Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1.[NH3:18]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH2:18])[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1
Reactant: N
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)ccn2n1
Solvent: C1CCOC1
Product: Nc1nc(Cl)nn2ccc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of 2,4-dichloro-5-phenylpyrrolo[2,1-f][1,2,4]triazine (0.500 g, 1.89 mmol) in THF (5 mL), NH3 gas was bubbled at −20° C. for 15 min. The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure to remove THF and water (30 mL) was added to the resulting residue. The aqueous solution was extracted with EtOAc (3×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by CombiFlash (REDISEP®, silica gel, 40 g, 45% EtOAc/petroleum ether) to afford 2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.300 g, 64.8%). LCMS Condition B-81: retention time 2.14 min, [M+1]=245.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.98 (br s, 1H), 6.75 (d, J=2.4 Hz, 1H), 7.38-7.43 (m, 2H), 7.46-7.52 (m, 3H), 7.80 (d, J=2.4 Hz, 1H), 8.40 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[S:23](Cl)(=[O:25])=[O:24])[CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[S:23]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)(=[O:25])=[O:24])[CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2cccc3cccnc23)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of ethyl 4-aminobenzoate (5 gm, 30.3 mmol) under nitrogen atmosphere was added pyridine (50 ml) at 0° C. and stirred for 10 min. Quinoline-8-sulfonyl chloride 89 (8.94 gm, 39.4 mmol) was then added to the reaction mixture at the same temperature. The resulting mixture was stirred for 16 hr at RT. After completion of the reaction, the solvent was removed under low pressure. The traces of pyridine were removed by co-distillation with toluene. Diethylether was added to the resulting residue, and the solid product was filtered out and air-dried. The resulting crude product (8.0 gm, 74%) was taken to the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11].[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1.O>[O:12]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11]
Reactant: COCCOCCOCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCCOCCOc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
Chloride 603 (26 g, 0.14 mol, 1.3 equiv) and p-hydroxybenzaldehyde (13 g, 0.11 mol, 1 equiv) were dissolved in dry THF (40 mL). K2CO3 (15 g, 0.11 mol, 1 equiv) was added followed by 18-crown-6 (3.0 g, 11 mmol, 0.11 equiv) and KI (0.20 g, 1.2 mmol, 0.01 equiv). The reaction mixture was stirred at reflux for 48 h. The resulting mixture was cooled to room temperature, and water (200 mL) was added. The product was extracted with 3×350 mL portions of ethyl acetate and the combined organic layers were dried and concentrated. The oil was loaded onto a silica gel column and eluted with a 1:9 mixture of ethyl acetate/hexane, followed by a ratio of 1:4, 3:7, 4:1 of ethyl acetate/hexane and finally washed with ethyl acetate to afford 21 g (70%) of 604 as a clear oil. IR(cm−1): 1697 (s), 1165 (s). 1H NMR (400, CDCl3): δ 3.36 (s, 3), 3.54 (t, 2, J=4.6), 3.63-3.68 (m, 4), 3.72-3.75 (m, 2), 3.88 (t, 2, J=4.8), 4.20 (t, 2, J=4.8), 7.01 (d, 2, J=8.8), 7.82 (d, 2, J=8.8), 9.87 (s, 1). 13C NMR (CDCl3): δ 58.86, 67.59, 69.29, 70.40, 70.47, 70.71, 71.73, 114.71, 129.84, 131.76, 163.69, 190.63. Calcd: [M+H]+ (C14H21O5) m/z=269.13889. Found FAB-HRMS: [M+H]+ m/z=269.134487. Anal. Calcd. for C14H20O5: C, 62.67; H, 7.51. Found: C, 62.47; H, 7.74.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[N:21][CH:20]=4)[CH:14]=3)=[O:12])[NH:8]2)=[CH:4][N:3]=1.[CH3:29][N:30]([CH3:37])[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:29][N:30]([CH3:37])[CH:31]1[CH2:36][CH2:35][N:34]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([C:11]([C:13]4[CH:18]=[CH:17][N:16]=[C:15]([C:19]5[C:28]6[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=6)[CH:22]=[N:21][CH:20]=5)[CH:14]=4)=[O:12])[NH:8]3)=[CH:4][N:3]=2)[CH2:33][CH2:32]1
Reactant: O=C(c1ccnc(-c2cncc3ccccc23)c1)c1nc2cnc(Cl)nc2[nH]1
Reactant: CN(C)C1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(c2ncc3nc(C(=O)c4ccnc(-c5cncc6ccccc56)c4)[nH]c3n2)CC1
