Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C@@H:10]1([NH2:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>>[C:1]1([CH2:7][CH2:8][NH:20][C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=CCc1ccccc1
Product: c1ccc(CCN[C@H]2CCCc3ccccc32)cc1

Procedure:
Phenylacetaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2=[CH:6][C:7]3[S:8][CH:9]=[CH:10][C:11]=3[CH:12]=[C:2]12.C([Li])(C)(C)C.[CH3:18][Sn:19](Cl)([CH3:21])[CH3:20]>O1CCCC1>[CH3:18][Sn:19]([CH3:21])([CH3:20])[C:5]1[S:1][C:2]2=[CH:12][C:11]3[CH:10]=[C:9]([Sn:19]([CH3:21])([CH3:20])[CH3:18])[S:8][C:7]=3[CH:6]=[C:3]2[CH:4]=1
Reactant: c1cc2cc3sccc3cc2s1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cc2cc3sc([Sn](C)(C)C)cc3cc2s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
A dry 1 L three-neck round bottom flask was flushed with N2 and was charged with benzo[1,2-b:4,5-b′]dithiophene (5.20 g, 26.3 mmol) and anhydrous tetrahydrofuran (THF) (300 mL, 0.01 M) via deoxygenated syringe. The reaction flask was cooled to −78° C. and a 1.3 M solution of tert-butyl lithium in hexanes (53.0 mL, 68.8 mmol) was added dropwise via deoxygenated syringe. After 30 minutes of stirring at −78° C., the solution was chilled to 0° C. and stirring was continued for 5 minutes, at which point the reaction mixture was cooled back to −78° C. A 1 M solution of trimethyltin chloride (105 mL, 100 mmol) in hexanes was added to the reaction flask dropwise and stirring continued for 30 minutes at −76° C. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. As the reaction was completed, cool DI water (50 mL) was slowly added to the reaction flask. Then, the reaction mixture was poured into 300 mL of cool water and extracted with MTBE (300 mL) three times. The combined organic layer was washed with water two times and dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The crude product was purified by precipitation into methanol from a THF solution to yield white solid (12.0 g, 88%).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[O:6]1[CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:7][C:16]1=[O:18]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCOCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OCCOCCO1

Procedure:
The procedure of Example 1 was followed using diethylene glycol (8.9 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry THF (600 mL) and triphosgene (8.3 g, 28.8 mmol). The filtrate was concentrated yielding only oligomeric compounds.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:35])[C@H:24]([CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:35])=[O:22])[CH2:26][O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)COCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](COCc2ccccc2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to O-benzylserine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [O:1]1C2C=CC(C(C3C4C(=C(CSC)C=CC=4)NC=3)(C3CC3)C)=CC=2[O:3][CH2:2]1.Cl[C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:39]2[C:47]3[C:42](=[C:43]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)([CH:36]2[CH2:38][CH2:37]2)[CH3:35])=[CH:30][CH:29]=1>>[O:1]1[C:28]2[CH:33]=[CH:32][C:31]([C:34]([C:39]3[C:47]4[C:42](=[C:43]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:44]=[CH:45][CH:46]=4)[NH:41][CH:40]=3)([CH:36]3[CH2:38][CH2:37]3)[CH3:35])=[CH:30][C:29]=2[O:3][CH2:2]1
Reactant: CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1
Reactant: CSCc1cccc2c(C(C)(c3ccc4c(c3)OCO4)C3CC3)c[nH]c12
Product: CC(c1ccc2c(c1)OCO2)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1

