Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]2[C:13]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]3[CH3:30])=[CH:14][CH:15]=[CH:16][C:9]1=2.[Cl:31]CCl.[ClH:34]>CO>[ClH:31].[ClH:34].[S:8]1[CH:12]=[CH:11][C:10]2[C:13]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH:18]3[CH3:30])=[CH:14][CH:15]=[CH:16][C:9]1=2
Reactant: ClCCl
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1cccc2sccc12
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC1CNCCN1c1cccc2sccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (6 ml) was added to a solution of 1.22 g (3.7 mmol) of tert-butyl 4-benzo[b]thiophen-4-yl-3-methylpiperazin-1-carboxylate in a dichloromethane solution (12 ml) and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous potassium carbonate solution was added to the residue and the resulting mixture was extracted with dichloromethane. The extraction solution with dichloromethane was dried over magnesium sulfate and thereafter concentrated under reduced pressure. To the residue obtained, concentrated hydrochloric acid (0.6 ml) and methanol (10 ml) were added and the resulting mixture was concentrated under reduced pressure. The obtained residue was subjected to recrystallization from acetonitrile to obtain 1-benzo[b]thiophen-4-yl-2-methylpiperazine dihydrochloride (0.98 g) as light brown powder.
Reaction SMILES: [C:1]([C:3]1[C:11]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[C:5]([CH3:18])[N:4]=1)#[N:2].OO.C(=O)([O-])[O-:22].[K+].[K+].[OH-].[K+]>CS(C)=O.O.CO>[NH2:2][C:1]([C:3]1[C:11]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:18])[N:4]=1)=[O:22]
Reactant: CCC(CC)Nc1cc(C(=O)[O-])c(C)nc1C#N
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: CCC(CC)Nc1cc(C(=O)O)c(C)nc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 348.5 %

Procedure:
To a solution of 6-cyano-2-methyl-5-(pentan-3-ylamino)nicotinate (0.543 g, 1.97 mmol) in DMSO (10 ml) were added 50% aqueous hydrogen peroxide (0.2441 g, 3.55 mmol) and potassium carbonate (0.068 g, 0.49 mmol) at 10° C. The reaction mixture was stirred at room temperature for two hours then a solution of potassium hydroxide (0.22 g, 3.94 mmol) in water (2 ml) and methanol (10 ml) were added to above reaction mixture. After being stirred for another two hours at 45° C., the reaction mixture was cooled to room temperature and neutralized to PH 7. 6-(Aminocarbonyl)-2-methyl-5-(pentan-3-ylamino)nicotinic acid (0.453 g, 87%) was obtained by filtration and drying. 1HNMR (400 MHz, MeOH-D4): 7.62 (s, 1H), 3.35 (m, 1H), 2.60 (s, 3H), 1.65 (m, 2H), 1.52 (m, 2H), 0.95 (t, J=7.20 Hz, 6H). MS (EI) for C13H20N3O3: 267.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][Mg+].[Br-].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([OH:12])([CH3:13])[CH3:11]
Reactant: COc1ccc(C(C)=O)c(Br)c1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)O)c(Br)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
To the mixture of 1-(2-bromo-4-methoxyphenyl)-ethanone (300 mg) dissolved in THF solution (3 ml), MeMgBr (3 M THF solution, 0.52 ml) was added at 0° C. under nitrogen atmosphere. Then, the mixture was stirred at room temperature for 6 hrs. The reaction mixture was added with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated brine, and the residues obtained after concentration under reduced pressure were purified by silica gel column (ethyl acetate/hexane) to obtain the title compound (220 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH2:43]([N:50]1[CH2:55][CH2:54][CH:53]([NH2:56])[CH2:52][CH2:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)(Cl)Cl.O>[CH2:43]([N:50]1[CH2:55][CH2:54][CH:53]([NH:56][C:35]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][N:11]=3)=[CH:8][C:2]=2[Cl:1])=[O:41])[CH2:52][CH2:51]1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5)CC4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 112 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (134 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 1-benzyl-4-piperidineamine (85 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (185 mg, yield 100%).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.C[O-].[Na+].C1(C)C=CC(S(O[CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:26]=2)[C:23]#[N:24])(=O)=O)=CC=1.O>CO>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([S:7][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:26]=2)[C:23]#[N:24])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(SC(C#N)c2cccc(Oc3ccccc3)c2)cc1
Reaction time: 0.17 h
Yield: 100.7 %

Procedure:
p-Toluenethiol (5.00 g) was dissolved in 6 ml of methanol, and 1.60 ml of a 2.5 M methanol solution of sodium methoxide was added to the solution at room temperature in a stream of argon. The mixture was stirred under ice cooling. Then, 1.516 g of O-(p-toluenesulfonyl)-m-phenoxymandelonitrile was added, and the mixture was stirred for 30 minutes under ice cooling and then for 10 minutes at room temperature. Water (20 ml) was added, and the mixture was extracted with 30 ml of methylene chloride three times. The extract was washed with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; benzene) to afford 1.334 g (yield 100%) of alpha-(p-tolylthio)(m-phenoxyphenyl)acetonitrile as a colorless oil.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C#C.I[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]I.[CH3:20][CH2:21][CH2:22][CH2:23][CH2:24]C>O1CCCC1>[CH3:4][C@:3]12[CH2:24][CH2:23][C@H:22]3[C@@H:11]([CH2:12][CH2:13][CH:14]4[C@:21]3([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]4)[C@@H:10]1[CH2:9][CH:1]=[CH:2]2
Reactant: [Li]CCCC
Reactant: CCCCCC
Reactant: ICCCCCCCCCCI
Agent: C#C
Solvent: C1CCOC1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3CCCC[C@]3(C)[C@H]1CC2
Temperature: -10 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of butyllithium (2.84 ml of a 1.6M solution in hexane, 4.5 mmol) in dry tetrahydrofuran (THF, 45 ml) was added dropwise a solution of acetylene 9 (500 mg, 1.13 mmol) in dry THF (10 ml) at -40° C. The reaction mixture was then allowed to warm up to -10° C. and stirred for 1 h. At this temperature, a solution of 1,10-diiododecan (2.15 g, 5.4 mmol) in dry THF (5 ml) was added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 15 h. Then, the solution was diluted with 100 ml of ether and was washed with water (6×30 ml), dried, filtered and concentrated to an oil. The residue was purified by flash chromatography (hexane:acetone, 96:4), followed by preparative thin-layer chromatography (TLC) to give 208 mg, 26% of compound 10 (n=10)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])=[O:14])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH3:25])[CH:3]=1.[H-].[Na+].[CH2:28](I)[CH3:29].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:9]2[CH:23]=[CH:22][C:12]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])=[O:14])=[C:11]([Cl:24])[CH:10]=2)[CH2:28][CH3:29])=[C:4]([CH3:25])[CH:3]=1
Reactant: CCI
Reactant: Cc1cc(Br)ccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(c1ccc(C(=O)c2ccccc2C)c(Cl)c1)c1ccc(Br)cc1C

Procedure:
A solution of 4-(4-bromo-2-methyl-phenylamino)-2-chloro-2′-methylbenzophenone (Compound 136)(110 mg) in dry tetrahydrofurane (2.0 ml was added sodium hydride (19 mg) in one portion under stirring. After 10 min at room temperature ethyl iodide (124 mg ) was added and the reaction mixture was stirred for 18 hours under reflux, then poured into water and extracted with EtOAc. The organic phases were separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography using a mixture of EtOAc/pentane 1:8 as eluant to yield the title compound as an oil.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH:15]1[C:20]([O:22][CH3:23])=[O:21]>>[C:1]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH:15]1[C:20]([O:22][CH3:23])=[O:21])(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:1]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH:15]1[C:20]([OH:22])=[O:21])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: COC(=O)C1COCCN1
Agent: Cl
Product: CCCCCCC/C=C/C(=O)N1CCOCC1C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCOCC1C(=O)OC

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and methyl morpholine-3-carboxylate hydrochloride as starting raw materials, to produce methyl 4-[(E)-2-decenoyl)morpholine-3-carboxylate (methyl ester of Compound 49).
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:30]O>>[CH3:30][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:2]=1[F:1]
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Yield: 81 %

