Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1([C:9]2[S:10][C:11]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[CH:12][N:13]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:6]2[CH2:5][CH2:4][C:3]([F:2])([C:9]3[S:10][C:11]([CH2:14][O:15][C:16]4[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=4)=[CH:12][N:13]=3)[CH2:8][CH2:7]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(OCc2cnc(C3(F)CCNCC3)s2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(F)(c3ncc(COc4ccc(S(C)(=O)=O)cc4)s3)CC2)nc1

Procedure:
A solution of 4-fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine hydrochloride (1.2 g, 2.76 mmol), 2-chloro-5-ethyl-pyrimidine (425 mg, 1.1 eq.) and DIPEA (1.4 g, 4 eq.) in 2-propanol (20 mL) in a sealed pressure vessel was stirred at 160° C. (oil bath temperature) overnight. After cooling, the solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified on silica gel (EtOAc:hexanes=1:1) to afford the desired product as a white solid. 1H NMR (CDCl3): δ 8.19 (2H, s), 7.90 (2H, d, J=8.8 Hz), 7.73 (1H, d), 7.10 (2H, d, J=8.8 Hz), 5.31 (2H, s), 4.67 (2H, m), 3.44 (2H, m), 3.04 (3H, s), 2.48 (2H, q, J=7.6 Hz), 2.13˜2.38 (4H, m), 1.20 (3H, t, J=7.6 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:10][CH2:9][N:8]([CH:11]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[CH2:12][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:14][NH2:15])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C=O.[C:47](O)(=O)C.C([BH3-])#N.[Na+]>CO.ClCCl.O.C(=O)(O)[O-].[Na+]>[C:1]([NH:4][C:5]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:6][CH2:7][N:8]([CH:11]([CH2:24][C:25]2[CH:26]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:28]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:30]=2)[CH2:12][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:14][NH:15][CH3:47])[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CN)c2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(=O)O
Agent: C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CNCC(CC(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(NC(C)=O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-(4-acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-N-[3,5-bis(trifluoromethyl)benzyl]butylamine (0.30 g) in methanol (4 mL) was added aqueous formaldehyde (37% w/w, 0.027 mL). The mixture was cooled to 0° C. and acetic acid (0.038 mL) was added followed by a solution of sodium cyanoborohydride (43 mg) in methanol (1 mL). The reaction mixture was allowed to warm to room temperature overnight and was diluted with dichloromethane (5 mL), water (5 mL), and saturated sodium bicarbonate (mL). The phases were separated and the aqueous layer was extracted with dichloromethane (10 mL). The combined organic phases were washed (brine), dried, and evaporated, to give material which was purified by chromatography with dichloro-methane:methanol (30:1) as the eluent, to give the title compound as a hemihydrate (0.175 g); mp 72°-74° C.; NMR (d6 -DMSO-trifluoroacetic acid): 7.7 (m,5), 7.25 (m, 6), 3.52 (d,1, J=14.4), 3.25 (d,1, J=14.4), 3.0 (m,1), 2.7-2.45 (m,4), 2.50 (s,3), 2.35-1.95 (broad m,4), 1.85 (s,3), 1.95-1.5 (broad m,4); MS: m/z=674(M+1,100%); TLC: Rf=0.55 (10:1 dichloromethane:methanol). Analysis for C33H35Cl2F6N3O.0.50 H2O: Calculated: C, 57.98; H, 5.31; N, 6.15; Found: C, 57.95; H, 5.24; N, 6.52.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:12]=2[CH2:11][CH:10]([CH3:21])[NH:9][CH:8]=1)=[O:6])[CH2:2][CH3:3].[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:9]2[CH:10]([CH3:21])[CH2:11][C:12]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][C:13]=3[C:7]([C:5]([O:4][CH2:1][CH2:2][CH3:3])=[O:6])=[CH:8]2)=[O:28])=[CH:25][CH:24]=1
Reactant: CCCOC(=O)C1=CNC(C)Cc2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)C(C)Cc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using 2-methyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid n-propyl ester (compound in Paragraph A) and 4-fluorobenzoyl chloride; MS (ES): 407 (MH+). The racemic sample was submitted to chiral separation using a 10 mm×250 mm Chiralcel OD column and a 10% iPrOH/hexane isocratic mobile phase to give two isomers.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:39])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6].[C:40](OC(=O)C)(=[O:42])[CH3:41].C(Cl)Cl.CO>O1CCCC1.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:39])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6].[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:39][C:40]([CH3:41])=[O:42])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6]
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
To a solution of 50 mg (91.9 μmol) of 10-deacetylbaccatin III and 13 μL (1.5 eq.) of acetic anhydride in 2.0 mL of freshly distilled tetrahydrofuran 100 μL of a solution of 4.5 mg of commercial scandium trifluoromethanesulfonate in 1.0 mL of tetrahydrofuran was added. The reaction mixture was stirred at room temperature for 48 hours. Usual workup and isolation of the product by means of preparative TLC (Silica 60, CH2Cl2/MeOH 10:1) afforded 9 mg of unreacted 10-deacetylbaccatin III (18%) along with 31 mg of baccatin III (58%). 1H-NMR and Rf-value (TLC) were in accordance with the product from example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([NH:7][C:8]1[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([CH:21](O)C)[CH2:17][CH2:16]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:47]>C(Cl)Cl>[Br:47][CH2:21][CH:18]1[CH2:19][CH2:20][N:15]([C:9]2[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=3)=[CH:13][C:12]([Cl:14])=[CH:11][N:10]=2)[CH2:16][CH2:17]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(O)C1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)cnc1N1CCC(CBr)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15.7 %

Procedure:
A mixture of 0.170 g (0.431 mmol) of 3-chloro-N-[5′-chloro-4-(1-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-benzamide and 0.135 g (0.517 mmol) of triphenylphosphine in methylene chloride (15 mL) is stirred under an atmosphere of nitrogen at 0 C for 5 minutes. To this is added 0.171 g (0.517 mmol) of carbon tetrabromide in several portions. The mixture is stirred at 0 C for 30 minutes and then warmed to room temperature and stirred for 2 days. The mixture is concentrated under reduced pressure and purified by flash silica gel chromatography to give 0.030 g (15%) of N-(4-bromomethyl-5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl)-3-chloro-benzamide as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[N:3]=1
Reactant: CN1CCC(O)CC1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CN1CCC(Oc2nc(N)nc(-c3ccco3)c2C#N)CC1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-hydroxy-1-methylpiperidine and DBU in DME. ES-MS m/e (%): 300 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:25]=[C:24]2[C:20]([C:21]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]=3[N:23]2[CH3:26])=[CH:19][CH:18]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]4[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]=4[N:23]3[CH3:26])=[CH:19][CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Product: Cn1c2c(c3ccc(-n4ncc(OCc5ccccc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 27.7 %

Procedure:
5-(Benzyloxy)pyridazin-3(2H)-one (197 mg, 0.974 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (353 mg, 0.966 mmol) were coupled following the procedure of Example 30 (step g) to provide the title compound (130 mg, 28%) as a yellow/green solid: 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=2.7 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.45-7.40 (m, 7H), 7.21 (dd, J=8.4, 1.5 Hz, 1H), 5.08 (s, 2H), 4.64 (br m, 2H), 3.75 (br m, 2H), 3.63 (s, 3H), 2.80 (br m, 2H), 1.52 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[Cl-].[Al+3].[Cl-].[Cl-].C[Si]([C:24]#[N:25])(C)C>C1C=CC=CC=1>[C:24]([CH2:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]=[CH:8]2)#[N:25]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(c1OC)CCCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COc1ccc2c(c1OCC#N)CCC=C2
Temperature: 70 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
5,6-dimethoxytetralone (20 g) was dissolved in benzene (20 ml) and trimethylsilyl cyanide (16 ml). A catalytic amount of aluminum chloride was added and the reaction heated at 70° C. under nitrogen for 30 minutes. The volatiles were removed in vacuo and methanol (20 ml) added. Gaseous hydrochloric acid was bubbled through the methanol solution for 30 minutes resulting in precipitation of a solid. Stirring was continued for 1 hour, then the mixture was filtered and dried affording 19.9 g. of product (96% yield); m.p. 138°-9° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH3:4].C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[F:24][C:2]([F:1])([F:23])[CH:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH3:4]
Reactant: CC(c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(c1cccc2c1OCCNC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A mixture of tert-butyl 9-(2,2,2-trifluoro-1-methylethyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (100 mg, 0.290 mmol), ethyl acetate (2 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (60.0 mg, 73.4%) as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[C:16]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:16]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][N:25]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: c1ccc(-c2ccc(N3CCNCC3)cc2)cc1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCN(c2ccc(-c3ccccc3)cc2)CC1
