Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]2[CH:13]=[N:14][C:15]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=3[O:27][CH3:28])=[N:16][C:5]1=2)([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:62][CH:63]1[CH2:68][CH2:67][N:66]([CH3:69])[CH2:65][CH2:64]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]([N:4]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]2[CH:13]=[N:14][C:15]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:62][CH:63]4[CH2:68][CH2:67][N:66]([CH3:69])[CH2:65][CH2:64]4)=[O:23])=[CH:20][C:19]=3[O:27][CH3:28])=[N:16][C:5]1=2)([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Reaction time: 0.08 h
Yield: 66.4 %

Procedure:
A mixture of 0.077 g (0.0002 mole) of 4-(9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-43a), 0.091 g (0.00024 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 mL (0.0003 mole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.034 g (0.0003 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.064 g of 4-(9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-43) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2O.P(Cl)(Cl)([Cl:28])=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:28]
Reactant: CCc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 1.08 h

Procedure:
A round-bottomed flask containing a mixture of 6-bromo-2-ethyl-3-(4-(trifluoromethyl)benzyl)quinolin-4-ol (4.00 g, 8.29 mmol, Intermediate 5: step b), phosphorous oxychloride (3.50 mL, 37.3 mmol) and acetonitrile (27 mL) was placed into a metal heating block at 90° C. After 65 minutes, the reaction mixture was cooled to room temperature. The acetonitrile and excess phosphorous oxychloride was removed by rotary evaporation. The residue was dissolved in dichloromethane (100 mL) and the solution was cooled in an ice-water bath. Ice (50 mL) was added. Concentrated aqueous ammonia solution was added dropwise until pH=8-9 by litmus paper test. The biphasic mixture was separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organics were dried with sodium sulfate and the dried solution was filtered. Silica gel (8 g) was added to the filtrate and the solvents were removed by rotary evaporation to provide a free-flowing powder. The powder was loaded onto a silica gel column. Elution with hexanes initially, grading to 20% ethyl acetate-hexanes provided the title compound as an off-white solid.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@:21]12[CH2:29][C@@H:28](O)[CH2:27][C@H:26]1[CH2:25][S:24][C:23]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[N:22]2.O>ClCCl>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@:21]12[CH2:29][C@H:28]([F:11])[CH2:27][C@H:26]1[CH2:25][S:24][C:23]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[N:22]2
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)C[C@@H](O)C[C@H]2CS1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)C[C@H](F)C[C@H]2CS1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
[Bis(2-methoxyethyl)amino]sulfur trifluoride (0.0564 mL) was added to a solution of tert-butyl [(4aR*,6S*,7aS*)-7a-(2-fluorophenyl)-6-hydroxy-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl]carbamate (51 mg) in dichloromethane (2 mL) at 0° C., and the mixture was stirred at 0° C. for 1.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate. The title compound (51 mg) was obtained by removal of the drying agent and concentration under reduced pressure.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[CH:20]=1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[CH:26]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2cccnc2)c1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-c2cccnc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-(pyridin-3-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.57 min.; [M+H]+: 389.36 g/mol.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:5]([O:12][CH3:13])=[C:6]([O:10][CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].O>C(Cl)Cl>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:8]1[CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:5]([O:12][CH3:13])=[C:6]([O:10][CH3:11])[CH:7]=1)=[O:25]
Reactant: COc1cccc(C(C)C)c1OC
Reactant: O=C(Cl)CCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)CCCCCBr)cc(C(C)C)c1OC
Temperature: 0 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
A solution of 5.0 g (0.028 mol) of 3-(1-methylethyl)-1,2-dimethoxybenzene in 5 mL of methylene chloride was added to an ice cooled mixture of 4.4 g (0.033 mol) of aluminum chloride and 7.0 g (0.033 mol) of 6-bromohexanoyl chloride in 50 mL of methylene chloride. The reaction mixture was kept at 0° for 18 hours. Water was added and the organic layer was separated and washed with sodium bicarbonate solution. The dried extract was concentrated under reduced pressure to an oil which was purified by HPLC using 5% ethyl acetate-hexane to give 8.1 g (82% yield) of 6-bromo-1-[3,4-dimethoxy-5-(1-methylethyl)phenyl]-1-hexanone as an oil. The nmr spectrum was consistent with the structure and the mass spectrum gave the molecular ion at m/z 356 (C17H25BrO3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.Br[C:38]1[CH:39]=[C:40]([CH:44]=[O:45])[CH:41]=[N:42][CH:43]=1.C(=O)(O)[O-].[Na+]>C(#N)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:38]3[CH:39]=[C:40]([CH:44]=[O:45])[CH:41]=[N:42][CH:43]=3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:28])=[O:29])[CH:10]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cncc(C=O)c3)cc12
Temperature: 80 °C
Yield: 55.5 %

Procedure:
3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (5.0 g, 9.91 mmol), commercial 5-bromo-pyridine-3-carbaldehyde 1.84 g, 9.91 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (405 mg, 0.495 mmol) were combined in a vial under nitrogen and dissolved in acetonitrile (25 mL) and tetrahydrofuran (25 mL). Saturated sodium bicarbonate (25 mL) was added and the system was purged with nitrogen gas. The reaction mixture was capped and heated for 15 h at 80° C. The cooled mixture was diluted with ethyl acetate and washed with brine. The combined organic layers were dried over sodium sulfate and purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridine-3-carbaldehyde (2.66 g, 55.7%). MS: m/z 484 (M+H+).
Reaction SMILES: Br[C:2]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.O>CS(C)=O>[CH2:11]([C:2]1([CH:25]2[CH2:26][NH:27][CH2:28][CH2:29][N:24]2[CH2:23][CH2:22][OH:21])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: OCCN1CCNCC1
Reactant: CCCCCCCCCCC1(Br)C(=O)NC(=O)NC1=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCC1(C2CNCCN2CCO)C(=O)NC(=O)NC1=O
Temperature: 0 °C
Yield: 43.7 %

Procedure:
To a solution of 5-Bromo-5-decylbarbituric Acid (0.619 g) in 1.3 ml of dimethylsulfoxide, kept under stirring at 0° C., a solution of 0.93 g of N-(2-hydroxyethyl)piperazine in 0.7 ml of dimethylsulfoxide is added dropwise, then the reaction is stirred at room temperature for 1 hour. The mixture is then cooled to 0° C. and added with 30 ml of water. A white solid separates, which is kept under stirring for 1 hour, then is filtered and dried under vacuum at 50° C. 0.309 g of the product are obtained, m.p. 181-182° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][C:18](=O)[NH:17][C@H:16]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][NH:17][C@H:16]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)[C@@H](Cc2ccc(F)cc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
To an ice-cooled suspension of lithium aluminum hydride (1.2 g) in tetrahydrofuran (91 ml) was added (3R)-1-benzyl-3-(4-fluorobenzyl)piperazine-2,5-dione (4.95 g) by small portions. The mixture was stirred at the same temperature for 15 minutes and at room temperature for one hour. After removal of solvent by evaporation, aqueous sodium hydrogen carbonate solution was added to the resulting residue. The mixture was warmed at near 50° C. for several minutes and the resulting precipitates were collected by filtration, washed with water and dried in vacuo to give (3R)-1-benzyl-3-(4-fluorobenzyl)piperazine (4.60 g) as an oil.
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH:6]([CH2:11][CH3:12])[CH2:7][C:8]([OH:10])=O)[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.C(N1C=CN=C1)(N1C=CN=C1)=O.[N+:31]([C:34]1[CH:35]=[CH:36][C:37]2[N:43]=[C:42]([NH:44][NH2:45])[CH2:41][N:40]=[C:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[Cl:52])[C:38]=2[CH:53]=1)([O-:33])=[O:32]>O1CCCC1>[N+:31]([C:34]1[CH:35]=[CH:36][C:37]2[N:43]=[C:42]([NH:44][NH:45][C:8](=[O:10])[CH2:7][CH:6]([N:5]3[C:1](=[O:18])[C:2]4=[CH:17][CH:16]=[CH:15][CH:14]=[C:3]4[C:4]3=[O:13])[CH2:11][CH3:12])[CH2:41][N:40]=[C:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[Cl:52])[C:38]=2[CH:53]=1)([O-:33])=[O:32]
Reactant: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1
Reactant: CCC(CC(=O)O)N1C(=O)c2ccccc2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCC(CC(=O)NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1)N1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 20, 3-phthalimidovaleric acid and carbonyldiimidazol are reacted in tetrahydrofuran. To this mixture is added 7-nitro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine to give 3-phthalimidovaleric acid, 2-(7-nitro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl)hydrazide which is warmed with acetic acid to give N-[2-[8-nitro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl]butyl]phthalimide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+]([O-])=O)=[CH:5][C:4]=1[C:12]#[N:13])#[N:2].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24])([CH3:17])([CH3:16])[CH3:15]>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]=1[C:12]#[N:13])#[N:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: CC(C)(C)c1ccccc1S
Product: CC(C)(C)c1ccccc1Sc1cccc(C#N)c1C#N
Yield: 50 %