Procedure:
To 2-fluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoic acid (23, 4.0 g, 11 mmol) in 40 mL of methanol, sulfuric acid (8.8 mL, 0.16 mol) was added and the reaction mixture was refluxed overnight. The resulting reaction mixture was concentrated, and the residue was poured into 5% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (24, 3.35 g, 81%). MS (ESI) [M−H+]−=376.4.
Reaction SMILES: Cl.[CH3:2][C@:3]1([OH:8])[CH2:7][O:6][NH:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[CH:18]1([CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34](O)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]([CH3:41])([CH3:40])[CH2:38][CH3:39])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:18]1([CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34]([N:5]4[CH2:4][C@@:3]([CH3:2])([OH:8])[CH2:7][O:6]4)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]([CH3:40])([CH3:41])[CH2:38][CH3:39])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: C[C@@]1(O)CNOC1
Reactant: CCC(C)(C)c1nc2cc(C(=O)O)ccc2n1CC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(C)c1nc2cc(C(=O)N3C[C@@](C)(O)CO3)ccc2n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
Following the same procedure in Example 3, Step A, using (4R)-4-methylisoxazolidin-4-ol hydrochoride (36.0 mg, 0.25 mmol), diisopropylethylamine (144 μL, 106.6 mg, 0.83 mmol) and a solution of 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazole-5-carboxylic acid (82.1 mg, 0.25 mmol) (for preparation, see in Example 4, Step E) in DMF (5 mL) at 0° C., and later, HATU ( 14.0 mg, 0.30 mmol). The mixture was stirred for 4 h at room temperature, added H2O (5 mL). Upon evapoartion, the desired title compound was purified by reversed-phase HPLC (C-18 column) using 20-50% CH3CN/H2O to give 90.5 mg (69%) of a white solid. [a]D: +16.6° (c 0.15,EtOH). 1H NMR (400 MHz, CD3OD): δ 0.86 (t, J=7.42 Hz, 3H), 1.26 (m, 5H), 1.50 (s, 3H), 1.66 (m, 3H), 1.69 (s, 6H), 1.79 (m, 2H), 2.04 (q, J=7.49 Hz, 2H), 2.13 (m, 1H), 3.82 (d, J=11.33 Hz, 1H), 3.89 (d, J=8.40 Hz, 1H), 3.97 (m, 2H), 4.50 (d, J=7.81 Hz, 2H), 7.99 (m,2H), 8.19 (s, 1H). MS (ESI) (M+H)+=414.2. Anal. Calcd for C24H35N3O3+1.50 TFA+1.10 H2O (604.42): C, 53.65; H, 6.45; N, 6.95. Found: C, 53.55; H, 6.44; N, 7.18.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[C:9]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:10]=[CH:11][C@@H:12]([OH:29])[CH2:13][C@@H:14]([OH:28])[CH2:15][C:16]([NH:18][C@H:19]([C:24]([O:26]C)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[C:9]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:10]=[CH:11][C@@H:12]([OH:29])[CH2:13][C@@H:14]([OH:28])[CH2:15][C:16]([NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)C[C@H](O)C[C@H](O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)C[C@H](O)C[C@H](O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C)C(=O)O

Procedure:
When a solution of the compound from Example 147 in dioxane-water is treated at a temperature of about 0° C. with 1N NaOH and then acidified after workup, the title compound is thereby produced.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][NH:21][CH:22]3[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]3)[CH:13]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[Cl:37][C:38]1[C:39]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([F:51])[C:40]=2[S:41][C:42]=1[C:43](Cl)=[O:44]>>[Cl:37][C:38]1[C:39]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([F:51])[C:40]=2[S:41][C:42]=1[C:43]([N:21]([CH2:20][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][CH:8]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19])[CH:22]1[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24][CH2:23]1)=[O:44]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(CS(C)(=O)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(CS(C)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Crude biaryl amine 198 (362 mg) is treated with acid chloride 8 (224 mg, 0.84 mmol) using Method D to give the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC1(C)C(C)(C)OB([C:54]2[CH:55]=[CH:56][C:57]([NH2:60])=[N:58][CH:59]=2)O1>ClCCCl>[CH3:19][N:20]([CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([C:54]3[CH:59]=[N:58][C:57]([NH2:60])=[CH:56][CH:55]=3)=[N:7][C:6]=2[CH:8]=1)[CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CNC1CCN(C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCC(N(C)Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (0.5 g, 1.8 mmol) in 1,2-dichloroethane (10 mL) was added N,1-dimethylpiperidin-4-amine (0.3 g, 2.3 mmol) and AcOH (100 μL, 1.8 mmol). After stirring 10 min at room temperature, Na(OAc)3BH (0.5 g, 2.1 mmol) was added and the resulting mixture stirred overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3 and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by silica gel chromatography (95:5; CH2Cl2: 2 M NH3 in MeOH). A portion of the purified intermediate (0.3 mmol) was coupled following General Procedure A with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine to provide 214 after reverse phase HPLC purification (25 mg). MS (Q1) 454 (M)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1.C(O)CCC>CCOC(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Reactant: Fc1ccc(F)c([C@H]2CCCN2)c1
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Temperature: 140 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
A suspension of 6-chloro-3-nitroimidazo[1,2-b]pyridazine (1.0 g, 5.0 mmol) and (R)-2-(2,5-difluorophenyl)pyrrolidine (Prepared as described in Preparation A; 1.9 g, 11 mmol) in n-butanol (4.6 mL, 50 mmol) was sealed in a pressure reaction tube and stirred in a 140° C. oil bath overnight. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc (250 mL), then washed with water (2×150 mL) and brine (150 mL), filtered through a Biotage Phase Separator filter paper and concentrated. The crude material was purified by silica gel chromatography, eluting with 2:1 EtOAc/hexanes to yield the product as a foamy yellow powder (1.3 g, 75% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:11]([NH2:13])=O>O>[N:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[C:8](=[O:10])[NH:13][CH:11]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: NC=O
Solvent: O
Product: O=c1[nH]cnc2cccnc12