Yield: 54.2 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (249 mg, 0.923 mmol), 1-biphenyl-4-ylpiperazine (200 mg, 0.839 mmol) and diisopropylethylamine (0.292 ml, 1.68 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 16 hours. Water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the titled compound (163 mg, 54.2%) as solid product.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH:12]3[CH:16]([C:17]([OH:19])=O)[CH2:15][CH2:14][N:13]3[CH3:20])[CH:9]=[C:8]([CH3:21])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:47]1[O:58][C:57]2[CH:56]=[CH:55][C:51]([CH2:52][CH2:53][NH2:54])=[CH:50][C:49]=2[O:48]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[O:58]1[C:57]2[CH:56]=[CH:55][C:51]([CH2:52][CH2:53][NH:54][C:17]([CH:16]3[CH2:15][CH2:14][N:13]([CH3:20])[CH:12]3[C:10]3[CH:9]=[C:8]([CH3:21])[N:7]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[N:11]=3)=[O:19])=[CH:50][C:49]=2[O:48][CH2:47]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1cc(C2C(C(=O)O)CCN2C)nc(-n2ccnc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C2C(C(=O)NCCc3ccc4c(c3)OCO4)CCN2C)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(2-Imidazol-1-yl-6-methyl-pyrimidin-4-yl)-1-methyl-pyrrolidine-3-carboxylic acid (31.9 mg, 0.111 mmol) was dissolved in DMF (1 mL). Next, the HBTU (64.0 mg, 0.167 mmol) was added. The reaction was stirred at room temperature for 30 minutes prior to addition of 3,4-methylenedioxyphenethyl amine hydrochloride (22.4 mg, 0.111 mmol) and triethylamine (50 μL). The reaction was stirred at rt for 12 h then heated to 60° C. for 16 h. After this period, the reaction mixture was transferred to a separatory funnel with ethyl acetate (20 mL). The organic layer was washed with sat. NaHCO3 (aq) (30 mL) and H2O (30 mL). The aqueous layers were back extracted with ethyl acetate (25 mL) and all of the organic portions were combined, dried over Na2SO4 and concentrated down under vacuum. The material was purified by Flash Chromatography (10 g, 0-10% methanol/DCM gradient) to afford 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-1-methyl-pyrrolidine-3-carboxylic acid (2-benzo[1,3]dioxol-5-yl-ethyl)-amide. Product isolated as a mixture of diasteromers; [M+H]+ 435.63.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:9]([CH2:26][CH2:27][CH3:28])=[N:8][C:7]=1[C:29]([OH:32])([CH3:31])[CH3:30])=[O:5])[CH3:2].C([Sn](Cl)(CCCC)CCCC)CCC.[N-:47]=[N+:48]=[N-:49].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:49][N:48]=[N:47][N:25]=3)=[CH:14][CH:13]=2)[C:9]([CH2:26][CH2:27][CH3:28])=[N:8][C:7]=1[C:29]([OH:32])([CH3:30])[CH3:31])=[O:5])[CH3:2]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 18 h
Yield: 134.3 %

Procedure:
The mixture of 0.56 g (0.8 mmol) ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[(2′-cyanobiphenyl-4-yl)-methyl]-imidazole-5-carboxylate, 3 ml toluene, 0.65 ml (2.1 mmol) tributyltin chloride and 0.13 mg (2 mmol) NaN3, were heated under reflux for 42 h. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in 5.5 ml of 2.5 M HCl in ethanol. The solution was stirred for 18 h and then concentrated. The residue was triturated in diisopropyl ether to give 0.51 g of the title compound as hydrochloride salt.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5](=[O:10])[NH:6][CH:7]=[N:8][CH:9]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>C1COCC1.CN(C=O)C>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:6]2[C:5](=[O:10])[C:4]([Br:3])=[CH:9][N:8]=[CH:7]2)=[CH:14][CH:13]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=c1[nH]cncc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1c(Br)cncn1Cc1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 15.1 %

Procedure:
Sodium hydride (0.343 g, 8.57 mmol) was added to a solution of 5-bromopyrimidin-4(3H)-one (1.5 g, 8.57 mmol) in THF (10 mL) and DMF (6 mL) and the reaction mixture was stirred for 10 minutes. 4-Chlorobenzyl bromide (1.76 g, 8.57 mmol) was added and the reaction mixture was stirred for an additional 1 hour. The reaction was quenched by pouring the reaction mixture into ice and diluting with ethyl acetate. The organic layer washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (Biotage 40S) to afford the title compound as white solid (0.388 g, 15.1%). LRMS (APCI pos) m/e 300.9 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 8.10 (s, 1H), 7.29-7.37 (m, 4H), 5.15 (s, 2H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([Si:9]([CH3:12])([CH3:11])Cl)([CH3:8])([CH3:7])[CH3:6].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:5]([Si:9]([CH3:12])([CH3:11])[O:2][CH2:1][CH2:3][NH2:4])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethanolamine (0.5 mL, 8.1 mmol), tert-butyldimethylchlorosilane (1.42 g, 8.9 mmol), Et3N (1.25 mL, 8.9 mmol) and DMAP (51 mg, 0.41 mmol) in DCM (25 mL) is stirred at RT for 18 h. The reaction mixture is quenched by H2O, DCM is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a colorless oil; ES-MS: M+=176.2; 1HNMR (CDCl3) 3.95-3.85 (m, 2H), 3.15-3.10 (m, 2H), 0.90 (s, 9H), 0.05 (s, 6H), NH2 is missing.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CC(C)=O>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A mixture of 200 g of methyl 4-hydroxyphenylacetate, 350.4 g of 1-bromotetradecane, 207.9 g of potassium carbonate, 10 g of potassium iodide and 1.5 L of acetone is heated at reflux temperature for 24 hours. The reaction is cooled to room temperature, concentrated in vacuo and the residue is recrystallized from cold hexane to give 276.0 g of the desired product.
