Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][CH:9]=1)=[O:4].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([O:10][C:11](=[O:13])[CH3:12])=[CH:7][S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)C1=CSCC1OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)c1cscc1OC(C)=O
Yield: 91 %

Procedure:
4.04 parts of 3-acetoxy-dihydrothiophene-4-carboxylic acid methyl ester are reacted with 1.76 parts by volume of sulfuryl chloride in 50 parts by volume of chloroform in the course of one hour at 0° C. The end product is isolated from the reaction mixture by the method described in Example 1c. 3.64 parts (91% of theory) of 3-acetoxy-thiophene-4-carboxylic acid methyl ester of melting point 56°-58° C. are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([O:11][C:12](=[O:19])[CH:13]=[C:14]([NH2:18])[S:15][CH2:16][CH3:17])[CH3:10]>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:13]([C:12]([O:11][CH2:9][CH3:10])=[O:19])[C:14]([S:15][CH2:16][CH3:17])=[N:18][C:14]=1[NH2:18])=[O:19])[CH3:10]
Reactant: O=Cc1ccncc1
Reactant: CCOC(=O)C=C(N)SCC
Solvent: CCO
Product: CCOC(=O)C1=C(N)N=C(SCC)C(C(=O)OCC)C1c1ccncc1
Yield: 47 %

Procedure:
Upon boiling a solution of 5.3 g of pyridine-4-aldehyde and 17.5 g of 3-amino-3-ethylmercaptoacrylic acid ethyl ester in 100 ml of ethanol for 5 hours, 2-amino-4-(4-pyridyl)-6-ethylmercapto-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 156° C is obtained. Yield: 47% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.BrC1C=CC=C2C=1C=CN=C2.[ClH:23].BrC1C=C2C(=CC=1)C=[N+]([O-:35])C=C2.Cl.BrC1C=CC=C2C=1C=C[N+]([O-])=C2>>[ClH:23].[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-:35])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccc2cc(Br)ccc2c1
Reactant: Brc1ccc2ccncc2c1
Agent: Brc1cccc2cnccc12
Agent: Cl
Agent: [O-][n+]1ccc2c(Br)cccc2c1
Product: [O-][n+]1ccc2ccc(Br)cc2c1

Procedure:
Compound 37a was prepared from 7-bromoisoquinoline (Tyson, F. L., J. Am. Chem. Soc. 61, 183 (1939), this procedure gave a mixture of 7-bromoisoquinoline and 5-bromoisoquinoline) using the procedure described for 1a. The title compound was contaminated with the 5-bromo-isoquinoline N-oxide hydrochloride. M.p. 107.0-112.5° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:43]([O:45][C:46](=[O:51])[C:47](Br)([CH3:49])[CH3:48])[CH3:44]>CN(C)C=O.C(OCC)(=O)C>[CH2:43]([O:45][C:46](=[O:51])[C:47]([O:25][C:23]1[CH:24]=[C:19]2[CH:18]=[C:17]([C:26]([C:33]3[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=3)=[CH:27][CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:16]([S:13]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:14])=[O:15])[C:20]2=[N:21][CH:22]=1)([CH3:49])[CH3:48])[CH3:44]
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(O)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
Potassium carbonate (828 mg, 5.99 mmol) was added to a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (prepared as in Example 13, 1.6 g, 3.07 mmol) in N,N-dimethylformamide (4.0 mL) at room temperature. The mixture was stirred for 30 min at room temperature and then 2-bromo-2-methyl-propionic acid ethyl ester (0.48 mL, 3.21 mmol) was added. The mixture was heated at 80° C. for 1 h. The resulting mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 2-{1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-2-methyl-propionic acid ethyl ester (1.34 g, 68.7%) as a light yellow solid: LC/MS m/e calcd for C33H36N2O7S2 [M+H]+ 637.79, observed 637.5.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([Cl:22])=[CH:8][C:3]=1[C:4](OC)=[O:5].C([SiH](CC)CC)C.FC(F)(F)S(O)(=O)=O.CCOC(C)=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([Cl:22])=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: CCc1ccc(C(=O)c2cc(Br)c(C(=O)OC)cc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(Cc2cc(Br)c(CO)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-bromo-5-chloro-4-(4-ethylbenzoyl)benzoate (7.64 g, 20 mmol) in 2,2,2-trifluoroacetic acid (38 mL) was added triethylsilane (5.88 mL, 40 mmol) under argon. After it was stirred for 10 min at room temperature, trifluoromethanesulfonic acid (0.1 mL) was added. The reaction temperature was raised from 26° C. to reflux. After stirring for 2 h, TLC (PE:EtOAc=6:1, Rf=0.7) showed the reaction was complete. The reaction mixture was evaporated and the residue was dissolved in EtOAc (150 mL). The organic layer was washed 2× with H2O, 2× with NaHCO3, and 2× with brine, and then dried over anhydrous Na2SO4 Concentration under reduced pressure provided the title compound as a white solid. Yield: 7.2 g (100%). 1H-NMR (CDCl3, 300 MHz) δ 7.85 (s, 1H), 7.44 (s, 1H), 7.17 (s, 1H), 7.14 (s, 1H), 7.10 (s, 1H), 7.07 (s, 1H), 4.05 (s, 2H), 3.92 (s, 3H), 2.63 (q, J=7.8 Hz, 2H), 1.24 (t, J=7.8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH2:8][C:9]([OH:11])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH2:12][C:13]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1)=[N:18]2>>[Cl:23][C:22]1[C:13]([NH:12][C:9](=[O:11])[CH2:8][C:2]2([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:29]1)[CH:16]=[CH:15]2
Reactant: CC1(CC(=O)O)CCCCC1
Reactant: CCOC(=O)C1CCN(c2ccc3c(N)c(Cl)ccc3n2)CC1
Product: CCOC(=O)C1CCN(c2ccc3c(NC(=O)CC4(C)CCCCC4)c(Cl)ccc3n2)CC1
Yield: 70.7 %

Procedure:
Prepared according to the method of example 62(a), using 1-methyl-cyclohexaneacetic acid (280 mg) and 1-(5-amino-6-chloro-2-quinolinyl)-4-piperidinecarboxylic acid, ethyl ester (Example 77(a)) (200 mg), to afford the sub-titled compound (200 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1>[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH:61][C:7](=[O:9])[C:6]3[CH:10]=[CH:11][N:12]=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: COc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)ccn1

Procedure:
From 2-methoxy-isonicotinic acid hydrochloride, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 402 (M+H+, 100).
Reaction SMILES: P(Br)(Br)[Br:2].O[CH:6]([C:8]1[O:9][C:10](=[O:31])[C:11]2[C:16]([C:17]=1[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:2][CH:6]([C:8]1[O:9][C:10](=[O:31])[C:11]2[C:16]([C:17]=1[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]
Reactant: CC(O)c1oc(=O)c2ccccc2c1C1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrP(Br)Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(Br)c1oc(=O)c2ccccc2c1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
1M PBr3 (0.36 ml, 0.363 mmol) in DCM was added drop-wise to a solution of tert-butyl 4-(3-(1-hydroxyethyl)-1-oxo-1H-isochromen-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (intermediate B12, 135 mg, 0.363 mmol) in DCM (5 ml). Reaction mixture was then dried under reduced pressure and dissolved in DCM (5 ml). Di-tert-butyl dicarbonate (0.34 ml, 1.454 mmol) and DMAP (89 mg, 0.727 mmol) were added simultaneously, and the mixture stirred overnight at RT. Reaction mixture was straightforward purified on Biotage SNAP 50 g silica cartridge with a gradient of hexane and EtOAc give the title compound (100 mg, 63.3%) as a yellowish oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:16]([NH:24][C:25]([NH:8][C:5]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ncc(Br)cc1Oc1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ncc(Br)cc1Oc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A 2 L flask was charged with 5-bromo-3-phenoxypyridin-2-amine (64.0 g, 241.4 mmol) and benzoyl isothiocyanate (35.82 mL, 265.6 mmol) in THF (600 mL) and stirred at ambient temperature overnight, then concentrated to about 50 mL. A mixture of Hexanes:EtOAc (9:1) (900 mL) was added with vigorous stirring. The resulting suspension was filtered and the solid was washed with hexanes then dried to afford 1-benzoyl-3-(5-bromo-3-phenoxypyridin-2-yl)thiourea (94.32 g, 91.2% yield) as a yellow solid.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:16][CH2:17]CC.[Li]C(C)(C)C.C(I)C>C1COCC1>[CH2:16]([C:11]1[C:12]2[NH:13][C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][CH:10]=1)[CH3:17]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: [Li]CCCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cccc2c1Nc1ccccc1S2
Temperature: 25 °C