Procedure:
As in Synthesis Example 1 but using 1.73 grams of 1,2-dicyano-4-nitrobenzene and 4.9 grams of 2-t-butylbenzenethiol, there was obtained 1.46 grams of 1,2-dicyano-3-(2-t-butylphenylthio)benzene (yield of 50%). Next, as in Synthesis Example 1 but using 1.46 grams of this benzene compound and 0.42 gram of BBr3 l there was obtained 0.73 gram of the end product (yield 45%, mp 160°-161° C.).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][C:39]([CH2:46][CH2:47][CH3:48])([CH2:43][CH2:44][CH3:45])[C:40](Cl)=[O:41]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:40](=[O:41])[C:39]([CH3:38])([CH2:46][CH2:47][CH3:48])[CH2:43][CH2:44][CH3:45])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCC(C)(CCC)C(=O)Cl
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCCC(C)(CCC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 42.2 %

Procedure:
A procedure similar to that described in Example 4, above, was followed, but using 2.0 g (3.6 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 1.92 g (10.9 mmol) of 2-methyl-2-propylvaleryl chloride, to provide 1.05 g of the title compound.
Reaction SMILES: Cl.FC1C([O:9][C:10]([C:12]2[N:13]=[N:14][C:15]([CH2:31][CH2:32][CH2:33][CH3:34])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)[CH:17]=2)=O)=C(F)C(F)=C(F)C=1F.N1C=CC=CC=1.[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][O:55][CH:54]([CH2:58][NH2:59])[CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46]>C1COCC1>[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][O:55][CH:54]([CH2:58][NH:59][C:10]([C:12]2[N:13]=[N:14][C:15]([CH2:31][CH2:32][CH2:33][CH3:34])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:20][CH:19]=3)[CH:17]=2)=[O:9])[CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46]
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCc1nnc(C(=O)NCC2CN(C(=O)OC(C)(C)C)CCO2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester hydrochloride (0.18 mmol, 0.1 g, Example 90) and 0.1 mL of pyridine in 2 mL of THF was added 2-aminomethyl-morpholine-4-carboxylic acid tert-butyl ester (0.4 mmol, 0.09 g). The mixture was shaken at room temperature, and upon completion of the reaction, the solvent was removed. The residue was chromatographed with 4% methanolic solution of ammonia (2.0 M ammonia in methanol) in EtOAc to provide 2-({[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-methyl)-morpholine-4-carboxylic acid tert-butyl ester. LCMS: m/z 553.0 [M+1].
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3].C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>>[CH3:20][N:21]([CH3:23])[CH:22]=[N:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]2[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=2)[CH:11]=1
Reactant: CCOC(OCC)N(C)C
Reactant: N=C(N)Nc1nc(-c2cccc(N)c2)cs1
Product: CN(C)C=Nc1cccc(-c2csc(NC(=N)N)n2)c1
Yield: 77.7 %

Procedure:
A solution of 2.5 gm of 2-guanidino-4-(3-amino-phenyl)-thiazole in 7.5 gm of N,N-dimethylformamide diethylacetal was stirred at room temperature for 2 days. Addition of diethyl precipitated a solid which was filtered off and dried, yielding 2.4 gm of the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:16]([NH2:18])[CH3:17]>C1COCC1.C(OCC)(=O)C>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:2](=[O:4])(=[O:3])[NH:18][CH2:16][CH3:17])[CH:6]=1
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Methyl 2-(3-chlorosulfonyl-phenyl)acetate (0.29 g, 1.17 mmol) was dissolved in THF (10 mL) and to this solution 1 mL (2 mmol) of 2M ethylamine in THF was added. Let stir at room temperature 30 minutes, diluted with ethyl acetate and the organic layer was washed with 10% citric acid, brine, dried over sodium sulfate and concentrated to an oil. 0.28 g, 1.09 mmol, 93% yield. 1H NMR 500 MHz (CDCl3) 7.72 ppm, 2H, m; 7.41 ppm, 2H, m; 4.32 ppm, 1H, t; 3.68 ppm, 3H, s; 3.67 ppm, 2H, s; 2.98 ppm, 2H, m; 1.07 ppm, 3H, t.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][CH3:6].[Br:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:8][C:9]1[C:10]([O:7][CH2:3][CH2:4][CH2:5][CH3:6])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cnc(Cl)c(Br)c1
Reactant: CCCCO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1ncc(C)cc1Br
Reaction time: 4 h
Yield: 71.7 %

