cautiously added and the mixture was transferred to a 250-mL separatory funnel. The aqueous phase was extracted with 3×100 mL of ethyl acetate. The organic layers were individually washed with 100 mL of brine, combined, dried over sodium sulfate, filtered, concentrated and chromatographed (6 cm×33 cm column, 9:1 hexane:dichloromethane) to afford 5.93 g (89%) of benzyl ether 3 as a clear, colorless liquid: Rf =0.20 (9:1 hexane:dichloromethane). [a]54622 -1.6° (c 2.21, CH2Cl2). IR (film): 3080m, 3070m, 3035m, 3005w, 2980s, 2960s, 2930s, 2910s, 2880s, 2860s, 2975w, 1645m, 1605w, 1495m, 1480w, 1455s, 1445m, 1415w, 1375m, 1365m, 1310w, 1255w, 1205w, 1160w, 1100s, 1040m, 995m, 915s, 745s, 695s, 605m. 1H-NMR: 7.36-7.24 (m, 5H, ArH); 5.85-5.72 (m, 1H, CH=CH2); 5.06-5.00 (m, 2H, CH=CH2); 4.51 (s, 2H, ArCH2O); 3.33 (dd, J=9.1, 6.2, 1H, one of CH2OBn); 3.28 (dd, J=9.1, 6.2, 1H, one of CH2OBn); 2.27-2.19 (m, 1H, CHCH3); 1.98-1.84 (m, 2H, CH2CH=CH2); 0.93 (d, J=6.5, 3H, CHCH3). 13C NMR: 138.7, 136.8, 128 2, 127.4, 127.3, 115.8, 75.2, 72.9, 38.0, 33.3, 16.7.
Reaction SMILES: [CH3:1][C:2](=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][OH:25].C1C=CC=CC=1>O>[CH2:24]1[O:25][C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])([CH3:1])[O:10][CH2:23]1
Reactant: C=CCCCCCC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=CCCCCCC1(C)OCCO1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
A solution containing 119.0 g of non-8-en-2-one, (prepared in Example 22 B-3), 1.2 g p-toluenesulfonic acid monohydrate, 63.1 g of ethylene glycol and 420 ml anhydrous benzene was prepared and refluxed for about 15 to 17 hr. Water which formed was collected in a Dean-Stark trap. The solution was cooled to room temperature and 250 ml of 5% aqueous sodium bicarbonate solution was added thereto. The benzene layer was separated and dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was distilled to yield 116.8 g of title compound having the following physical characteristics: