Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.C1(CN2CCN(C3CCCCC3(C(C3C=CC(OC(F)(F)F)=CC=3)C)O)CC2)CCCCC1.[CH:36]1([CH2:42][N:43]2[CH2:48][CH2:47][N:46]([C:49](=O)[CH:50]([C:62]3([OH:68])[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]3)[C:51]3[CH:56]=[CH:55][C:54]([O:57][C:58]([F:61])([F:60])[F:59])=[CH:53][CH:52]=3)[CH2:45][CH2:44]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[ClH:1].[ClH:1].[CH:36]1([CH2:42][N:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH:50]([C:62]3([OH:68])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]3)[C:51]3[CH:52]=[CH:53][C:54]([O:57][C:58]([F:59])([F:60])[F:61])=[CH:55][CH:56]=3)[CH2:45][CH2:44]2)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: O=C(C(c1ccc(OC(F)(F)F)cc1)C1(O)CCCCC1)N1CCN(CC2CCCCC2)CC1
Agent: CC(c1ccc(OC(F)(F)F)cc1)C1(O)CCCCC1N1CCN(CC2CCCCC2)CC1
Agent: Cl
Product: OC1(C(CN2CCN(CC3CCCCC3)CC2)c2ccc(OC(F)(F)F)cc2)CCCCC1

Procedure:
In an analogous manner Example 1, step 2 1-{2-[4-(cyclohexylmethyl)piperazin-1-yl]-1-[4-(trifluoromethoxy)phenyl]ethylcyclohexanol dihydrochloride was prepared from 1-{2-[4-(cyclohexylmethyl)piperazin-1-yl]-1-[4-(trifluoromethoxy)phenyl]2-oxoethyl}cyclohexanol. MS(ESI) m/z 469 ([M+H]+). Anal Calcd for C26H39F3N2O22HCl: C, 57.67; H, 7.63; N, 5.17. Found: C, 57.23; H, 7.64; N, 4.86.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)=[CH:5][C:4]([CH3:18])=[N:3]1.Cl[CH2:20][CH2:21][CH2:22][S:23][C:24]1[N:25]([CH3:40])[C:26]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([CH3:39])=[N:34]3)=[N:27][N:28]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:1][N:2]1[C:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][N:13]([CH2:20][CH2:21][CH2:22][S:23][C:24]4[N:25]([CH3:40])[C:26]([C:29]5[CH:38]=[CH:37][CH:36]=[C:35]6[C:30]=5[CH:31]=[CH:32][C:33]([CH3:39])=[N:34]6)=[N:27][N:28]=4)[CH2:14][CH2:15][C:9]=3[CH:8]=2)=[CH:5][C:4]([CH3:18])=[N:3]1
Reactant: Cc1cc(-c2ccc3c(c2)CCNCC3)n(C)n1
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5ccc(-c6cc(C)nn6C)cc5CC4)n3C)cccc2n1
Temperature: 60 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
To a stirred solution of 7-(1,3-dimethyl-1H-pyrazol-5-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine (4 g) (intermediate 3) in dimethylformamide, at room temperature, 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (intermediate 8) (6.8 g), sodium iodide (3.06 g) and anhydrous potassium carbonate (2.82 g) were subsequently added and the reaction mixture was warmed to 60° C. and kept reacting for 24 h. After allowing the reaction mixture to reach room temperature, water (70 ml) was added and the reaction mixture was extracted twice with ethyl acetate (50 ml×2). The organic phase was dried with sodium sulphate and after evaporation the crude product was purified by chromatography on silica gel with 100-95% dichloromethane-methanol elution to give the title compound (3.3 g) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH2:11][CH3:12])=[C:9]([CH3:13])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:14][C:15]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[Se:17][C:16]=1[C:24]([NH2:26])=[O:25].CN(C=O)C.[OH-].[Na+]>>[CH2:11]([C:10]1[C:3]2[C:2]([NH:14][C:15]3[CH:19]=[C:18]([C:20]([CH3:23])([CH3:21])[CH3:22])[Se:17][C:16]=3[C:24]([NH2:26])=[O:25])=[N:7][CH:6]=[N:5][C:4]=2[S:8][C:9]=1[CH3:13])[CH3:12]
Reactant: CCc1c(C)sc2ncnc(Cl)c12
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCc1c(C)sc2ncnc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c12

Procedure:
The reaction of 4-chloro-5-ethyl-6-methylthieno[2,3-d]pyrimidine with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as an off-white color solid, mp 234-236° C. IR (KBr) vmax 3332, 3154, 2962, 1665, 1585, 1362, 1221, 1048, 927, 838, 778 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.04 (1H, s, exchangeable with D2O), 8.64 (1H, s), 8.56 (1H, s), 5.34 (2H, br s, exchangeable with D2O), 3.15 (2H, q, J=7.5 Hz), 2.49 (3H, s), 1.45 (9H, s), 1.25 (3H, t, J=7.6 Hz); 13C NMR (100 MHz, CDCl3): δ 168.0, 167.3, 167.0, 152.7, 151.7, 146.9, 131.0, 130.9, 122.8, 117.7, 110.6, 37.1, 32.5, 20.8, 15.6, 13.4; LC-MS (negative ion mode): m/z 419, 421 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[N:6][C:7]1[N:8]2[CH:13]=[N:14][C:15]=1[C:16](=[N:18][OH:19])[NH2:17].[CH:26]1([C:29](OCC)=O)[CH2:28][CH2:27]1.[H-].[Na+]>CN(C=O)C.C(O)(=O)C.C(Cl)Cl>[CH:26]1([C:29]2[O:19][N:18]=[C:16]([C:15]3[N:14]=[CH:13][N:8]4[C:9]5[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=5)[C:5]([N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)=[N:6][C:7]=34)[N:17]=2)[CH2:28][CH2:27]1
Reactant: COc1cccc2c1c(N1CCOCC1)nc1c(C(N)=NO)ncn12
Reactant: CCOC(=O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cccc2c1c(N1CCOCC1)nc1c(-c3noc(C4CC4)n3)ncn12
Temperature: 120 °C

Procedure:
A mixture of 6-methoxy-5-morpholino-imidazo[1,5-a]quinazoline-3-carboxamide oxime (0.9 g), ethyl cyclopropylcarboxylate (1.7 g), molecular sieves (3 g), and 80% sodium hydride (0.1 g) in 20 ml of dry DMF was heated for 11/2 hours at 120° C. The mixture was cooled to room temperature, diluted with acetic acid (0.5 ml) and methylene chloride (20 ml) and filtered. The filtered mixture was evaporated and the residue was purified by column chromatography (HPLC) (eluent: methylene chloride:acetone (2:1)) to give yellow crystals of the title compound, m.p. 227°-228° C. Yield 0.38 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C:11](=[O:17])[N:10]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][CH:8]=1.B(F)(F)F.[CH3:28]O>>[CH3:28][O:15][C:14]([CH:13]1[CH2:12][C:11](=[O:17])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:16]
Reactant: COc1cccc(C2C(C(=O)O)CC(=O)N2c2ccccc2)c1
Reactant: CO
Agent: FB(F)F
Product: COC(=O)C1CC(=O)N(c2ccccc2)C1c1cccc(OC)c1

