Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[N:6]=1.CN1CCOCC1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C)C=O.ClCCl>[S:36]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)[N:6]=1)([CH3:35])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Reaction time: 1 h
Yield: 34 %

Procedure:
To a stirred mixture of 2-amino-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (0.78 g), N-methylmorpholine (1.15 ml) in N,N-dimethylformamide (8 ml) was added dropwise a solution of methanesulfonyl chloride (0.5 g) in dichloromethane (0.5 ml) under ice-bath cooling. After 1 hour, the reaction mixture was filtered. The filtrate was made basic with 1N sodium hydroxide solution (12 ml). After being stirred for 30 minutes, the mixture was neutralized with 1N hydrochloric acid and extracted with dichloromethane (40 ml×2). The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel, and eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give white crystals. The crystals were recrystallized from ethanol to give 2-mesylamino-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (0.32 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4].O=P(Cl)(Cl)Cl.[OH-].[Na+].CN([CH:26]=[O:27])C>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:26]=[O:27])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4]
Reactant: CCn1ccc2ccc(C(=O)OC)cc21
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1cc(C=O)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
1-Ethyl-1H-indole-6-carboxylic acid methyl ester (900 mg, 4.45 mmol) was dissolved in DMF (3.3 mL). This was added dropwise to an ice-cold solution of POCl3 (430 μL, 4.5 mmol) in DMF (1.5 mL). The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was then treated with 6N NaOH (3.5 ml). The mixture was then partitioned between H2O and ethyl acetate. Purification by silica gel chromatography (5-10% EtOAc/CH2Cl2) yielded 1-ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (985 mg, 96%) as a white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH:10]([CH2:15][F:16])[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[F:16][CH2:15][CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[CH3:14]
Reactant: CN1CCN(Cc2ccccc2)CC1CF
Agent: [Pd]
Solvent: CO
Product: CN1CCNCC1CF
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.7 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 336c (3.0 g, 13.5 mmol), methanol (80 mL), and Pd/C (10%) (300 mg). The reaction mixture was stirred at 25° C. under H2 for 15 h. After the reaction was finished, it was filtered and concentrated to afford 336d as a yellow oil (1.6 g, 90%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.O.[NH2:13][NH2:14]>>[NH:13]([C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1)[NH2:14]
Reactant: CC(C)(O)c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Product: CC(C)(O)c1ccc(NN)nc1
Temperature: 110 °C

Procedure:
A mixture of 2-(6-chloropyridin-3-yl)propan-2-ol (975 mg, 5.68 mmol), and hydrazine hydrate (5512 μl, 114 mmol) was heated in a microwave on high absorbance for 10 hr at 110° C. The mixture was cooled to room temperature and the hydrazine was removed via rotary evaporation. The resulting yellow residue was used without further work-up.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[OH:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].Cl>CCOCC>[Cl:21][C:18]1[CH:19]=[CH:20][C:7]([OH:6])=[C:8]([C:9]([CH2:3][CH:2]=[CH2:1])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[OH:10])[CH:17]=1
Reactant: C=CC[Mg]Br
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Agent: Cl
Solvent: CCOCC
Product: C=CCC(O)(c1ccccc1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
360 ml of an ether solution titrating 1 M/liter of allyl magnesium bromide were added dropwise with stirring to a mixture of 40 g of 2-hydroxy-5-chloro-benzophenone and 400 ml of anhydrous ether and the suspension was iced and stirred at room temperature for 16 hours. 180 ml of 2 N hydrochloric acid were added to the mixture and the decanted organic phase was washed with water, dried over mangesium sulfate and evaporated to dryness under reduced pressure. The oil residue was chromatographed over silica gel and was eluted with methylene chloride to obtain 18.9 g of 5-chloro-2-hydroxy-α-(2-propenyl)-α-phenyl-benzene-methanol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1.C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>C1COCC1>[O:21]=[C:20]1[N:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)CNc1ncccc1N
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(=O)[nH]c2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of ethyl N-(3-aminopyridin-2-yl)glycinate (18 g) in THF (200 mL) was added CDI (15 g) at room temperature, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residual crystals were washed with AcOEt to give the title compound (5.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN1C(=O)CCC1.Cl.O1CCOCC1>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]=3[CH3:11])=[CH:14][CH:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: Cc1cc2cc(F)ccc2[nH]1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1[nH]c2ccc(F)cc2c1-c1ccnc2cc(Cl)ccc12
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A solution of 5-fluoro-2-methylindole (149 mg) and 4,7-dichloroquinoline (198 mg) in NMP (2 ml) and 4M hydrogen chloride in dioxan (0.2 ml) was stirred at 140° C. overnight and then at 150° C. for 1 h. and evaporated. The residue was taken up in ethyl acetate, washed with brine (3×), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica chromatography using acetone/isohexane (2:8) as eluent to give the sub-title compound (250 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)=[N:13][C:14]([S:17]([CH3:18])=[O:38])=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ccccc2)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(COc2nc(S(C)=O)ncc2C(=O)NCc2ccccc2)cc1Cl