Procedure:
The title compound was prepared starting from 214 mg (0.59 mmol) of the compound from Example 189 in analogy to the synthesis of the compound from Example 209. 162 mg (69% of theory) of the target compound were obtained.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C@@H:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([OH:10])=[O:9].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([S:28](Cl)(=[O:30])=[O:29])=[C:23]([CH3:32])[CH:22]=1>O1CCOCC1.O.O1CCOCC1>[C:15]([O:14][C:12](=[O:13])[CH2:11][C@H:7]([NH:6][S:28]([C:24]1[C:25]([CH3:27])=[CH:26][C:21]([O:20][CH3:19])=[CH:22][C:23]=1[CH3:32])(=[O:30])=[O:29])[C:8]([OH:10])=[O:9])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Sodium bicarbonate (1.5 eq) was added to a suspension of (S)-2-amino-4-tert-butoxy-4-oxobutanoic acid (5.1 mmol, 1.2 eq) in dioxane/water (1:1, 20 ml) and the mixture was stirred for 30 min at room temperature. A solution of 4-methoxy-2,6-dimethylbenzenesulfonic acid chloride (4.3 mmol, 1.0 eq) in dioxane (10 ml) was added and the reaction mixture stirred for 16 h at room temperature. On completion of the reaction the organic solvent was removed under vacuum and the aqueous phase acidified with 10% HCl (eq). Extraction was then performed with DCM and the organic phase was washed with saturated sodium chloride solution, dried (Na2SO4) and concentrated to small volume under vacuum. Yield: 45%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[CH2:7][CH2:6][CH2:5]2.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([NH:1][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:11][CH:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:23])=[CH:20][CH:19]=1)#[N:22]
Reactant: O=Cc1ccccc1
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(N)ccc32)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(CCC(=O)N2CCCc3cc(NCc4ccccc4)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2.9 g (9.5 mmol) of 6-amino1-[3-(4-cyano-phenyl)propionyl]-1,2,3,4-tetrahydro-quinoline are dissolved in 80 ml of methanol and 0.6 ml of acetic acid, combined with 1.06 g (10 mmol) of benzaldehyde and stirred for 20 minutes at 0° C. Then 0.63 g sodium cyanoborohydride are added in small batches, stirring is continued for half an hour and the mixture is then allowed to warm up to ambient temperature. The solution is then concentrated by rotary evaporation and the residue is taken up in a little ice water. Then the solution is acidified and sodium hydroxide solution is added until an alkaline reaction is obtained and the mixture is then extracted with me-thylene chloride. The dried solution is concentrated by rotary evaporation and the residue is chromatographed over a silica gel column with toluene/ethyl acetate (1:1).
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:16]([C:18]([CH2:25]OS(C)(=O)=O)([CH2:21][CH2:22][CH2:23][CH3:24])[CH:19]=[O:20])[CH3:17].C(N(CC)CC)C.Cl>COCCOCCOC>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[S:1][CH2:25][C:18]([CH2:16][CH3:17])([CH2:21][CH2:22][CH2:23][CH3:24])[CH:19]=[O:20])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccccc1S
Reactant: CCCCC(C=O)(CC)COS(C)(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: CCCCC(C=O)(CC)CSc1ccccc1C(=O)c1ccccc1
Yield: 57.8 %

Procedure:
A mixture of 31 g (0.144 mol) of 2-mercaptobenzophenone, prepared according to the procedure described in WO 93/16055, 24.4 g (0.1 mole) of 2-ethyl-2-(mesyloxymethyl)-hexanal 1, 14.8 g (0.146 mole) of triethylamine, and 80 mL of 2-methoxyethyl ether was held at reflux for 24 h. The reaction mixture was poured into 3N HCl and extracted with 300 mL of methylene chloride. The methylene chloride layer was washed with 300 mL of 10% NaOH, dried over MgSO4 and concentrated in vacuo to remove 2-methoxyethyl ether. The residue was purified by HPLC (10% EtOAc-hexane) to give 20.5 g (58%) of 2 as an oil.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]1[S:20][C:19]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[CH:18][CH:17]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]1[S:20][C:19]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[CH2:26][CH2:27][NH2:28])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccsc1-c1ccc(-c2sccc2CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccsc1-c1ccc(-c2sccc2CCN)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate L (208 mg, 0.283 mmol) was dissolved DCM (2 ml) and TFA (2 ml) was added. The mixture was stirred at rt for 1 h. Solvents evaporated and residue dissolved in water. The solution was added 1 M NaOH (2 ml) and the aqueous layer extracted with CHCl3. The combined organic layers were dried (MgSO4) and 1.2 M HCl in EtOH (2 ml) was added. Solvents were evaporated to give the HCl-salt of the title compound. Yield: 105 mg (99%); yellow-orange solid. HPLC: RT=2.68 min, 95% (254 nm, 10-40% MeCN in 0.1% TFA, 3 min, ACE) and RT=2.68 min, 94% (350 nm, 10-40% MeCN in 0.1% TFA, 3 min, ACE). 1H NMR (400 MHz, DMSO-d6): δ 3.06 (br s, 12H), 7.14 (d, J 5.2 Hz, 2H), 7.27 (s, 2H), 7.58 (d, J 5.2 Hz, 2H). LC-MS: m/z=335 (M+1).
Reaction SMILES: [C:1]([N:7]1[CH2:11][CH2:10][O:9][C:8]1=[O:12])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].Br[CH2:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22]>>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[CH2:14][CH:2]([CH2:3][CH:4]=[CH2:5])[C:1]([N:7]1[CH2:11][CH2:10][O:9][C:8]1=[O:12])=[O:6]
Reactant: Fc1cccc(Cl)c1CBr
Reactant: C=CCCC(=O)N1CCOC1=O
Product: C=CCC(Cc1c(F)cccc1Cl)C(=O)N1CCOC1=O
Yield: 74 %

