Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].C(N(CC)CC)C.Cl.Cl.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C@@H:30]3[CH:35]4[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]4)[CH2:31]3)=[O:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.O>CN(C=O)C>[CH3:1][NH:2][C:3]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([C@@H:30]3[CH:35]4[CH2:34][CH2:33][N:32]([CH2:37][CH2:36]4)[CH2:31]3)=[O:29])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)=[O:4]
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: CN=C=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reaction time: 18 h

Procedure:
17.4 mg (0.30 mmol) of methyl isocyanate and 84.8 μl (0.61 mmol) of triethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)-N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, 5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction, washed with water and dried under high vacuum. 47 mg (73.5% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.[C:17]([NH:24][CH2:25][CH2:26][NH2:27])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:27][CH2:26][CH2:25][NH:24][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)C=Cc1ccc(NCCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
A mixture of 3-(4-chloro-3-nitro-phenyl)-acrylic acid methyl ester (Ia, 0.243 g, 1.00 mmol), N-Boc-ethylenediamine (0.316 mL, 2.0 mmol) and triethylamine (0.50 mL, 3.59 mmoL) in dioxane (7 mL) was heated at 80° C. for about 80 h. The solution was evaporated and the residue was added MeOH. The resulting solid was filtered and washed with MeOH. 3-[4-(2-tert-Butoxycarbonylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester (IIIa1) was obtained as bright yellow solid (0.193 g, 52.6%). HPLC purity at 254 nm: 96.0˜98.1%; tR=3.27 min. LCMS (ESI) m/z: 366 ([M+H]+), 310 (M+H-56), 266 (M+H-Boc). 1H NMR (CDCl3) δ 8.41 (1H, br t like, NHAr), 8.31 (1H, d, J=1.8 Hz), 7.63 (1H, dd, J=9.0, 1.7 Hz), 7.57 (1H, d, J=16.0 Hz), 6.98 (1H, d, J=8.9 Hz), 6.30 (1H, d, J=15.9 Hz), 3.80 (3H, s), 3.52 (2H, m), 3.45 (2H, m), 1.45 (9H, s); 13C NMR (CDCl3) δ 166.9, 155.7, 145.8, 142.3, 134.1, 131.5, 127.1, 121.8, 115.4, 113.9, 79.5, 51.2, 42.7, 39.1, 27.9.
Reaction SMILES: [C:1]1([C:6]([C:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([O:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.O>[C:1]1([C:6]([C:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)COc1ccc(C(=O)c2cccs2)c2c1CCCC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1ccc(C(=O)c2cccs2)c2c1CCCC2

Procedure:
9 g of the ester according to (b) are dissolved in 100 ml aqueous ethanol. 1.8 g potassium hydroxide dissolved in 25 ml water are added and the mixture refluxed for 8 hours. The ethanol is evaporated and the remaining aqueous phase acidified by addition of mineral acid. The acid is extracted in ethyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[N+:23]([O-])=O)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=1)=[O:8])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[NH2:23])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1cc(C(F)(F)F)ccn1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1N

Procedure:
Prepared analogously to example 1b by hydrogenation of 3,4-dinitro-N-(4-trifluoromethyl-pyridin-2-yl)-benzamide using palladium/charcoal 10% in methanol.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]#[N:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Solvent: C1CCOC1
Product: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Benzenesulfonyl-naphthalene-1-carbonitrile is dissolved in dry THF and cooled to ice bath temperature. Borane-THF complex is added and the reaction mixture is stirred under nitrogen overnight at room temperature. The reaction is quenched by addition of HCl and methanol, and made basic by addition of 1M NaOH. The resulting residue is extracted with EtOAc, and the organic layer is dried (MgSO4), filtered and concentrated under reduced pressure. The residue is recrystallized from HCl/EtOH to give C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine as a hydrochloride salt.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([C:12]1[C:13]([CH3:24])=[N:14][N:15]([C:17]2[C:22](Br)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:16]=1)=[O:11])C.O1[CH2:29][CH2:28][CH2:27]C1>>[CH:27]1([C:22]2[C:17]([N:15]3[CH:16]=[C:12]([CH2:10][OH:11])[C:13]([CH3:24])=[N:14]3)=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:28][CH2:29]1
Reactant: CCOC(=O)c1cn(-c2ncccc2Br)nc1C
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1nn(-c2ncccc2C2CC2)cc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirred suspension of lithium aluminium hydride (0.44 g, 11.7 mmol) in dry tetrahydrofuran (25 mL) is added a solution of 1-(3-bromo-pyridin-2-yl)-3-methyl-pyrazole-4-carboxylic acid ethyl ester (1.6 g, 5.8 mmol) in dry tetrahydrofuran (5 mL) under nitrogen atmosphere at −78° C. After complete addition the reaction mixture is warmed to room temperature then stir overnight. The reaction mixture is quenched with 1N sodium hydroxide then filtered through the celite. The organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layer is washed with water and brine, dried on sodium sulfate, filtered and concentrated to yield 1.1 g (84%) of [1-(3-cyclopropyl-pyridin-2-yl)-3-methyl-pyrazol-4-yl]-methanol. MS (m/z): 230 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH:19]1[CH2:28][OH:29].Cl>>[O:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH:19]1[CH2:28][O:29][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: OCC1CCc2ccccc2O1
Reactant: Clc1nc2ccccc2nc1N1CCNCC1
Agent: Cl
Product: c1ccc2c(c1)CCC(COc1nc3ccccc3nc1N1CCNCC1)O2
Yield: 23 %