Procedure:
N-benzyl-4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxamide (100 mg, 0.23 mmol) was dissolved in 10 mL of dichloromethane, m-CPBA (m-chloroperbenzoic acid, 40 mg, 0.23 mmol) was added and reacted at room temperature for 3 h, washed with water after the reaction is complete, extracted with dichloromethane, the organic layer was dried and dried by rotation to obtain yellow solid, and this product was directly used in the next reaction without purification.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[C:6]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:5]1)([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Pt]=O>[NH2:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=3)=[CH:5][N:4]2[CH:1]([CH3:2])[CH3:3])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CC(C)n1cc(-c2ccc(C#N)cc2)c2ccc([N+](=O)[O-])cc21
Agent: O=[Pt]
Solvent: C1CCOC1
Product: CC(C)n1cc(-c2ccc(C#N)cc2)c2ccc(N)cc21
Yield: 99.7 %

Procedure:
Method E Placc 4-(1-isopropyl-6-nitro-1H-indol-3-yl)-benzonitrile (4, R1=i-Pr, R3=4-benzonitrile) 250 mg, 0.82 mmol) in a 50 mL flask and add a suspension of platinum (II) oxide (16 mg) in tetrahydrofuran (9 mL). Place the reaction under 1 atmosphere of hydrogen and stir until the starting material is consumed. Filter through a celite pad and wash the pad with ethyl acetate (50 mL). Concentrate the combined filtrates to give 225.0 mg of the title compound (99%). LRMS (API ES+)=276.0 (M+H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([C:15]([N:17]2[CH2:21][CH2:20][C@H:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18]2)=[O:16])=[CH:13][CH:12]=1.C(N(CC)CC)C.[C:36]1([S:42](Cl)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]/[C:49]([OH:51])=[O:50]>ClCCl.ClCCl.CO>[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]/[C:49]([OH:51])=[O:50].[C:36]1([S:42]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[CH2:10][C:11]2[CH:28]=[CH:27][C:14]([C:15]([N:17]3[CH2:21][CH2:20][C@H:19]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:18]3)=[O:16])=[CH:13][CH:12]=2)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(c1ccc(Cc2nc3ccccc3[nH]2)cc1)N1CC[C@H](N2CCCC2)C1
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(c1ccc(Cc2nc3ccccc3n2S(=O)(=O)c2ccccc2)cc1)N1CC[C@H](N2CCCC2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (3′S)-1′-[4-(1H-benzimidazol-2-ylmethyl)benzoyl]-1,3′-bipyrrolidine (100 mg, 0.267 mmol) in anhydrous dichloromethane was cooled to 0° C. under an inert atmosphere, treated with triethylamine (TEA) (32 mg, 0.32 mmol) followed by dropwise addition of a solution of benzenesulfonyl chloride (51.7 mg, 0.293 mmol) in anhydrous dichloromethane, stirred at 0° C. for 1 h, warmed to room temperature for 1 h and concentrated under reduced pressure. The resultant residue was partitioned between dichloromethane and 5% aqueous NaHCO3. The organic phase was separated, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give a residue. This residue was treated with fumaric acid in dichloromethane/methanol to afford the title compound, 1H NMR (300 MHz, DMSO-d6, +TFA): 7.96 (d, 1 H), 7.90 (d, 2 H), 7.78-7.66 (m, 2 H), 7.59 (m, 2 H), 7.49 (d, 2 H), 7.45-7.29 (m, 4 H), 6.63 (s, 2 H), 4.67 (s, 2 H), 3.58-3.41 (m, 4 H), 3.10-2.76 (m, 5 H), 2.19 (m, 1 H), 2.00 (m, 1 H), 1.91-1.73 (m, 4 H). [M+H] 515.1
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[CH:18]=[N:17][C:16]([S:24]([CH3:26])=[O:25])=[CH:15][C:14]2=1)=[O:10])[C:2]1C=CC=CC=1.[H-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[CH:18]=[N:17][C:16]([S:24]([CH3:26])=[O:25])=[CH:15][C:14]2=1)=[O:10])[CH3:2]
Reactant: CS(=O)c1cc2c(cn1)[nH]c1ccc(C(=O)OCc3ccccc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc2[nH]c3cnc(S(C)=O)cc3c2c1

