Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCC(CC1)C(O)C2.[CH:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[N:25]([C:26]([O:28][C@@H:29]3C4CCN(CC4)[CH2:30]3)=[O:27])[CH2:24][CH2:23][C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]2=3)=[CH:14][CH:15]=1>>[C:13]1([C@H:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:23][CH2:24][N:25]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:12]=[CH:11][CH:10]=[CH:15][CH:14]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Agent: OC1CN2CCC1CC2
Product: CCOC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1

Procedure:
This solution was taken for condensation reaction with (RS)-3-quinuclidinol in the next stage to prepare Solifenacin and its diastereomer.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH2:17][CH:18]=[CH2:19])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.Br[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][C:46]([O:48][CH3:49])=[O:47].[I-].[K+]>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:45]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:39]=2)[C:46]([O:48][CH3:49])=[O:47])=[C:12]([CH2:17][CH:18]=[CH2:19])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: C=CCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.4 %

Procedure:
To a suspension of KH (1.3 eq) in DMF (1 mL) was added a solution of the product of Step C (157 mg, 0.566 mmol) in DMF (1 mL), followed by 18-crown-6 (30 mg; 0.2 eq). The reaction mixture was stirred for 5 minutes at room temperature. A solution of methyl 2-bromophenylacetate (168 mg, 0.735 mmol) in DMF (1 mL) was added, followed by a catalytic amount of potassium iodide. The reaction was heated to 80° C. for 0.5 hours then stirred at room temperature for 16 hours. After concentration in vacuo, the residue was partitioned between water and ethyl acetate. The combined organic layers were washed with water, brine, then dried (MgSO4). After filtration and concentration in vacuo, the residue was chromatographed on silica (MPLC, ethyl acetate/hexanes (5/95)) to afford 158 mg (66%) of the title compound (Rf =0.22, 5% ethyl acetate/hexanes).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:32]([O:33]C(=O)C)[C@H:31]([O:37]C(=O)C)[C@@H:30]([CH2:41][O:42]C(=O)C)[O:29][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][CH2:26][O:27][CH3:28])=[CH:19][CH:18]=1)(=O)C.[OH-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][CH2:26][O:27][CH3:28])=[CH:19][CH:18]=1)[C@@H:6]1[O:29][C@H:30]([CH2:41][OH:42])[C@@H:31]([OH:37])[C@H:32]([OH:33])[C@H:5]1[OH:4]
Reactant: COCOCCc1ccc(Cc2ccc(OC)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCOCCc1ccc(Cc2ccc(OC)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 55.5 %

Procedure:
To a solution of 5-methoxy-2-(4-[2-(methoxymethyloxy)ethyl]benzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.13 g) in methanol (8 mL) was added 2 mol/L aqueous sodium hydroxide solution (0.50 mL), and the mixture was stirred at room temperature for 25 minutes. The solvent was removed under reduced pressure, and the residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=7/1) to give 5-methoxy-2-{4-[2-(methoxymethyloxy)ethyl]benzyl}phenyl β-D-glucopyranoside (0.053 g).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br-:32].[Li+].[CH2:34]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47](O)[CH2:46][CH2:45]1)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[CH2:34]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([Br:32])[CH2:46][CH2:45]1)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: [Br-]
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(Br)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
Diethylazodicarboxylate (24.6 ml) was added dropwise to a stirred solution of triphenylphosphine (39.3 g) in THF (120 ml) at 0° C. under argon. The mixture was stirred for 20 minutes, then treated sequentially with lithium bromide (26.1 g) and a solution of 1-benzyloxycarbonylpiperidine-4-ol (7.1 g) in THF (50 ml). The mixture was allowed to warm to room temperature and stirring was continued for 1 hour. The mixture was concentrated, the residue treated with ether (100 ml) and silica (60 ml), and the solvent was evaporated under reduced pressure. The resulting powder was added to the top of a flash column and the column was eluted with hexane/ether (4:1) to give 1-benzyloxycarbonyl-4-bromopiperidine (3.6 g) as a colourless oil. NMR: (CDCl3): δ, 1.8-2.0(2H,m); 2.0-2.2(2H,m); 3.3-3.5(2H,m); 3.6-3.8(2H,m); 4.35(1H,m); 5.1(2H,s); 7.3(5H,m). m/e 298/300(M+H)+ ; 320/322(M+Na)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][NH:17][C:18]4[C:23]([NH2:24])=[CH:22][N:21]=[CH:20][N:19]=4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:25][CH2:26][CH2:27][CH2:28][C@H:4]2[O:3]1.Br[C:31]1C=C(N)C(NCC2C=CC3N=C(SC)SC=3C=2)=CC=1OC>>[N:21]1[CH:22]=[C:23]2[C:18]([N:17]([CH2:16][C:14]3[CH:13]=[CH:12][C:10]4[N:11]=[C:7]([N:6]5[C@@H:5]6[CH2:25][CH2:26][CH2:27][CH2:28][C@H:4]6[O:3][C:2]5([CH3:29])[CH3:1])[S:8][C:9]=4[CH:15]=3)[CH:31]=[N:24]2)=[N:19][CH:20]=1
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(CNc3ncncc3N)cc2s1
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Product: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cncnc43)cc2s1

Procedure:
(3aR,7aR)-3-(6-((9H-Purin-9-yl)methyl)benzo[d]thiazol-2-yl)-2,2-dimethyloctahydrobenzo[d]oxazole was synthesized as an oil (220 mg) using a procedure analogous to that described in Step 3 of Example 41, substituting N4-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)pyrimidine-4,5-diamine from Step 6 of this Example for 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine used in Example 41. LCMS (ESI) m/z 421 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2([OH:20])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23](=[O:45])[C@H:24]([CH2:43]O)[NH:25][C:26]([O:28][CH2:29][CH:30]1[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27]>C1C=CC=CC=1.S(=O)(=O)(O)O>[CH3:21][O:22][C:23](=[O:45])[C@H:24]([CH2:43][O:20][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:25][C:26]([O:28][CH2:29][CH:30]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=2[C:37]2[C:42]1=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:27]
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: OC1(c2ccccc2)c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COC(=O)[C@H](COC1(c2ccccc2)c2ccccc2-c2ccccc21)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
A solution of 6.2 g (24 mmol) of 9-phenyl-9H-fluoren-9-ol (Example 1b) and 6.8 g (20 mmol) of Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester in benzene (150 mL) was placed in a round bottomed flask fitted with a Dean-Stark trap. Two drops of concentrated sulfuric acid were added and the mixture heated under reflux with stirring for 1 h. Removal of the solvent under vacuo gave the crude Nα -(9-fluorenylmethoxycarbonyl)--O--(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester which was subjected to the Fmoc deprotection in Step 2 without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:24][CH2:23][C:12]2=[C:13]([CH2:20][CH2:21]O)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(#N)C>[CH2:37]([NH:44][CH2:21][CH2:20][C:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[N:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:24][CH2:23][C:12]=12)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCc1ccccc1
Reactant: OCCc1c2n(c3ccccc13)CCN(Cc1ccccc1)CC2
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(CNCCc2c3n(c4ccccc24)CCN(Cc2ccccc2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
A solution of 2-(3-benzyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)-1-ethanol (320 mg, 1.0 mmol) in dichloromethane (10 mL) is cooled to 0° C., treated with methanesulfonyl chloride (93 μL, 1.2 mmol), and triethylamine (0.21 mL, 1.5 mmol). After 30 min, the yellow solution is diluted with additional dichloromethane (15 mL) and washed once with water (15 mL), once with brine (15 mL), dried over MgSO4, filtered, and concentrated to give a yellow oil. This crude material is diluted with acetonitrile (10 mL) and treated with benzylamine (0.33 mL, 3.0 mmol), and powdered potassium carbonate (415 mg, 3.0 mmol) followed by heating to reflux. After 18 hrs, the yellow suspension is cooled to rt, concentrated, diluted with water (15 mL), and extracted twice with dichloromethane (20 mL). The combined organics are washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to give a crude oil. This material is purified by LC (230-400 silica gel) eluting with 4:0.5:95.5 methanol/NH4OH/dichloromethane to afford 220 mg of N-benzyl-2-(3-benzyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)-1-ethanamine as a yellow oil. IR (liq.) 3025, 2913, 2811, 1494, 1478, 1469, 1453, 1427, 1372, 1363, 1347, 1324, 1120, 733, 698 cm−1; MS (EI) m/z 409 (M+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:18][O:19][P:20]([O:23]C)[O:21][CH3:22]>>[CH3:18][O:19][P:20]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)(=[O:23])[O:21][CH3:22]
Reactant: COP(OC)OC
Reactant: O=S(=O)(c1ccccc1)c1ccc(CBr)cc1
Product: COP(=O)(Cc1ccc(S(=O)(=O)c2ccccc2)cc1)OC
Yield: 86 %

Procedure:
1-(Bromomethyl)-4-(phenylsulfonyl)benzene (Step 1, 10.1 g, 32.5 mmol) was heated to reflux in trimethylphosphite (40 mL) for 16 hours. The cooled reaction was azeotroped with xylene then purified by flash column chromatography on silica, eluting with ethyl acetate to give dimethyl[4-(phenylsulfonyl)benzyl]phosphonate (9.5 g, 86%). δH (360 z, CDCl3): 7.92-7.84 (4H, m), 7.55-7.39 (5H, m), 3.64 (6H, d, J=10.9 Hz), 3.16 (2H, d, J=21.6 Hz).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:34]([CH3:35])=[N:33][C:32]2=[CH:36][C:29]3=[N:30][N:31]2[C:11]=1[N:12]1[CH2:38][CH2:37][C:15]([CH3:39])([O:16][CH2:17][CH:18]=[CH:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[CH2:26][CH:27]=[CH:28]3)[CH2:14][CH2:13]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CO.[Pd]>[C:1]([O:5][C@@H:6]([C:10]1[C:34]([CH3:35])=[N:33][C:32]2=[CH:36][C:29]3=[N:30][N:31]2[C:11]=1[N:12]1[CH2:13][CH2:14][C:15]([CH3:39])([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[CH2:26][CH2:27][CH2:28]3)[CH2:37][CH2:38]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=Cc1ccccc1CC=C3
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCc1ccccc1CCC3
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of the (2S)-2-(tert-butoxy)-2-[4,23-dimethyl-22-oxa-1,5,7,8-tetraazapentacyclo[21.2.2.16,9.02,7.013,18]octacosa-2,4,6(28),8,10,13(18),14,16,19-nonaen-3-yl]acetic acid (21 mg, 0.040 mmol) and triethylamine (5.52 μl, 0.040 mmol) in MeOH (2 mL) was added palladium on carbon (0.42 mg, 3.96 μmol). The mixture was flushed with hydrogen then stirred under a hydrogen balloon. After 1 h, the mixture was filtered over celite rinsing with MeOH then concentrated. The crude material was purified via preparative HPLC to give the title compound (9.1 mg, 0.016 mmol, 41.3% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.21 (d, J=3.4 Hz, 2H), 7.14 (d, J=3.7 Hz, 2H), 6.30 (s, 1H), 5.86 (s, 1H), 4.74-4.59 (m, 1H), 3.77 (t, J=11.4 Hz, 1H), 3.52 (d, J=1.8 Hz, 3H), 3.22-2.94 (m, 5H), 2.90 (s, 3H), 2.72-2.58 (m, 2H), 2.37-2.20 (m, 1H), 2.00-1.54 (m, 7H), 1.38 (s, 1H), 1.17 (br. s., 9H). LCMS (M+H) calcd for C31H43N4O4: 535.32. found: 535.5.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5].[C:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[C:27]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:1][C:2]2[CH:18]=[CH:17][C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:15][C:3]=2[C:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)=[O:5])=[O:36])=[CH:38][CH:39]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1ccc(NC(=O)c2cc(O[Si](C)(C)C(C)(C)C)ccc2N)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 84.4 %