Procedure:
The title product was prepared according to the procedure described in Example 162, Step 2, starting from 2-chloro-3-(1-piperazinyl)quinoxaline (described in Example 162. Step 1) and 3.4-dihydro-2H-chromen-2-ylmethanol.* The product was obtained as a yellow amorphous substance yield 23%; mp 202-204° C.; HRMS m/z calcd for C13H16N4O2 (M)+ 376.1899, found 376.1899. Anal. (C22H24N4O2 . HCl) H; C: calcd, 61.32; found, 60.7; N: calcd, 13.00; found 13.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.I[CH2:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]1
Reactant: CCCI
Reactant: FC(F)(F)c1ccc(Cl)c(N2CCNCC2)c1
Product: CCCN1CCN(c2cc(C(F)(F)F)ccc2Cl)CC1

Procedure:
Beginning with 1-(2-Chloro-5-trifluoromethyl-phenyl)-piperazine and 1-iodopropane, the title compound was recovered by the procedure described in Example 2. m.p. 234° C. (HCl), MS m/z (rel. intensity, 70 eV) 306 (M+, 20), 279 (34), 277 (bp), 70 (99), 56 (48).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C([O:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:27]([O-])=[CH:26][C:25]=2[N:24]=[C:23]1[CH2:36][CH2:37][CH2:38][CH3:39])(=O)CCCC.[OH-].[NH4+:41]>C(Cl)Cl>[NH2:41][C:26]1[C:25]2[N:24]=[C:23]([CH2:36][CH2:37][CH2:38][CH3:39])[N:22]([CH2:21][CH2:20][CH2:19][OH:18])[C:34]=2[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:27]=1
Reactant: [NH4+]
Reactant: CCCCC(=O)OCCCn1c(CCCC)nc2c[n+]([O-])c3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCO
Reaction time: 3 h

Procedure:
p-Toluenesulphonyl chloride (0.93 g) was added portionwise to a vigourously stirred mixture of the product from step (iv) (1.77 g) in DCM (50 mL) and ammonium hydroxide solution (35%, 5 mL) at rt. The reaction mixture was stirred for 3 h then partitioned between water/DCM. The organics were washed with saturated NaHCO3 solution, water, dried, and the solvent evaporated under reduced pressure. The residue was dissolved in MeOH (40 mL), water (20 mL) then 6M NaOH solution (2 mL) added and the mixture stirred at rt for 18 h. The solid formed was filtered off washed with water and dried, yield 965 mg.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[C:22]([N+:23]([O-])=O)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1>[Pd].CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1cccnc1NC1CCN(c2nc3ccccc3s2)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1cccnc1NC1CCN(c2nc3ccccc3s2)CC1
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A mixture of N-(1-(benzo[d]thiazol-2-yl)piperidin-4-yl)-3-nitropyridin-2-amine (270 mg, 0.76 mmol) and palladium on activated carbon (50% by wt, 0.15 g) in methanol (10 mL) was stirred under hydrogen at 30 psi for 2 hours. The mixture was filtered through a pad of CELITE™ and the filtrate was concentrated to give N2-(1-(benzo[d]thiazol-2-yl)piperidin-4-yl)pyridine-2,3-diamine (200 mg, 0.61 mmol, 81.3% yield) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[CH:8]1)[C:2]#[CH:3].[C:21]1([O:27][C:28]2[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>>[O:27]([C:28]1[CH:29]=[CH:30][C:31]([C:3]#[C:2][CH2:1][O:4][CH2:5][CH2:6][N:7]2[C:19]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=[C:11]([NH2:20])[C:10]=3[N:9]=[CH:8]2)=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Ic1ccc(Oc2ccccc2)cc1
Reactant: C#CCOCCn1cnc2c(N)nc3ccccc3c21
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2ccccc2c2c1ncn2CCOCC#Cc1ccc(Oc2ccccc2)cc1
Yield: 2.9 %

Procedure:
Using the general method of Example 7, 1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.50 g, 1.88 mmol) was reacted with 4-iodophenyl phenyl ether (0.78 g, 2.63 mmol). The crude product was purified by column chromatography eluting with 95/5 dichloromethane/methanol to provide a solid. The solid was slurried with aqueous sodium hydroxide to remove salts and then purified by column chromatography eluting with 9/1 ethyl acetate/methanol to provide a solid. This material was further purified by column chromatography eluting with 99/1 ethyl acetate/methanol to provide 24 mg of 1-(2-{[3-(4-phenoxyphenyl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 146-148° C.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH3:17])[CH:11]=1.O>C(#N)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:12]([CH3:17])[CH:11]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CC(C)(C)CC(=O)Cl
Solvent: O
Solvent: CC#N
Product: Cc1cc(Br)ccc1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
3,3-Dimethylbutanoyl chloride (724 mg, 0.75 mL, 5.4 mmol) was added to a solution of 4-Bromo-2-methyl-phenylamine (1.0 g, 5.4 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (830 mg, 56% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.I[CH:12]([CH3:14])[CH3:13]>>[CH3:10][C:4]1[CH:3]=[C:2]([O:1][CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: Cc1cc(O)ccc1C=O
Reactant: CC(C)I
Product: Cc1cc(OC(C)C)ccc1C=O
Yield: 75.7 %

Procedure:
The compound was synthesized as in Example 87.1, using 4-hydroxy-2-methylbenzaldehyde (54.4 mg, 0.40 mmol) in place of 4-hydroxybenzaldehyde and 2-iodopropane (100 μL, 0.80 mmol) in place of 1-iodo-(3,3,3-trifluoro)propane to give 2-methyl-4-isopropoxybenzaldehyde (54 mg, 76%). Used without further characterization.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][OH:26])[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([CH:25]=[O:26])[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCc1cc(Oc2ccc3nc(NCC4CCCCC4)sc3c2)ccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1cc(Oc2ccc3nc(NCC4CCCCC4)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To the solution of (4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)pyridin-2-yl)methanol (30 mg, 0.081 mmol) in 2 ml of THF and 2 ml of DCM was added Dess-Martin Periodinane (38 mg, 0.089 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The crude reaction mixture diluted with ethyl acetate (60 ml), washed with saturated sodium bicarbonate (2×15 ml), brine (1×15 ml), dried with Na2SO4, filter and concentrated in vaccuo to give 4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)picolinaldehyde as solid (29 mg). ES/MS m/z 386.1 (MH+) as the hydrate (+18).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].ClCCl.[Si:9]([O:26][CH2:27][CH:28]1[CH2:33][CH2:32][C@@H:31]([OH:34])[C@@H:30]([OH:35])[CH2:29]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>O>[Si:9]([O:26][CH2:27][CH:28]1[CH2:33][CH2:32][C@@H:31]([O:34][S:2]([CH3:1])(=[O:4])=[O:3])[C@@H:30]([O:35][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:29]1)([C:22]([CH3:25])([CH3:23])[CH3:24])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](OCC1CC[C@@H](O)[C@@H](O)C1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCC1CC[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C1)(c1ccccc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
Methanesulfonyl chloride (2.5 ml) was added dropwise to a dichloromethane solution (300 ml) of (1R*,2S*)-4-(tert-butyldiphenylsilyloxymethyl)-1,2-cyclohexanediol (4.2 g) and triethylamine (9.1 ml) at 0° C., and the mixture was stirred for 1.5 hours. Water was added to conduct extraction with dichloromethane, and the resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel (hexane:ethyl acetate=3:2) to obtain the title compound (4.9 g) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH2:23])=[N:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[Cl:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][N:44]=1)[C:39](Cl)=[O:40].CO>C1COCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:39]([C:38]4[CH:42]=[CH:43][N:44]=[C:36]([Cl:35])[CH:37]=4)=[O:40])=[N:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(N)nc12
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.1 %