Procedure:
Using the procedure to synthesize Example 1, alkylation of 3-pent-4-enoyl-oxazolidin-2-one (Preparation 23) (5.0 g, 30.0 mmol) with 2-bromomethyl-1-chloro-3-fluoro-benzene affords 6.81 g (74%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](=O)[CH:5]=[CH2:6].O.[NH2:11][NH2:12].[Cl-].[Na+]>O>[CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4]1[CH:5]=[CH:6][NH:12][N:11]=1
Reactant: NN
Reactant: C=CC(=O)C(OC)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(OC)c1cc[nH]n1
Reaction time: 8 h

Procedure:
A stirred solution of 1,1-dimethoxy-but-3-en-2-one in water (300 mL) was treated dropwise with hydrazine hydrate (21 ml). After standing at room temperature overnight the reaction mixture was treated with sodium chloride (108 g) and the mixture was then extracted with methyl-t-butylether (200 mL then 100 mL). The combined extracts were dried with magnesium sulfate and then evaporated to give 1H-pyrazol-3-carbaldehyde dimethyl acetal as a light brown oil (18.47 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1C2C=CC(O[CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([C:34]4([C:38]5[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=5)[CH2:37][CH2:36][CH2:35]4)=[O:33])[CH2:27]3)=CC=2OC1>>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C:34]2([C:32]([N:28]3[CH2:29][CH2:30][CH2:31][CH:26]([CH2:25][O:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:27]3)=[O:33])[CH2:37][CH2:36][CH2:35]2)=[CH:39][CH:40]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C(N1CCCC(COc2ccc3c(c2)OCO3)C1)C1(c2ccc(Cl)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(N1CCCC(COc2ccc(F)cc2)C1)C1(c2ccc(Cl)cc2)CCC1

Procedure:
Compound 84 was synthesized from 4-fluorophenol (0.29 g, 2.60 mmol), cesium carbonate (1.27 g, 3.89 mmol) and compound 43 (1.0 g, 2.60 mmol), using the method described for the synthesis of compound 44 to give 0.60 g of the desired product 84. C23H25ClFNO2, LRMS (m/z)=402 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[O:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]1.[BH4-].[Na+]>CO>[O:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][NH:27][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[CH:5][CH:4]=2)[CH2:21][CH2:20]1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2)cn1
Reactant: NCCC1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cnc(Oc2ccc(CNCCC3CCOCC3)cc2)cn1
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Place 5-(4-formylphenoxy)pyrazine-2-carboxamide (Example 437, Part B) (0.150 g, 0.617 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.0797 g, 0.617 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.1 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO®10 column with 2.0 M NH3 in methanol and ethyl acetate. After concentrating, take the product up in dichloromethane (25 mL) and wash with 1.0 N NaOH solution (2×10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.0819 g, 37.2%): MS ES+ 357.1 (M+H)+, base peak 228.0 (M-C7H14NO)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=7.4 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([O:26]C)[CH:20]=[C:19]3[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][CH3:36])[CH:29]=2)([C:10]2[N:11]([CH3:15])[CH:12]=[N:13][CH:14]=2)[OH:9])=[CH:4][CH:3]=1.Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:9])([C:10]2[N:11]([CH3:15])[CH:12]=[N:13][CH:14]=2)[C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[C:19]3[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][CH3:36])[CH:29]=2)=[CH:4][CH:3]=1
Reactant: CCOc1cccc(-c2cc(OC)nc3ccc(C(O)(c4ccc(Cl)nc4)c4cncn4C)cc23)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4ccc(Cl)nc4)c4cncn4C)cc23)c1
Yield: 85.1 %