Temperature: 120 °C

Procedure:
To a 0.5 mL DMA solution of crude (2-chloro-9H-purin-8-yl)-(2-isoquinolin-4-yl-pyridin-4-yl)-methanone (60 mg, 0.155 mmol) was added dimethyl-piperidin-4-yl-amine (199 mg, 1.55 mmol) and DIEA (270 μl, 1.55 mmol). The mixture was heated to 120° C. for 1 hour. The mixture was then cooled and evaporated to dryness. Purification by preparative LCMS gave the title compound. HRMS m/z 479.2329 (M+H)+.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:13]([Cl:38])=[CH:14][C:15]2[N:21]3[CH2:22][CH2:23][CH2:24][C@@H:25]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C@H:20]3[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[O:17][C:16]=2[CH:37]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:38][C:13]1[C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:37][C:16]2[O:17][C:18]3[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=3[C@@H:20]3[C@H:25]([NH:26][C:27](=[O:32])[C:28]([F:30])([F:29])[F:31])[CH2:24][CH2:23][CH2:22][N:21]3[C:15]=2[CH:14]=1
Reactant: Nc1cc2c(cc1Cl)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)c(NS(=O)(=O)c4ccccc4)cc3Oc3ccccc3[C@H]12)C(F)(F)F
Temperature: 35 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
Benzenesulfonyl chloride (10 μL, 0.08 mmol) was added under N2 to trans-N-(8-amino-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (5.0 mg, 0.01 mmol) in 1 mL of CH2Cl2 and 2 μL (1.1 eq) of triethylamine. The resulting mixture was stirred at 35° C. for 4 h. After cooling the mixture was evaporated and the crude compound was purified by chromatography on silica. Elution with toluene/ethyl acetate 1:0→0:1 (gradient) gave trans-N-(7-chloro-2,3,4,14b-tetrahydro-8-[(phenylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (2.4 mg, 32%). Data: (m/z)=552 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([N:15]([CH2:17][CH2:18][OH:19])[CH3:16])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]1OCC[O:23]1.Cl>C1COCC1>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([N:15]([CH2:17][CH2:18][OH:19])[CH3:16])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]=[O:23]
Reactant: CN(CCO)c1ccc(C#N)c(Oc2ccc(Br)c(C3OCCO3)c2)n1
Agent: Cl
Solvent: C1CCOC1
Product: CN(CCO)c1ccc(C#N)c(Oc2ccc(Br)c(C=O)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of 2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile (8) (400 mg, 0.95 mmol) in THF (30 mL) was added HCl solution (1 M, 10 mL). The reaction was stirred at room temperature overnight. After the reaction, all THF was evaporated under vacuum. The aqueous solution was extracted with EtOAc (2×50 mL). The organic layer was washed with water (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated under vacuum to afford the desired product 320 mg (89% yield) that was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.35 (s, 1 H), 7.91 (d, J=2.7 Hz, 1 H), 7.67 (t, J=9.2 Hz, 2 H), 7.32 (dd, J=8.6, 2.7 Hz, 1 H), 6.24 (d, J=8.6 Hz, 1 H), 3.70-3.62 (m, 2 H), 3.56-3.49 (m, 2 H), 3.04 (s, 3 H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[C:6]2[OH:17].[C:19]1([C:25]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)(O)[C:26]#[CH:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:18][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]2[C:10]([CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[C:7]3[CH:27]=[CH:26][C:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:31][CH:30]=4)[O:17][C:6]=32)=[CH:11][CH:12]=1
Reactant: C#CC(O)(c1ccccc1)c1ccc(N2CCCCC2)cc1
Reactant: COC(=O)c1cc(O)c2cc(N(C)C)ccc2c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccc(N(C)C)cc2c2c1C=CC(c1ccccc1)(c1ccc(N3CCCCC3)cc1)O2

Procedure:
A solution of methyl 6-dimethylamino-4-hydroxy-2-naphthoate (5 mmol) and 1-phenyl-1-(4-piperidinophenyl)prop-2-yn-1-ol (5 mmol) in toluene (60 cm3) containing acidic alumina (Brockrmann 1) (5 g) was refluxed for 90 minutes. The cooled solution was filtered and the alumina residue washed well with ethyl acetate (5×40 cm3). Removal of the dried solvent gave a brown gum which was flash chromatographed using 30% ethyl acetate in hexane as the eluent to give an off-white solid. Recrystallisation from ethyl acetate and hexane gave the title compound (m.p. =155-156.5° C.).