Procedure:
270 mg of 6-benzyloxycarbonyl-3-methylsulfinyl-β-carboline are refluxed for 1.5 hours with an alcoholate solution prepared from 27 mg 80% sodium hydride and 15 ml of absolute ethanol. After concentration, it is picked up in ethyl acetate and suctioned off. 78 mg of 6-ethoxycarbonyl-3-methylsulfinyl-β-carboline with a 240°-243° C. melting point are obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>O1CCCC1>[C:24]([CH:6]1[C:2](=[O:1])[CH2:3][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C1CN(C(=O)OC(C)(C)C)CC1=O
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (370 mg) in tetrahydrofuran (20 mL) at −78° C. was added sodium bis(trimethylsilyl)amide (4.18 mL, 1.0M in tetrahydrofuran). The reaction mixture was stirred for 1.5 h, then treated with acetic anhydride (0.21 mL) and stirred at room temperature for 20 min. The reaction mixture was quenched by the dropwise addition of water and concentrated under vacuum. To the basic residue, ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (30 mL) with an equal volume of water were added. The aqueous layer was separated, acidified by careful addition of hydrochloric acid to pH 3 and extracted with ethyl acetate (75 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to yield desired product which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:19][C:20]1[C:27]([O:28]C)=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.[CH3:30]C([O-])=O.[Na+]>CC(O)=O>[OH:28][C:27]1[C:20]([O:19][CH3:30])=[C:21]([CH:22]=[CH:1][C:2]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccccc1
Reactant: CC(=O)[O-]
Reactant: COc1cccc(C=O)c1O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(O)cccc1C=Cc1nc2ccccc2c(=O)n1-c1ccccc1
Yield: 75.6 %

Procedure:
In a 50 mL round-bottom flask a mixture of compound 27 (0.67 g, 0028 mol), 3-hydroxy-2-methoxy-benzaldehyde (9, 0.003 mol 0.45 g) and NaOAc (0.233 g, 0.002 mol) in AcOH was heated under reflux for 10 hours. After cooling the precipitate formed was filtered off, washed with water, dried and recrystallized from acetic acid to yield 28 (0.56 g, 55%). M. Wt. 370. LCMS [M+H]+=371.
Reaction SMILES: [OH:1][NH2:2].[C:3]1([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:22][CH2:21][C@@H:20]([O:23][CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH2:19][C@@H:18]3[C:31](OC)=[O:32])=[O:16])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO>>[OH:1][NH:2][C:31]([C@H:18]1[CH2:19][C@H:20]([O:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:22][C@@H:17]1[C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][CH2:11]1)=[O:16])=[O:32]
Reactant: NO
Reactant: COC(=O)[C@H]1C[C@H](OCc2cccnc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Solvent: CO
Product: O=C(NO)[C@H]1C[C@H](OCc2cccnc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 M of hydroxyamine solution (0.7 ml) was added to a solution of methyl(1S,2S,5R)-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-3-ylmethoxy)cyclohexanecarboxylate (0.075 mmol, 0.000075 mol) made above in methanol (0.5 mL, 0.01 mol). It was stirred at rt for 2 hrs then purified by Prep-HPLC. LCMS: (M+H)+=439.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[CH3:29][C@H:30]1[O:35][C@@H:34]([CH3:36])[CH2:33][NH:32][CH2:31]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:11]([C:4]2[C:5]([C:8]([N:32]3[CH2:31][C@H:30]([CH3:29])[O:35][C@H:34]([CH3:36])[CH2:33]3)=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:12][O:13][CH3:14])(=[O:17])=[O:16])=[CH:19][C:20]=1[C:25]([F:28])([F:27])[F:26]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COCN(c1cc(Cl)cnc1C(=O)Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCN(c1cc(Cl)cnc1C(=O)N1C[C@@H](C)O[C@@H](C)C1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl chloride (50mg, 0.11 mmol), cis-2,6-dimethylmorpholine (50 mg, 0.40 mmol) and di-isopropylethylamine (DIEA, 0.07 mL, 0.40 mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature overnight. The mixture was concentrated to provide 4-chloro-N[5-chloro-2-(cis-2,6-dimethyl-morpholine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide, which was directly used in the next step without any purification.
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)C(=O)NC2SC(SC[C:16](O)=[O:17])=CN=2)CCCC1.[CH:28]1([NH:34][CH:35]2[CH2:40][CH2:39][CH:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:37][CH2:36]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C([O:49][C:50](=[O:61])[C:51]([S:54][C:55]1[S:59][C:58]([NH2:60])=[N:57][CH:56]=1)([CH3:53])[CH3:52])C>>[CH:28]1([N:34]([CH:35]2[CH2:36][CH2:37][CH:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:39][CH2:40]2)[C:16](=[O:17])[NH:60][C:58]2[S:59][C:55]([S:54][C:51]([CH3:53])([CH3:52])[C:50]([OH:49])=[O:61])=[CH:56][N:57]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: c1ccc(C2CCC(NC3CCCCC3)CC2)cc1
Product: CC(C)(Sc1cnc(NC(=O)N(C2CCCCC2)C2CCC(c3ccccc3)CC2)s1)C(=O)O