Procedure:
A mixture of 6.5 g of 3-amino-pyridine-2-carboxylic acid in 9 g of formamide was heated in an oil bath while stirring. The temperature was increased from 130° C. to 180° C. over a two hour period, then the mixture was allowed to cool. The mixture was then diluted with water. The solids were collected and washed with fresh water, then dried. Yield 4.6 g. M.P. 346-347° C.
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[O:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]1(/[CH:28]=[CH:29]/[C:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCOCC.O>[C:22]1(/[CH:28]=[CH:29]/[C:30]2[CH2:35][CH2:34][N:33]([CH2:6][C:7]3[C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[O:10][CH:11]=3)[CH2:32][CH:31]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C1=C(/C=C/c2ccccc2)CCNC1
Reactant: OCc1coc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: O
Product: C1=C(/C=C/c2ccccc2)CCN(Cc2coc3ccccc23)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.2 %

Procedure:
Thionyl chloride (0.25 ml 3.4 mmol) was added to a solution of 3-hydroxymethylbenzo[b]furan (0.4515 g, 3.05 mmol) in anhydrous ether (10 ml), the mixture was stirred at room temperature for 2.5 hours and evaporated to dryness. The residue was dissolved in anhydrous dimethylformamide (10 ml), potassium carbonate (1.05 g, 7.60 mmol) and (E)-4-(2-phenylethenyl)-1,2,3,6-tetrahydropyridine (0.68 g, 3.67 mmol) was added and the mixture stirred at room temperature, under nitrogen, overnight (20 hours). The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (2×50 ml). The extracts were washed with saturated brine (50 ml), combined and dried (magnesium sulfate). The residue after evaporation of the solvent was purified by flash chromatography, eluting with 20% then 25% ethyl acetateetrol (60°-80°), to afford the title compound (0.4734 g, 49%). Recrystallisation from ethyl acetate/petrol (60°-80°) gave pale yellow needles, m.p. 122°-123° C.; (Found: C, 8.29; H, 6.58; N, 4.36. C22H21NO.0.1H2O requires C, 83.30; H, 6.74; N, 4.42%); δH (CDCl3) 2.43 (2H, br s, tetrahydropyridinyl CH2), 2.73 (2H, t, J 5.7 Hz, tetrahydropyridinyl CH2), 3.21 (2H, d, J 2.7 Hz, tetrahydropyridinyl CH2), 3.76 (2H, s, ArCH2N), 5.82 (1H, br s, tetrahydropyridinyl CH), 6.44 (1H, d, J 16.1 Hz, C H=CHPh), 6.79 (1H, d, J 16.1 Hz, CH=C HPh), 7.17-7.32 (5H, m, ArH), 7.39 (2H, m, ArH), 7.48 (1H, m, ArH), 7.58 (1H, s, 2-H), 7.73 (1H, m, ArH); m (ES+) 316 (M+1)+.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH3:17])[N:15]=[C:14]([C:18](=O)[CH3:19])[C:13]=2[OH:21])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[NH:22]([C:24]([NH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=[S:25])[NH2:23].CN(C)C=O>Cl.O>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH3:17])[N:15]=[C:14]([C:18](=[N:23][NH:22][C:24]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)=[S:25])[CH3:19])[C:13]=2[OH:21])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCc1ccc(-c2c(O)c(C(C)=NNC(=S)Nc3ccc(C(=O)O)cc3)nn2C)cc1
Yield: 75.7 %

Procedure:
1-[5-(4-n-Pentylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.2381 mmol, HPLC purity 86.3%, 79.0 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.2381 mmol, 50.3 mg) were stirred with dimethylformamide (3 mL) and three drops of concentrated hydrochloric acid at room temperature for 8.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (86.4 mg, yield 76%).