Procedure:
To a solution of 0.25 g (0.69 mMol) 4-(2-amino-4-methoxy-benzothiazol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 10 ml THF were added 0.26 ml ethyl diisopropyl amine and 0.16 g (0.76 mMol) 2-chloro-isonicotinoyl chloride, dissolved in 5 ml of dichloro methane. The reaction mixture was stirred at room temperature for 16 h. Then 5 ml methanol were added. The solvent was evaporated to dryness, the residue taken up in ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane 1:1) to yield 0.308 g (89%) of 4-{2-[(2-chloro-pyridine-4-carbonyl)-amino]-4-methoxy-benzothiazol-7-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a yellow foam. ES-MS m/e (%): 501 ([M+H]+, 100).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].C([N:16]1[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26](F)=[C:25]([Cl:30])[CH:24]=2)[CH2:17]1)C1C=CC=CC=1.O>CN(C)C=O>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C@H:18]2[O:19][CH2:20][CH2:21][NH:16][CH2:17]2)=[CH:24][C:25]=1[Cl:30]
Reactant: Fc1ccc(C[C@@H]2CN(Cc3ccccc3)CCO2)cc1Cl
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 10 °C
Reaction time: 18 h

Procedure:
To a suspension of sodium hydride (50 mg, 1.25 mmol) in N,N-dimethyl formamide (0.5 mL) at 0° C. was added 2,2,2-trifluroethanol (125 mg, 1.25 mmol), and the resultant mixture stirred for 5 mins. N-Benzyl-(R)-2-(4-fluoro-3-chlorobenzyl)morpholine, example 27, intermediate (a) (100 mg, 0.31 mmol) was added in one portion as a solution in N,N-dimethyl formamide (1.0 mL) via syringe and the reaction mixture warmed to 10° C. and shaken at that temperature for 18 hrs. The reaction was cooled to room temperature and poured into water (20 ml). The suspension was extracted with ethyl acetate (20 mL×2). Combined organic extracts were washed with water (20 mL×2) and brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica; 20% ethyl acetate/isohexane) to yield the desired product as a light yellow oil (38 mg) and used directly in the next reaction. The material was dissolved in 1,2-dichloroethane (2 mL), and 1-chloro-ethyl-chloroformate (33 mg, 0.23 mmol) added in one portion. The resulting mixture was heated at 90° C. for 24 hrs. The reaction was then concentrated in vacuo. The residue was dissolved in methanol (10 mL), and heated at 80° C. for 5 hrs. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane and poured onto an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The column was then washed with ammonia (2N solution in methanol, 2 mL×3) and the ammonia washes were concentrated in vacuo to yield example 40 as a yellow oil (20 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[NH:33]1[CH2:41][CH2:40][CH:36]([C:37]([NH2:39])=[O:38])[CH2:35][CH2:34]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:33]3[CH2:41][CH2:40][CH:36]([C:37]([NH2:39])=[O:38])[CH2:35][CH2:34]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: NC(=O)C1CCNCC1
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCC(C(N)=O)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with isonipecotamide. A yellow solid 105 was obtained (0.0272 g, 57%). 1H-NMR (CDCl3, 400 MHz) δ 1.90-1.99 (m, 2H), 2.08-2.14 (m, 2H), 2.59-2.66 (m, 1H), 3.39-3.47 (m, 2H), 3.83 (s, 3H), 4.29-4.34 (m, 2H), 5.57 (br s, 1H), 5.99 (br s, 1H), 6.97 (d, J=6.6 Hz, 1H), 6.99 (s, 1H), 7.00-7.05 (m, 2H), 7.06 (d, J=8.4 Hz, 1H), 7.46-7.52 (m, 3H), 7.85 (s, 1H), 8.20 (d, J=6.6 Hz, 1H); MS (APCI) m/z 488 (M+H)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:22]=1[CH:23]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C.C(N(CC)CC)C>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[C:22]=1[CH2:23][N:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2c(F)cccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added triethylamine (0.35 mL) and 2-fluoro-6-(trifluoromethyl)benzaldehyde (123 mg). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (554 mg) was added. The reaction mixture was stirred at room temperature overnight, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (83 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[NH:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=O)=[CH:10][CH:9]=1.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:3]4[CH2:4][CH2:5][CH2:6][NH:7][S:2]4(=[O:1])=[O:19])=[CH:18][CH:17]=3)=[O:14])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: CCOC(=O)c1ccc(N2CCCNS2(=O)=O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCNS4(=O)=O)cc3)CC2)c(C)c1
Yield: 44.1 %

Procedure:
Using ethyl 4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-2-yl)benzoate (300 mg) described in Preparation Example 47 and 1-(3,5-dimethylpyridin-2-yl)piperazine (202 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (200 mg) was obtained.