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]([C:16](=[O:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>ClCCl.CO>[C:1]([NH:9][CH2:10][CH:11]([CH:16]([OH:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(CNC(=O)c1ccccc1)C(C)=O
Reactant: [H][H]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(CNC(=O)c1ccccc1)C(C)O
Reaction time: 20 h
Yield: 77.6 %

Procedure:
Into a 200-ml stainless steel-made autoclave was placed 3.56 g (0.0143 mole) of methyl 2-benzamidomethyl-3-oxobutyrate. After nitrogen replacement, 7 ml of a separately prepared dichloromethane/methanol (7/1 by volume) mixed solvent solution containing 0.01 g (0.00894 mmole) of [RuI(p-Cymene)((-)-OcH-BINAP)]I as obtained in Example 5 was added. The resulting mixture was stirred at a hydrogen pressure of 50 kg/cm2 and a temperature of 65° C. for 20 hours. After the reaction, the reaction mixture was analyzed- by high-speed liquid chromatography. As a result, it was found that 2.79 g (percent yield: 78%) of methyl 2-benzamidomethyl-3-hydroxybutyrate had been formed and that the conversion was 80%, diastereomer selectivity 91.6%, and optical percent yield 99% ee.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([C:12]([C:14]2[O:15][C:16]3[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=2)=[O:13])[CH2:11][CH2:10]1.O>C(#N)C>[Br:1][C:19]1[C:17]2[CH:18]=[C:14]([C:12]([CH:9]3[CH2:10][CH2:11]3)=[O:13])[O:15][C:16]=2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc2cc(C(=O)C3CC3)oc12
Solvent: O
Solvent: CC#N
Product: COc1ccc(Br)c2cc(C(=O)C3CC3)oc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
N-bromosuccinimide (0.21 g) was added in a single portion to a stirred solution of cyclopropyl-(7-methoxybenzofuran-2-yl)-methanone (0.25 g) in acetonitrile (20 ml) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 24 h. Water (20 ml) was added, the mixture extracted with ethyl acetate (100 ml), the organic layer separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 5-10% ethyl acetate in hexane afforded the title compound as an off-white solid (0.24 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:26]=[CH:25][C:11]([O:12][C:13]2[C:18]([C:19]3[CH2:23][CH2:22][C:21](=[O:24])[CH:20]=3)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:10][CH:9]=1.[BH4-].[Na+]>O1CCCC1.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[C:18]([C:19]3[CH2:23][CH2:22][CH:21]([OH:24])[CH:20]=3)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:25][CH:26]=1
Reactant: O=C1C=C(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OC1C=C(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A suspension of 3-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclopent-2-enone (791 mg, 2.304 mmol, Example 1) in Tetrahydrofuran (150 mL) and Methanol (15.00 mL) was cooled to 0° C. under nitrogen, and was treated with sodium borohydride (349 mg, 9.21 mmol, 4.0 equiv) in 4 lots over 15 min. The reaction was warmed to 23° C. and was stirred under nitrogen. After 24 h, the reaction was quenched with saturated ammonium chloride solution (15 mL). The suspension was diluted with EtOAc (250 mL) and washed with saturated ammonium chloride solution (100 mL) and brine (100 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 1-4% methanol/dichloromethane), affording 3-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclopent-2-enol.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:20][F:21])[CH:8]=[C:7]([C:9](O)=[O:10])[C:6]2[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:5]=2[O:4]1.[C:22]([CH2:24][CH2:25][NH2:26])#[N:23]>O1CCCC1>[C:22]([CH2:24][CH2:25][NH:26][C:9]([C:7]1[C:6]2[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:5]=2[O:4][C:3]([CH2:2][F:1])([CH2:20][F:21])[CH:8]=1)=[O:10])#[N:23]
Reactant: N#CCCN
Reactant: O=C(O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Solvent: C1CCOC1