Procedure:
A solution of 25.0 gm. of 2-(3-methoxyphenyl)-5-oxo-1-phenylpyrrolidin-3-carboxylic acid in 200 ml 10-15% boron fluoride-methanol was refluxed for 8 hours and upon following the workup for example 1C the product was obtained as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:40])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[CH:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([C:33]4[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[CH:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:40])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cc(C(=O)CC(=O)OC(C)(C)C)ccn2)ccn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(-c2cc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)ccn2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (67 mg, 0.26 mmol) and 3-(2′-methyl-[2,4′]bipyri-dinyl-4-yl)-3-oxo-propionic acid tert-butyl ester (Example K59) (81 mg, 0.26 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (69 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH2:16].[CH2:17]([O:19][C:20]([C:22]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[C:29](I)[N:28]=2)[N:24]([CH3:34])[CH:23]=1)=[O:21])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:17]([O:19][C:20]([C:22]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:16][C:4]3[CH:5]=[CH:6][C:7]([N:9]4[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]4)=[CH:8][C:3]=3[O:2][CH3:1])[N:28]=2)[N:24]([CH3:34])[CH:23]=1)=[O:21])[CH3:18]
Reactant: COc1cc(N2CCN(C)CC2)ccc1N
Reactant: CCOC(=O)c1cc(-c2ccnc(I)n2)n(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)n(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
Palladium acetate [Pd(OAc)2] (60 mg, 0.271 mmol), (±)-BINAP (169 mg, 0.271 mmol) and dimethylformamide (15 mL) were charged to a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. The mixture was stirred under argon for 30 minutes and added to a mixture of 2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamine (600 mg, 2.712 mmol), 5-(2-iodo-pyrimidin-4-yl)-1-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (484 mg, 1.356 mmol), and potassium carbonate (1.87 g, 13.56 mmol) in dimethylformamide (15 mL). The resulting mixture was stirred at 80° C. for 4 hours under argon. After cooling to room temperature, the reaction mixture was filtered on a pad of celite. The solvent was concentrated, the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 95/5) to afford 160 mg (26%) of the title compound as white solid.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(O)(=O)C.C(O)(=O)C.[NH2:13][C:14]1([C:20]([O:22][CH2:23][CH:24](OCN2C=NC3C(=O)NC(N)=NC2=3)[CH2:25][O:26]C(C2(N)CCCCC2)=O)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.[OH-].[NH4+]>O>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:13][C:14]1([C:20]([O:22][CH2:23][CH2:24][CH2:25][OH:26])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1nc2c(ncn2COC(COC(=O)C2(N)CCCCC2)COC(=O)C2(N)CCCCC2)c(=O)[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: NC1(C(=O)OCCCO)CCCCC1
Reaction time: 7 h

Procedure:
2-((2-Amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy)-1,3-propanediyl bis-(1-amino-cyclohexane-carboxylate) tris acetate, 98 mg (lyophilized sample contained 3.0 equivalents of acetic acid by NMR), 0.143 mmol (=a total of 0.43 mmol of acetic acid) is dissolved in de-ionized water, 0.4 mL, and 38 μL of a 0.015M ammonium hydroxide solution (=0.57 mmol) is added. The mixture is left at room temperature for 7 hrs., the vial is placed in a oil bath maintained at 48°-50° C. and left in the oil bath for 22 hrs. The sample is injected in two equal lots onto a preparative reverse phase HPLC column (YMC-Pack, ODS-AM DM-33-5, 20×250 mm; YMC Inc.). Separation is achieved with a solvent system of 15% methanol/85% 0.1M ammonium acetate buffered to pH 4 with acetic acid, flow rate: 9.5 mL/min and the detector set to 256 nm. The peak representing the mono ester is collected. The solvent is removed under high vacuum to about 2 mL and the residue is lyophilized three times from water containing acetic acid (0.1%) to remove the buffer. Excess acetic acid is then removed by drying at room temperature under high vacuum for 42 hrs. 30 mg (0.068 mmol=48%) of 2-(2-amino-1,6-dihydro-6-oxo purin-9-yl)methoxy)-3-hydroxy-1-propanyl (1-amino-cyclohexane-carboxylate) acetate, identical by HPLC and NMR with the product of Example 4B, is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-:20].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([OH:20])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3n2)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12

Procedure:
A solution of 2,4-dichloro-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidine (0.76 g, 2.58 mmol) and sodium hydroxide (2.6 ml, 1N) in THF (30 mL) was heated at 50° C. for 1 hour. 1N HCl (3 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated to provide 0.73 g of 2-chloro-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidin-4-ol which was characterized by its mass spectrum as follows: MS (m/z) 276 [M+H]+.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]1[O:15][C:14](=[O:16])[C:13]([O:17][CH3:18])=[C:12]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:18][O:17][C:13]1[C:14](=[O:16])[O:15][CH:11]([CH2:10][CH2:9][OH:8])[C:12]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC1=C(c2ccccc2)C(CCOCc2ccccc2)OC1=O
Agent: [Pd]
Solvent: CO
Product: COC1=C(c2ccccc2)C(CCO)OC1=O
Yield: 90.4 %