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclohexyl-(4-phenyl-cyclohexyl)-amine and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[C:8]2[C:17]3[CH:16]=[CH:15][C:14]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:13][C:12]=3[N+:11]([O-])=[CH:10][C:9]=2[N:27]=1)(=[O:3])[CH3:2].[OH-].[NH4+:34].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[C:8]2[C:17]3[CH:16]=[CH:15][C:14]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:34])[C:9]=2[N:27]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)OCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [7-benzyloxy-1-(2-hydroxy-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinolin-2-yl]methyl acetate (40.0 g, 0.0918 mol) in dichloromethane (650 mL) was cooled to 0° C.; ammonium hydroxide (250 mL of 28%) was added. A solution of p-toluenesulfonyl chloride (29.1 g, 0.153 mol) in dichloromethane (200 mL) was added over a period of 12 minutes while maintaining the reaction temperature below 5.5° C. The reaction mixture was then allowed to warm to room temperature and stirred for one hour. The reaction mixture was diluted with dichloromethane (100 mL), and the organic layer was washed with deionized water (2×400 mL), dried over magnesium sulfate, and filtered. The solution was then treated with activated charcoal for one hour, filtered through a layer of CELITE filter aid, concentrated under reduced pressure, and further dried under vacuum at 60° C. to provide 40.1 g of [4-amino-7-benzyloxy-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH:9]2[NH:11]C(=O)OCCCC)[CH:5]=[CH:6][CH:7]=1.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH:9]2[NH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOC(=O)NC1CC1c1cccc(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CC1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 9 (560 mg, 2.2 mmol) in CH2Cl2 (15 mL) was added trifluoroacetic acid (15 mL). The reaction mixture was stirred at room temperature for 30 min. The solvent was removed by rotary evaporation. The yellow oil was put under vacuum for 24 h to give crude amine 4b (579 mg, 2.2 mmol, 100%) as a yellow oil, which was used in the next step without further purification: 1H NMR (500 MHz, CDCl3) δ 1.10-1.30 (br s, 1H), 1.40-1.60 (br s, 1H), 2.30-2.50 (br s, 1H), 2.70-2.90 (br s, 1H), 6.70-6.72 (m, 1H), 6.72-6.77 (m, 1H), 6.89-7.00 (m, 1H), 7.10-7.30 (m, 1H), 7.80-8.20 (br s, 2H), 10.8-11.8 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.2, 21.5, 31.6, 113.5, 113.7, 114.2, 114.4, 122.29, 122.31, 130.4, 130.5, 140.1, 140.2, 162.2, 164.1; LCQ-MS (M+H+) calcd for C9H11FN 152. found 152; LC-TOF (M+H+) calcd for C9H11FN 152.08755. found 152.08703.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](F)=[N:9][CH:10]=1>C(O)(C)C>[Br:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([NH:2][NH2:3])=[N:9][CH:10]=1
Reactant: Fc1ncc(Br)cc1-c1ccccc1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: NNc1ncc(Br)cc1-c1ccccc1
Temperature: 82 °C

Procedure:
Hydrazine monohydrate (1.76 mL, 13 mmol) was added into a solution of 5-bromo-2-fluoro-3-phenylpyridine (326 mg, 1.29 mmol) in isopropanol (12 mL) at room temperature. The reaction mixture was heated gradually to 82° C. over 5 h and continued to heat overnight, cooled to room temperature and concentrated to give 1-(5-bromo-3-phenylpyridin-2-yl)hydrazine which was used directly in next step.
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[F:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:15]=1C(O)=O>CN(C)C1C=CN=CC=1.CC(O)(C)C>[F:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:15]=1[C:1]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12]
Reactant: O=C(O)c1c(F)cc(F)cc1F
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1c(F)cc(F)cc1F
Temperature: 40 °C
Yield: 100.2 %

Procedure:
Di-tert-butyl carbonate (4.95 g, 22.7 mmol) was added to a solution of 2,4,6-trifluorobenzoic acid (2.0 g, 11.3 mmol) and 4-dimethylaminopyridine (139 mg, 1.14 mmol) in tBuOH (30 mL) and the reaction mixture was heated at 40° C. for 18 hours. The reaction mixture was then quenched with aqueous 1M HCl and extracted into EtOAc. The combined organics were washed with aqueous 1M NaOH, followed by brine, dried and concentrated in vacuo to afford the title compound as a pale yellow oil (2.63 g, 52% yield):
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[N:11]([CH2:20][C:21]([OH:23])=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:25][CH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([NH:33][C:34]2[NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[N:35]=2)[CH2:29][CH2:28]1>>[NH:35]1[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=[C:34]1[NH:33][CH:30]1[CH2:29][CH2:28][CH:27]([CH2:26][NH:25][C:21](=[O:23])[CH2:20][N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:24])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]2=[O:19])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)CC1CCN(CC(=O)O)C(=O)c2ccccc21
Reactant: NC[C@H]1CC[C@H](Nc2nc3ccccc3[nH]2)CC1
Product: CC(C)(C)OC(=O)CC1CCN(CC(=O)NCC2CCC(Nc3nc4ccccc4[nH]3)CC2)C(=O)c2ccccc21

Procedure:
Analogously to Example V, compound 3 was reacted with 0.57 g (1.8 mmol) of compound 7 and the mixture was purified; 0.5 g of white amorphous powder; ESI-MS [M+H+]: 560.