Procedure:
Following the same procedure as described in example 1F, (6-chloro-pyridin-3-yl)-[4-(3-ethoxy-phenyl)-2-methoxy-quinolin-6-yl]-(3-methyl-3H-imidazol-4-yl)-methanol (1.58 g 2.92 mmol) was treated with HCl in aqueous THF to yield the title compound (1.21 g, 85% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1.O>CS(C)=O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(N2CCC(O)CC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a mixture of 1-fluoro-4-nitrobenzene (2.82 g, 20 mmol) and K2CO3 (6.92 g, 50 mmol) in dimethyl sulfoxide (20 mL) was added piperidin-4-ol (2.22 g, 22 mmol) and the reaction was heated to 100° C. for 4 hours. This solution was poured into 200 ml of water and extracted with ethyl acetate (30 mL×3). The organic phase was combined and washed with saturated brine and dried over anhydrous sodium sulfate. The solid was filtered and the filtrate, 10% Pd/C (100 mg) was added and the mixture was stirred under hydrogen atmosphere at ambient temperature overnight. The catalyst was filtered, and the filtrate was concentrated to afford tan solid 3.7 g. MS (m/z): 193 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[C:31]5[O:30][CH2:29][CH2:28][C:27]=5[CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(O[C:37](=O)[N:38]([CH2:40][CH2:41][NH2:42])C)(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[C:31]5[O:30][CH2:29][CH2:28][C:27]=5[CH:26]=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:42][CH2:41][CH2:40][NH:38][CH3:37])=[O:14])=[CH:4][CH:3]=1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: CNCCNC(=O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, after treatment with TFA and neutralisation, the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]([CH3:33])[CH2:23][CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:32][C:29]2[CH:28]=[N:27][C:26]([NH:25][CH2:24][CH2:23][N:22]([CH3:33])[CH3:21])=[CH:31][CH:30]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN(C)CCNc1ccc(N)cn1
Product: CN(C)CCNc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cn1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (200 mg, 0.57 mmol) and N2-(2-(dimethylamino)ethyl)pyridine-2,5-diamine (113 mg, 0.63 mmol). The title compound was obtained as a yellow solid (9.0 mg, 3% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.37 (1H, br), 8.99 (2H, m), 8.61 (1H, m), 8.20 (1H, m), 7.60 (1H, m), 6.53 (2H, m), 2.65 (2H, m), 2.50 (6H, m), 2.37 (2H, m). MS m/z: 513.17, 515.17 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][C:10]([F:9])=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cccc(N)n1
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Dissolve 2,6-diaminopyridine (1.637 g, 15 mmol) in dioxane (15 mL) and cool to 0° C. for 10 min. Add 4-fluorobenzoyl chloride (793 mg, 0.59 mL, 5.0 mmol) slowly. After 40 min, remove ice bath and stir the reaction at room temperature. Use the work-up and purification procedures described in Preparation 43 to provide N-(6-Amino-pyridin-2-yl)-4-fluoro-benzamide as a slightly yellow solid (1.170 g, 100%): mass spectrum (ion spray): m/z=232.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:20]1[CH2:24][CH2:23][N:22]([CH3:25])[C:21]1=[O:26]>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH:20]2[CH2:24][CH2:23][N:22]([CH3:25])[C:21]2=[O:26])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CN1CCC(Br)C1=O
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OC2CCN(C)C2=O)c1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
To a stirred solution of Methyl 3,5-dihydroxybenzoate (20 g) [CAS No. 2150-44-9] in dry DMF was added potassium carbonate (48 g) and the suspension stirred at ambient temperature under nitrogen. To this 3-Bromo-1-methyl-pyrrolidin-2-one (40 g) (Intermediate 5) [J. Med. Chem., 1987, 30, 1995-98] was added in three equal portions in 4 h intervals at room temperature and stirred overnight at ambient temperature. It was then quenched with water. The aqueous suspension was extracted with DCM. The to combined extracts were washed with water, brine, dried over Na2SO4, and filtered, concentrated under reduced pressure to get the thick liquid residue. The crude product was purified by column chromatography using silica gel as stationary phase and ethyl acetate: petroleum ether as a mobile phase to yield the product as white solid (15 g).
Reaction SMILES: C1(S)C=CC=CC=1.[NH:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[N:23][C:22]([N:25]([CH3:36])[CH:26]3[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]3)=[CH:21][CH:20]=2)=[C:15]([O:37]C)[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[NH:10]1[CH:11]=[CH:12][N:8]=[C:9]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[N:23][C:22]([N:25]([CH3:36])[CH:26]3[CH2:31][C:30]([CH3:32])([CH3:33])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]3)=[CH:21][CH:20]=2)=[C:15]([OH:37])[CH:14]=1
Reactant: COc1cc(-c2ncc[nH]2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(c1ccc(-c2ccc(-c3ncc[nH]3)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Yield: 14.8 %