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH:10]([OH:35])/[CH:11]=[CH:12]/[C:13]1[C:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]2[C:25]=1[CH:26]([CH3:28])[CH3:27])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]>[O-2].[O-2].[Mn+4].C(OCC)C>[OH:1][CH:2]([CH2:9][C:10](=[O:35])/[CH:11]=[CH:12]/[C:13]1[C:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]2[C:25]=1[CH:26]([CH3:28])[CH3:27])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(O)CC(O)/C=C/c1c(-c2ccccc2)c2c3ccccc3ccn2c1C(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Product: CCOC(=O)CC(O)CC(=O)/C=C/c1c(-c2ccccc2)c2c3ccccc3ccn2c1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
A mixture of ethyl (E)-3,5-dihydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]isoquinolin-2-yl)hept-6-enoate (157 mg; prepared as described in Example 3), activated manganese dioxide (1.74 g) and diethyl ether (25 ml) was stirred at the ambient temperature under an argon atmosphere for 2 hours. The suspension was then filtered and the solid was extracted with diethyl ether (3×15 ml). The filtrate was combined with the extracts and evaporated in vacuo, to give ethyl (E)-3-hydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]-isoquinolin-2-yl)-5-oxohept-6-enoate (80 mg), in the form of an orange gum. [N.M.R. (in CDCl3): 1.26 (3H, t, J=7 Hz), 1.55 (6H, d, J=7 Hz), 2.48 (2H, d, J=7 Hz), 2.55 (2H, d, J=7 Hz), 3.76 (1H, septet, J=7 Hz), 4.19 (2H, q, J=7 Hz), 4.41 (1H, quintet, J=7 Hz), 5.71 (1H, d, J=16 Hz), 6.73 (1H, d, J=8 Hz), 7.01-7.59 (9H, m), 7.03 (1H, d, J=8 Hz), 7.04 (1H, d, J=16 Hz); Mass spectrum (electron impact) m/e =469].
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([S:12][CH3:13])[N:5]=1)[CH3:2].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]CC)=O)=[C:17]([Cl:27])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CC(N(C)C)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22](=[O:24])[N:3]([CH2:1][CH3:2])[C:4]3[N:5]=[C:6]([S:12][CH3:13])[N:7]=[CH:8][C:9]=3[CH:10]=2)=[C:17]([Cl:27])[CH:16]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1Cl
Reactant: CCNc1nc(SC)ncc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCn1c(=O)c(-c2ccc(Br)cc2Cl)cc2cnc(SC)nc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
To a solution of 4-ethylamino-2-(methylthio)pyrimidine-5-carbaldehyde (9, 1.00 g, 5.07 mmol) in anhydrous dimethylacetamide (10 mL) was added ethyl 4-bromo-2-chlorophenylacetate (1.70 g, 6.12 mmol) and cesium carbonate (3.30 g, 10.13 mmol). The reaction mixture was stirred at 100° C. for 2 h. The mixture was poured into ice water and the orange solid was collected, washed with water, dried and purified by Teledyne-Isco using a hexane:ethyl acetate gradient (1:0→4:1) to afford the title compound as a white solid (0.30 g, 0.73 mmol, 14%). ESMS m/z 410 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.65 (s, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.63 (s, 1H), 7.47 (dd, J=8.3, 1.5 Hz, 1H), 7.26 (d, J=8.3 Hz, 1H), 4.55 (q, J=7.0 Hz, 2H), 2.66 (s, 3H), 1.37 (t, J=7.0 Hz, 3H).