Procedure:
5-(2-Benzyloxyethyl)-3-methoxy-4-phenyl-2(5H)furanone (2.06 g) was dissolved in methanol (20 ml), and palladium black (20 mg) was added. Catalytic reduction was carried out in ordinary temperature and atmosphere. After completion of the reaction, the palladium black was filtered off and the methanol was distilled off under reduced pressure. The crude crystals thus obtained were recrystallized from chloroform to give 3-methoxy-5-(2-hydroxyethyl)-4-phenyl-2(5H)-furanone (1.345g).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[O:43])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:28]C2CCCCO2)[CH:21]([CH3:27])[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C@H:16]([O:35]C2CCCCO2)[CH2:15][C@H:14]1[Cl:42])(=[O:4])=[O:3]>C(O)(=O)C.O.O1CCCC1>[CH3:1][S:2]([NH:5][C:6](=[O:43])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([OH:28])[CH:21]([CH3:27])[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C@H:16]([OH:35])[CH2:15][C@H:14]1[Cl:42])(=[O:3])=[O:4]
Reactant: CC(C)=CCC(C)[C@@H](/C=C/[C@@H]1[C@@H](CCCCCCC(=O)NS(C)(=O)=O)[C@H](Cl)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCC(C)[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)NS(C)(=O)=O)[C@H](Cl)C[C@H]1O
Yield: 45 %

Procedure:
103 mg of (13E)-(8R,9R,11R,12R,15S,16RS)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-13,18-prostadienoic acid methylsulfonylamide was stirred for 24.5 hours under argon at room temperature with 1.9 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10). Then the mixture was concentrated under vacuum and the residue purified by column chromatography on silica gel with hexane/0-100% ethyl acetate as the eluent, thus obtaining 34.3 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4OC)[C:22]4[S:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:11](=[O:38])[NH:10][N:9]=2)[CH:7]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O.[NH4+].[OH-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:11](=[O:38])[NH:10][N:9]=2)[CH:7]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4cc(Cl)ccc4OC)n[nH]c(=O)c3c2)c(OC)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A vial was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (70.7 mg, 0.282 mmol) and THF (938 μl). The resulting solution was cooled to −78° C. for 10 min. Then lithium bis(trimethylsilyl)amide (1M in THF) (413 μl, 0.413 mmol) was added drop wise. The vial was removed from the cold bath temporarily to ensure complete deprotonation of PMB-aminothiadiazole. When the suspension became homogenous, the reaction was cooled back down to −78° C. Then perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (100 mg, 0.188 mmol) in 0.5 mL of THF was added drop wise. LCMS after 15 min showed complete conversion of SM to product. The reaction was warmed to rt, quenched with 1 mL of MeOH and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(5-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (38 mg, 33.7% yield) as white solid. m/z (ESI) 600.0 (M+H)+, 622.0 (M+Na)+. 1-(5-Chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (38 mg, 0.063 mmol) was dissolved in DCM (633 μl, 0.063 mmol) and then TFA (24.4 μl, 0.317 mmol) was added. After 30 min at rt, LCMS showed a complete conversion of SM to product. Purification was done with 0.1% NH4OH in ACN and water as mobile phase to afford 1-(5-chloro-2-methoxyphenyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (17 mg, 59.7% yield) and NH4OH as a triplet at ˜7.07 ppm. To remove NH4OH, the product was dissolved in MeOH (1 mL) and loaded onto a 2 g SCX column. The product was flushed out with MeOH. Concentration afforded 1-(5-chloro-2-methoxyphenyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide as white solid. m/z (ESI) 450.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[CH2:8][C:9](=[CH:12]N(C)C)[C:10](=O)[C:4]=2[CH:3]=1.[NH2:19][C:20]([NH2:22])=[NH:21]>>[NH2:21][C:20]1[N:22]=[CH:12][C:9]2[CH2:8][C:7](=[O:16])[NH:6][C:5]3[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][C:4]=3[C:10]=2[N:19]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Br)cc2C1=O
Product: Nc1ncc2c(n1)-c1cc(Br)ccc1NC(=O)C2