Procedure:
Using the procedure described in Example 68, Part A, 2-amino-5-(tert-butyldimethylsilyloxy)-N-(4-methoxyphenyl)benzamide (460 mg, 1.23 mmol) was reacted with 4-tert-butylbenzoyl chloride (0.243 mL, 1.24 mmol) in N,N-dimethylformamide (10 mL). After quenching the reaction with saturated aqueous sodium carbonate, the resulting precipitate was filtered and washed with 2:1 diethyl ether/hexane. The solid was vacuum dried at 85° C./0.1 mm for 14 h to give 553 mg (84%) of the title compound as a white solid; mp 207° C.
Reaction SMILES: C(O)(C)(C)C.[Li].[CH3:7][C:8]1([CH3:17])[C@@H:10]([C:11](Cl)=[O:12])[C@@H:9]1[C:14](=[O:16])[CH3:15].[Cl-].[Na+]>O1CCCC1>[CH3:7][C:8]1([CH3:17])[C@@H:10]([CH:11]=[O:12])[C@@H:9]1[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)[C@H]1[C@H](C(=O)Cl)C1(C)C
Agent: [Cl-]
Agent: [Li]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(=O)[C@H]1[C@H](C=O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
36.6 g (0.495 mol) of tert.-butanol were added dropwise to a mixture of 6.3 g (0.165 mol) of lithium alanate and 100 ml of tetrahydrofuran at 20°-30° C. in the course of 1 hour. The mixture was subsequently stirred at room temperature for 2 hours and was then added dropwise to a solution of 26.1 g (0.15 mol) of trans-3,3-dimethyl-2-acetyl-cyclopropane-carboxylic acid chloride in 75 ml of tetrahydrofuran at -50° to -60° C. When the addition has ended, the mixture was subsequently stirred for 1 hour, without cooling, poured onto a mixture of 30 ml of concentrated sodium chloride and 300 g of ice and extracted twice by shaking with 400 ml of ether each time. The organic phases were first washed with 50 ml of saturated sodium bicarbonate solution and then with 100 ml of water, dried over sodium sulphate and evaporated in vacuo. Distillation of the residue in vacuo gave 12.7 g (62% of theory) of trans-3,3-dimethyl-2-acetyl-cyclopropane-carbaldehyde in the form of a colorless oil with a boiling point of 80°-86° C./10 mbars.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6].C(O)(=O)C>C(OCC)(=O)C.C(Cl)Cl.[Fe]>[NH2:12][C:10]1[C:9]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[CH:8][C:3]([NH:4][C:5](=[O:7])[CH3:6])=[C:2]([F:1])[CH:11]=1
Reactant: COc1ccccc1Nc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccccc1Nc1cc(NC(C)=O)c(F)cc1N
Temperature: 65 °C

Procedure:
A mixture of 2'-fluoro-5'-(o-methoxyanilino)-4'-nitroacetanilide (14.6 g, 0.046 mol) in ethyl acetate is slowly added to a mixture of iron powder (7.65 g, 0.137 mol) in a 5% acetic acid solution at 65° C. After the addition is complete, the reaction mixture is heated at 65° C. overnight, treated with additional iron powder (2.55 g), heated at 65° C. for one hour and filtered. The resultant filtrate is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a brown oil. Flash column chromatography of the oil using silica gel and 10% to 30% ethyl acetate in methylene chloride solutions gives the title product as a brown oil which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Cl[C:23]1[N:28]=[N:27][C:26]([N:29]([CH3:40])[CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[C:23]1[N:28]=[N:27][C:26]([N:29]([CH3:40])[CH:30]2[CH2:35][C:34]([CH3:36])([CH3:37])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[CH:25][CH:24]=1
Reactant: COc1cc2c(cc1B1OC(C)(C)C(C)(C)O1)CCC2=O
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Product: COc1cc2c(cc1-c1ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn1)CCC2=O
Yield: 100 %

Procedure:
Following standard GENERAL METHOD 1-4 for Suzuki coupling using 6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (300 mg, 1.06 mmol) and 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1, 611 mg, 2.12 mmol) afforded 6-methoxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one (433 mg) MS [M+H+]=409.7.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].COCCl.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:17]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1ccc(O)cc1
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccc(CCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(4-hydroxyphenyl)ethanol (1.4 g) in tetrahydrofuran (30 ml) was added 60% sodium hydride in mineral oil (405 mg) under ice-cooling, and the mixture was stirred for 1 hour at room temperature. To the stirred reaction mixture was added chloromethyl methyl ether (770 μl) under ice-cooling, and the resulting mixture was stirred for 16 hours at room temperature. Additionally, to the stirred reaction mixture was added 60% sodium hydride in mineral oil (405 mg) under ice-cooling. After the mixture was stirred for 1 hour at room temperature, benzyl bromide (1.2 ml) was added under ice-cooling and the resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 ml), trifluoroacetic acid (20 ml) was added to the solution under ice-cooling with stirring, and the mixture was stirred for 1 hour. After the reaction mixture was concentrated under reduced pressure, 2N aqueous sodium hydroxide solution (20 ml) and water (20 ml) were added to the residue, and the resulting mixture was vigorously shaken. The aqueous layer was separated, washed with diethyl ether, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent:hexane/diethyl ether=2/1) gave 4-(2-benzyloxyethyl)phenol (440 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])=[O:17])([O-:3])=[O:2]
Reactant: CCOCCOC(=O)CC(C)=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOCCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O