Procedure:
Following GENERAL METHOD 3-1 for methoxy deprotection using thiophenol, 6-(4-(1H-imidazol-2-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (40 mg, 0.1 mmol) was treated with thiophenol (0.01 mL, 0.11 mmol) and K2CO3(13 mg, 0.1 mmol) in NMP (2 mL) for 30 min at 190° C. to afford 5-(1H-imidazol-2-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol as pale yellow powder (6 mg). MS: 407.4 [M+H+]; LCMS Rt=0.40 min [Method Q]; 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.00 (d, J=10.11 Hz, 1H), 7.68-7.78 (m, 1H), 7.32-7.41 (m, 2H), 7.19 (d, J=10.11 Hz, 1H), 7.05 (s, 2H), 4.96 (br. s., 1H), 2.90 (s, 3H), 1.58 (dd, J=12.38, 3.28 Hz, 2H), 1.46 (t, J=12.38 Hz, 2H), 1.28 (s, 6H), 1.12 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[C:17]4[C:18](Cl)=[N:19][N:20]([CH3:23])[C:21](=[O:22])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+].CO.O>CO>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][N:13]3[C:17]4[C:18]([O:30][CH3:29])=[N:19][N:20]([CH3:23])[C:21](=[O:22])[C:16]=4[N:15]=[CH:14]3)=[CH:25][CH:26]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cn1nc(Cl)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nn(C)c(=O)c2ncn(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c12
Yield: 39 %

Procedure:
The procedure of Example 34 was repeated except that 1-[4-(4-chlorobenzoyl)benzyl]-5-methyl-7-chloroimidazo[4,5-d]pyridazin-4(5H)-one was used as the starting compound. Thus, this starting compound (52 mg) was dissolved in methanol (5 ml) followed by addition of 28% sodium methoxide/methanol (0.5 ml), and the mixture was refluxed for 3 hours. To this reaction mixture was added a large quantity of water and the resulting crystals were rinsed with water and dried under reduced pressure to provide 20 mg (yield 39%) of the title compound. 1H-NMR (CD3OD) δ: 3.73(3H,s), 3.97(3H,s), 5.70(2H,s), 7.41(2H,d,J=8.4Hz), 7.51(2H,d,J=8.8Hz), 7.73(2H,d,J=8.6Hz), 7.76(2H,d,J=8.2Hz), 8.36(1H,s).