Product: N#CCCNC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A mixture of 0.20 g of 2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran-4-carboxylic acid, 0.12 g of N,N-carbonyl diimidazole and 3 ml of tetrahydrofuran was stirred at room temperature for one hour. The reaction mixture was combined with 0.06 g of 2-cyanoethylamine and further stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluent; ethyl acetate:hexane=1:1) to give 0.20 g of N-(2-cyanoethyl)-2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran-4-carbamide; m.p. 135-136° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([O:29][CH3:30])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[CH3:16])(C)(C)C>ClCCl>[CH3:30][O:29][C:24]1[C:23]([C:20]2[CH:21]=[CH:22][C:17]([C@H:15]([NH2:14])[CH3:16])=[CH:18][CH:19]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: COc1ncccc1-c1ccc([C@@H](C)NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncccc1-c1ccc([C@@H](C)N)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
2M Aqueous sodium carbonate solution (3.25 ml, 6.50 mmol) was added to a mixture of 2-methoxypyridine-3-boronic acid (994 mg, 6.50 mmol), (R)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (650 mg, 2.16 mmol) and tetrakis(triphenylphosphine)palladium (0) (125 mg, 0.108 mmol) in 1,2 dimethoxyethane (27 ml). The mixture was heated at 95° C. for 16 h under nitrogen atmosphere. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed twice with brine, dried over anhydrous magnesium sulfate and the solvent evaporated. The resulting gum was chromatographed over silica gel eluting with heptane/dichloromethane and the solvent evaporated to give (R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (593 mg, 1.71 mmol, 83.5%) as a crystalline solid. Trifluoroacetic acid (6.45 ml, 86.8 mmol) was added dropwise to a solution of (R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}carbamic acid tert-butyl ester (645 mg, 1.97 mmol) in dichloromethane (6.45 ml) under a nitrogen atmosphere at 0° C. After stirring for 1 h at 0° C. the solvent was evaporated. Methanol (20 ml) was added and the mixture added to a Strata™ 5 g/20 ml SCX column. The intermediate amine was eluted with 2M ammonia in methanol. The solvent was evaporated to give (R)-1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethylamine as a gum (425 mg, 1.86 mmol, 94.6%). The title compound was then prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) using 4-bromo-3-thiophenesulfonyl chloride and 1-[4-(2-Methoxy-pyridin-3-yl)-phenyl]-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 8.17 (d, 1H), 7.56 (d, 1H), 7.41, 7.20 (a/b, 4H), 7.38 (m, 1H), 6.99-6.92 (m, 2H), 5.27 (d, 1H), 4.60 (m, 1H), 3.97 (s, 3H), 1.54 (d, 3H) ppm; MS (ESI) m/z: 453 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[C:15]([C:29]([O:31]CC)=[O:30])=[C:14]2[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH:42]2[CH2:44][CH2:43]2)=[CH:36][CH:35]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO.O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[C:15]([C:29]([OH:31])=[O:30])=[C:14]2[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH:42]2[CH2:43][CH2:44]2)=[CH:36][CH:35]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(-c2ccc(OCC3CC3)cc2)c2cc(OCc3ccccc3)ccc2n1Cc1cccc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(Cn2c(C(=O)O)c(-c3ccc(OCC4CC4)cc3)c3cc(OCc4ccccc4)ccc32)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 40.4 %

Procedure:
1 M Aqueous sodium hydroxide (1 mL) was added to a stirred solution of ethyl 5-(benzyloxy)-3-[4-(cyclopropylmethoxy)phenyl]-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 61, 100 mg, 0.178 mmol) in methanol (1 mL). The reaction was warmed (50° C.) and stirring was continued for 18 h. After cooling the reaction was diluted with water (20 mL) and then the solution was adjusted to pH=2 using 1 M hydrochloric acid. The product was extracted with ethyl acetate (3×20 mL) and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 50% ethyl acetate/hexane gave 38.4 mg (40%) of the desired product as a pure white solid (mp=185-187° C.). The product had: 1H NMR (300 MHz, CDCl3) δ 7.25-7.48 (m, 8 H), 6.89-7.17 (m, 3 H), 6.65-6.78 (m, 2 H), 5.83 (s, 2 H), 5.05 (s, 2 H), 3.84 (d, 2 H), 3.68 (s, 3 H), 1.25-1.35 (m, 1 H), 0.57-0.67 (m, 2 H), 0.31-0.41 (m, 2 H); mass spectroscopy gave MH+=534.1 (calcd exact mass for C34H31NO5=533.22).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([CH2:8][C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[N:6]([C:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])=[C:19]([CH3:21])[CH3:20])[C:5]1=[O:35])[CH3:3].[N+:36]([C:39]1[CH:49]=[CH:48][C:42]([CH2:43][O:44][C:45](Cl)=[O:46])=[CH:41][CH:40]=1)([O-:38])=[O:37].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:20][C:19]([CH3:21])=[C:18]([N:6]1[C@H:7]([CH2:8][C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[C@@H:4]([C@H:2]([O:1][C:45]([O:44][CH2:43][C:42]2[CH:41]=[CH:40][C:39]([N+:36]([O-:38])=[O:37])=[CH:49][CH:48]=2)=[O:46])[CH3:3])[C:5]1=[O:35])[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)=[O:23]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@H]([C@@H](C)O)[C@H]1CC(=O)Sc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1CC(=O)Sc1ccccc1
Temperature: 0 °C
Yield: 35.2 %

Procedure:
44 mg (0.088 mmole) of (3S, 4R)-3-[(R)-1-hydroxyethyl]-1-[2-methyl-1-(p-nitrobenzyloxycarbonyl)prop-1-enyl]-4-[(phenylthio)carbonylmethyl]-2-azetidinone were dissolved in 2 ml of methylene chloride. To the solution were added 32 mg (0.26 mmole) of 4-(N,N-dimethylamino)pyridine and 57 mg (0.26 mmole) of p-nitrobenzyloxycarbonyl chloride, with stirring at 0° C. The mixture was stirred at that temperature for 3 hours, after which it was poured into a dilute aqueous solution of sodium bicarbonate and extracted with chloroform. The chloroform extract was washed successively with dilute hydrochloric acid and a dilute aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulphate. The solvent was then distilled off. The residue was subjected to thin layer chromatography using silica gel developed with a 3:1 by volume mixture of benzene and ethyl acetate, to afford 21 mg (yield 35%) of the title product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([C:14]2[C@H:23]3[C@H:18]([CH2:19][CH:20]=[CH:21][CH2:22]3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1.Cl>CN(C)C=O.O>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([C:14]2[C@H:23]3[C@H:18]([CH2:19][CH:20]=[CH:21][CH2:22]3)[C:17](=[O:24])[N:16]([CH2:28][C:29]3[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=3)[N:15]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)c2c1OC(C)(C)C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CC=CC[C@@H]23)c2c1OC(C)(C)C2
Reaction time: 18 h

Procedure:
To a solution of 0.05 mole of (cis)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one (starting compound A12) and 0.15 mole of sodium hydride in 100 ml of dimethylformamide is stirred at RT for 30 min, after which 0.05 mole of 4-chloromethylbenzoic acid is added. This mixture is left stirring for 18 h, after which it is poured into water. This solution is acidified with hydrochloric acid and subsequently extracted with dichloromethane. The organic solution is dried over magnesium sulfate and evaporated. The compound is crystallized from diethyl ether.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH3:20])(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[CH3:6][NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH3:20]
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cnccc1N1CCCCC1C

Procedure:
Methyl-(2-methyl-3,4,5,6-tetrahydro-2H-[1,4]bipyridinyl-3′-yl)-carbamic acid tert-butyl ester (60 mg, 0.20 mmol) was stirred in a solution of TFA (300 μL) and CH2Cl2 (2 mL) for 1 h after which all volatiles were removed under reduced pressure. The resulting compound was pure enough to be used directly in the next step without further purification.