Procedure:
A mixture of 3-nitrobenzaldehyde (4.54 g), 2-ethoxyethyl acetoacetate (5.23 g) and piperidine (85.2 mg) in benzene (15 ml) was refluxed under azeotropic dehydration for 3 hours. The resultant mixture was washed with water, an aqueous solution saturated with sodium chloride and water in turn, dried and concentrated to give an oil of 2-ethoxyethyl 2-(3-nitrobenzylidene)acetoacetate. To this oily product was added ethyl 3-amino-4,4-diethoxycrotonate (6.5 g). The mixture was heated at 110° C. for about 3 hours. The reaction mixture was dissolved in ethyl acetate and washed with water twice and dried. The solvent was removed from the mixture to give an oil (15.58 g). This oil was subjected to column chromatography on silica gel with an eluent (a mixture of 10 parts of benzene and one part of ethyl acetate by volume) to give an oily substance (8.09 g). This oily substance (0.93 g) was treated with a mixture of n-hexane and diethyl ether to give crystals, which were further recrystallized from a mixture of n-hexane and diethyl ether to give yellow granules (565.2 mg) of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 99° to 100° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]1[C@@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=O.C(C1C=CC=CC=1C(O)=O)=O.[C:29]([O:33][C:34](=[O:52])[CH2:35][C@H:36]([NH2:51])[CH:37]([OH:50])[CH2:38][O:39][C:40]1[C:45]([F:46])=[C:44]([F:47])[CH:43]=[C:42]([F:48])[C:41]=1[F:49])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:52])[CH2:35][C@H:36]([NH:51][C:13](=[O:15])[C@@H:12]([N:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]1=[O:1])[CH2:16][CH3:17])[C:37](=[O:50])[CH2:38][O:39][C:40]1[C:45]([F:46])=[C:44]([F:47])[CH:43]=[C:42]([F:48])[C:41]=1[F:49])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(O)COc1c(F)c(F)cc(F)c1F
Reactant: CC[C@@H](C(=O)O)n1ccc2ccccc2c1=O
Agent: O=Cc1ccccc1C(=O)O
Product: CC[C@@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F)n1ccc2ccccc2c1=O

Procedure:
This compound was prepared using (S)-2-(1-oxo-1H-isoquinolin-2-yl)-butyric acid (prepared from 2-formylbenzoic acid using procedures similar to those described in methods A-E) and (3S)-3-Amino-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (prepared as described in methods H-J) using procedures similar to those described in methods F-G. This compound was isolated as a white solid
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:15]OS(OC)(=O)=O.[BH4-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:15])[CH2:7]2
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1ccc(Br)c2ccncc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCc2c(Br)ccc([N+](=O)[O-])c2C1
Temperature: 100 °C

Procedure:
5-Bromo-8-nitroisoquinoline (216.9 g, 0.86 mol) was added in portions during 10 min to a solution of dimethylsulphate (750 ml). Some heat was developed. The mixture was heated at 100° C. for 10 minutes. 5-Bromo-2-methyl-8-nitroquinolinium methyl sulphate precipitated. The mixture was cooled on ice and diethyl ether (1 l) was added. The crude mixture was filtered and crystals were isolated. The salt was solved in acetic acid (1.5 l). To the ice-cooled mixture was added: sodium borohydride (47 g, 1.24 mol) over 4 hours. The temperature was kept below 30° C. The crude mixture was evaporated and sodium hydroxide (2 l, 1 M) was added. The crystals were filtered. Yield 205.2 g (88%). Mp 85-87° C.