Procedure:
In a manner similar to that described in method H, 7-bromo-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-k) and guanidine were converted to I-44 (79%): HRMS Calcd. for C12H9BrN4O: 305.0037, Found 305.0042.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5](/[N:8]=[CH:9]/[C:10]2[CH:21]=[CH:20][C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[I-].ClC1C=CC=C[N+]=1C.[Si:38]([O:45][C@H:46]([C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=1)[CH2:47][S:48][CH2:49][C:50](O)=[O:51])([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Si:38]([O:45][C@H:46]([C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=1)[CH2:47][S:48][C@H:49]1[C:50](=[O:51])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[C@@H:9]1[C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]
Reactant: COC(=O)COc1ccc(/C=N/c2ccc(I)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CSCC(=O)O)c1ccc(F)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)COc1ccc([C@@H]2[C@@H](SC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(I)cc2)cc1
Yield: 62.9 %

Procedure:
Methyl (4-{(E)-[(4-iodophenyl)imino]methyl}phenoxy)acetate (7.0 g, 17.7 mmol), was placed in a dry 250 ml 3-necked flask under inert atmosphere and dissolved in 100 ml dry DCM. Et3N (5.5 ml, 39.5 mmol) and 2-chloro-1-methylpyridinium iodide (4.2 g, 16.4 mmol) were added. {[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}acetic acid (5.4 g, 15.7 mmol) was dissolved in 50 ml dry DCM and slowly added to the above solution over 7-8 h. The mixture was stirred over night and diluted with 50 ml DCM. HCl (1 M, 100 ml) was added followed by NaHCO3 (5%) until pH was 8-9 of the aqueous. The organic phase was washed with 0.3 M KHSO4, brine until neutral pH, dried with MgSO4 and concentrated. The solid was dissolved in EtOAc:heptane (4:1) and filtered on a short SiO2 column using a gradient from ¼ to 1/1 of EtOAc/heptane as eluent. Concentration yielded 10.65 g. The mixture was purified by preparative HPLC on a C8 column (500×50 mm) using a gradient from 20-100% MeCN in 0.1 M ammonium acetate as eluent. The product fraction was concentrated to yield 7.13 g of the trans diastereomeric mixture. M/z: 720.2 (M−1). The diastereomeric mixture was separated by HPLC on a Chiralpak IA column (4.6×250 mm) using heptane/THF (80/20) as mobile phase. The second eluting diastereomer was collected and the solution concentrated to yield the title compound. 1H-NMR (400 MHz, MeOD) δ: −0.13 (s, 3H), 0.02 (s, 3H), 0.85 (s, 9H), 3.00 (ddd, 2H), 3.81 (s, 3H), 4.02 (d, 1H), 4.76 (s, 2H), 4.84-4.90 (m, 1H), 4.94 (dd, 1H), 6.97-7.06 (m, 4H), 7.09 (d, 2H), 7.30-7.40 (m, 4H), 7.61 (d, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16]CCCC(C)(C#N)C)[C:12]([CH2:25][CH3:26])=[CH:11][C:10]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][CH2:39][CH2:40]Br)#[N:35]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:40][CH2:39][CH2:38][CH2:37][C:36]([CH3:43])([C:34]#[N:35])[CH3:42])[C:12]([CH2:25][CH3:26])=[CH:11][C:10]=1[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCC(C)(C)C#N
Reactant: CC(C)(C#N)CCCCBr
Product: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N