Procedure:
Sodium hydride dispersion in oil (55-65%, 1.16 g) was added in portions to a well stirred solution of 1-butanol (2.4 mL, 27 mmol) in DMF (50 mL). After stirring the mixture for 1 h at room temperature 3-bromo-2-chloro-5-methyl-pyridine (5.0 g, 24 mmol) was added and stirring continued for 18 h at room temperature and for 4 h at 70° C. The cooled mixture was poured into saturated sodium bicarbonate solution and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (n-heptane/ethyl acetate 8:1) to yield 4.2 g of the title compound as a light red oil, MS (EI) 243.1, 245.1 (M)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([N+:24]([O-])=O)=[C:6]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]4)[CH:7]=2)[O:2]1>C(OCC)(=O)C.[Pd]>[NH2:24][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:9][C:8]2=[CH:7][C:6]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]2
Reactant: COc1cc2ccc(-c3cc4c(cc3[N+](=O)[O-])OCO4)cc2cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2ccc(-c3cc4c(cc3N)OCO4)cc2cc1OC
Yield: 65.3 %

Procedure:
6-(4,5-Methylenedioxy-2-nitrophenyl)-2,3-dimethoxynaphthalene (25 mg, 0.071 mmol) was hydrogenated overnight in ethyl acetate (40 mL) at 40˜45 lb./sq. in. under catalysis of palladium (10 wt % on activated carbon, 20 mg). The solution was passed through celite bed and the catalyst was washed with ethyl acetate (3×10 ml). Concentration in vacuo gave the crude product. Chromatography using 60:40 hexanes:ethyl acetate gave compound 13 (15 mg) in 66% yield; 1H NMR (CDCl3) d 4.01(3H, s), 4.02(3H, s), 5.91(2H, s), 6.40(1H, s), 6.73(1H, s), 7.13(1H, s), 7.15(1H, s), 7.39(1H, dd, J=8.2, J=1.8), 7.72(1H, s), 7.74(1H, d, J=8.5); 13C NMR d 56.4, 98.3, 101.2, 106.6, 106.8, 110.7, 120.5, 126.3, 127.0, 127.3, 128.5, 129.9, 135.7, 138.9, 141.1, 148.0, 150.1, 150.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]1[CH:11]=[C:10]([N:18]([CH3:20])[CH3:19])[CH:9]=[CH:8][C:7]=1[S:6]2(=[O:22])=[O:21])#[N:2].[CH2:23](N)[CH2:24][NH2:25].C[O-].[Na+].O.[ClH:31]>CO>[ClH:31].[ClH:31].[CH3:19][N:18]([CH3:20])[C:10]1[CH:9]=[CH:8][C:7]2[S:6](=[O:22])(=[O:21])[C:5]3[C:14](=[CH:15][CH:16]=[C:3]([C:1]4[NH:25][CH2:24][CH2:23][N:2]=4)[CH:4]=3)[C:13](=[O:17])[C:12]=2[CH:11]=1
Reactant: CN(C)c1ccc2c(c1)C(=O)c1ccc(C#N)cc1S2(=O)=O
Reactant: NCCN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)c1ccc2c(c1)C(=O)c1ccc(C3=NCCN3)cc1S2(=O)=O

Procedure:
A mixture of 6-cyano-2-dimethylaminothioxanthen-9-one 10,10-dioxide, 2.0 g (0.006 mol), ethylenediamine, 3 g, 0.05 mol, and sodium methoxide, 0.1 g (0.002 mol) in methanol, 30 ml, was refluxed for 48 hr. The mixture was poured into H2O and the resultant precipitate was dissolved in boiling in 1N HCl. This solution was cooled and the dihydrochloride salt was filtered and recrystallized from 95% ethanol to yield 2-dimethylamino-6-(2-imidazolin-2-yl)thioxanthen-9-one 10,10-dioxide dihydrochloride 0.3 g with m.p. 330°-335° C. (dec); TLC on silica gel (ethylacetate:ethanol:acetic acid/80:15:5), Rf =0.4.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=[O:7].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[O:7]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:34][CH2:35]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: O=C(CCCCCl)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-[4-(trifluoromethyl)phenyl]-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 473.2 (M+H)+.