Procedure:
1-(Benzyloxy)-4-ethyl-2-(4-fluorophenyl)-5-[(6-methyl-6-cyanoheptyl)oxy]-benzene was prepared as described in Example 1 for the synthesis of 1-(benzyloxy)-4-ethyl-2-(4-fluorophenyl)-5-[(5-methyl-5-cyanohexyl)oxy]-benzene substituting 6-cyano-6-methyl-1-bromoheptane for 5-cyano-5-methyl-1-bromohexane.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:26]([C:23]4[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=4)(=[O:28])=[O:27])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C3=CCN4CCCC4C3)c3cnccc32)cc1

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418 mmol), 4-methyl-benzenesulfonyl chloride (20 mg, 0.105 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: CC1C(C)=CC=CC=1OCCCC(N1C2C(=C(C3C=CN=C(C(OC)=O)C=3)C=CC=2)CCC1)=O.CC1C(C)=CC=CC=1OCCCC(N1C2C(=C(B3OC(C)(C)C(C)(C)O3)C=CC=2)CCC1)=O.CC1(C)C(C)(C)OB([C:76]2[CH:77]=[C:78]([CH:93]=[CH:94][CH:95]=2)[CH2:79][O:80][C:81]([NH:83][CH2:84][CH2:85][C:86]([O:88][C:89]([CH3:92])([CH3:91])[CH3:90])=[O:87])=[O:82])O1.BrC1C=CN=C(C(OC)=O)C=1.Br[C:109]1[CH:118]=[CH:117][CH:116]=[C:115]2[C:110]=1[CH2:111][CH2:112][CH2:113][N:114]2[C:119]([O:121][CH2:122][CH2:123][O:124][C:125]1[CH:130]=[CH:129][CH:128]=[C:127]([CH3:131])[C:126]=1[CH3:132])=[O:120]>>[C:89]([O:88][C:86](=[O:87])[CH2:85][CH2:84][NH:83][C:81]([O:80][CH2:79][C:78]1[CH:77]=[C:76]([C:109]2[CH:118]=[CH:117][CH:116]=[C:115]3[C:110]=2[CH2:111][CH2:112][CH2:113][N:114]3[C:119]([O:121][CH2:122][CH2:123][O:124][C:125]2[CH:130]=[CH:129][CH:128]=[C:127]([CH3:131])[C:126]=2[CH3:132])=[O:120])[CH:95]=[CH:94][CH:93]=1)=[O:82])([CH3:90])([CH3:91])[CH3:92]
Reactant: Cc1cccc(OCCOC(=O)N2CCCc3c(Br)cccc32)c1C
Reactant: CC(C)(C)OC(=O)CCNC(=O)OCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: COC(=O)c1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)ccn1
Agent: COC(=O)c1cc(Br)ccn1
Agent: Cc1cccc(OCCCC(=O)N2CCCc3c(B4OC(C)(C)C(C)(C)O4)cccc32)c1C
Product: Cc1cccc(OCCOC(=O)N2CCCc3c(-c4cccc(COC(=O)NCCC(=O)OC(C)(C)C)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to methyl 4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)picolinate except that 4-(2,3-dimethylphenoxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one was replaced by tert-butyl 3-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)carbonylamino)propanoate, and methyl 4-bromopicolinate was replaced by 2-(2,3-dimethylphenoxy)ethyl 5-bromo-3,4-dihydroquinoline-1(2H)-carboxylate. LCMS, [M-tBu+2H]+=547.2. 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.1 Hz, 1H), 7.46-7.35 (m, 2H), 7.34-7.27 (m, 1H), 7.27-7.20 (m, 1H), 7.16 (t, J=7.9 Hz, 1H), 7.03 (t, J=7.9 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.79 (d, J=7.7 Hz, 1H), 6.70 (d, J=8.1 Hz, 1H), 5.12 (s, 2H), 4.60-4.52 (m, 2H), 4.24-4.19 (m, 2H), 3.73 (t, J=6.4 Hz, 2H), 3.41 (dd, J=12.0, 6.0 Hz, 2H), 2.57 (t, J=6.3 Hz, 2H), 2.44 (t, J=5.9 Hz, 2H), 2.26 (s, 3H), 2.17 (s, 3H), 1.86-1.75 (m, 2H), 1.42 (s, 9H).