Procedure:
This compound was prepared according to a procedure by A. R. Katritzky et al., Synthesis, 1988, 215-217. To a solution of phenothiazine (10.0 g, 50.18 mmol) in anhydrous THF (200 mL) and cooled to −78° C. was added a solution of n-BuLi (24.1 mL, 60.2 mmol, 2.5 M in hexanes) dropwise. The mixture is stirred until a yellow precipitate forms and then allowed to warm to room temperature, until a clear yellow solution results. the solution is again cooled to −78° C. and CO2 gas is bubbled through the mixture for 5 min. The resulting solution is allowed to warm to RT and the solvent was evaporated to give a residue. The residue was again dissolved in anhydrous THF (200 mL) and cooled to −78° C., before t-BuLi (50 mL, 85 mmol, 1.7 M in pentane) was added dropwise. The resulting mixture was allowed to warm to −20° C. and was stirred at this temperature for 2 h. The reaction mixture was again cooled to −78° C. and a solution of ethyl iodide (100.0 mmol) in THF (50 mL) was added dropwise. The mixture was stirred at this temperature for 1 hour then allowed to warm to −20° C. and stirred for 2 h. The reaction mixture was quenched with ice cold 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give a residue. The residue was purified by flash silica gel chromatography to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O-:13].[K+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([O:13][CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: [K+]
Solvent: CO
Product: COc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 37.9 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (10 g, 51.55 mmol) in methanol (150 ml) at −10° C. a solution of potassium methanolate (3.62 g, 51.55 mmol) in methanol (150 ml) was added over a period of 10 minutes. The mixture was allowed to warm to 0° C. and the solvent was evaporated under reduced pressure at 30° C. The residue was purified by silica gel chromatography with n-heptane/ethyl acetate (3:1) as eluent affording 3.7 g (37.9%) of the title compound. 1.34 g (13.7%) 4-chloro-2-methoxy-5-nitropyrimidine was obtained as a side product
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[N:10]=1)=[O:5])[CH3:2].[Br:14]Br>CO>[CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11](=[O:13])[CH2:12][Br:14])[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C(C)=O)cs1
Reactant: BrBr
Solvent: CO
Product: CCOC(=O)c1nc(C(=O)CBr)cs1

Procedure:
A solution of 4-acetylthiazole-2-carboxylic acid ethyl ester (1.5 g) and bromine (1.4 g) in methanol (50 ml) was stirred for 8 hours at room temperature. The solvent was removed under reduced pressure to give 4-bromoacetylthiazole-2-carboxylic acid ethyl ester. A suspension of the above residue and diaminomethylenethiourea (800 mg) in ethanol (50 ml) was refluxed for 4 hours. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and diisopropyl ether afforded 4-[2-(diaminomethyleneamino)thiazol-4-yl]thiazole-2-carboxylic acid ethyl ester hydrobromide (800 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.S(Cl)([Cl:19])=O>ClCCl>[O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([Cl:19])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(c2ccc(C(=O)O)cc2)=NN1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1CCC(c2ccc(C(=O)Cl)cc2)=NN1
Reaction time: 24 h

Procedure:
10 mmol (2.2 g) of 4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)benzoic acid are suspended in 50 ml of dichloromethane, after which 1.5 ml (20 mmol) of thionyl chloride are added and the mixture is stirred for 24 hours while being boiled gently.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([C:27]4[CH:26]=[N:25][N:24]([CH3:28])[C:23]=4[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:16]3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:29][CH3:30])[CH:3]=1.[CH3:31][SH:32]>CN(C=O)C>[CH3:30][O:29][C:4]1[CH:3]=[C:2]([S:32][CH3:31])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:11][CH2:12][C:13]2([C:27]3[CH:26]=[N:25][N:24]([CH3:28])[C:23]=3[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:16]2)[CH2:14][CH2:15]1)=[O:9]
Reactant: CS
Reactant: COc1cc(F)ccc1C(=O)N1CCC2(CC1)Oc1ccccc1-c1c2cnn1C
Solvent: CN(C)C=O
Product: COc1cc(SC)ccc1C(=O)N1CCC2(CC1)Oc1ccccc1-c1c2cnn1C
Temperature: 80 °C

Procedure:
A mixture of (4-fluoro-2-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (500 mg, 1.23 mmol) and methanethiol (172 mg, 2.45 mmol) in DMF (5 mL) was heated at 80° C. for 36 h. The reaction led to the desired product as well as O-demethylated version of the product. To the crude reaction mixture was added 3 eq of iodomethane to remethylate to the desired product. The reaction mixture was washed with 1N HCl, sat. aq. NaHCO3, and brine. The organics were dried over sodium sulfate and evaporated. The crude product was purified by column chromatography eluting with 50-100% ethyl acetate in hexanes to give (2-methoxy-4-(methylthio)phenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (60%). ESI-MS m/z calc. 435.2. found 436.1 (M+1)+. Retention time: 1.53 minutes (3 min run).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[C:15]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cl
Reactant: Clc1cncc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)cncc1Br
Reaction time: 0.75 h
Yield: 85 %

Procedure:
To a solution of LDA (2 M solution in THF/heptane/ethylbenzene, 2.78 g, 12.97 mL, 25.95 mmol) in anhydrous THF (20 mL) under nitrogen atmosphere and cooled to −78° C. was added a solution of 3-bromo-5-chloropyridine (5.0 g, 25.98 mmol) in anhydrous THF (40 mL) at −78° C. The reaction mixture was allowed to stir at the same temperature for 45 minutes. Then, a solution of chloro(ethoxy)methanone (28.19 g, 259.7 mmol) was added slowly over 15 minutes. After stirring for 20 minutes, the reaction mixture was quenched with saturated NaHCO3 solution. The mixture was extracted into ethyl acetate (3×100 mL), and the combined organic layers were washed with water and brine. The separated organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated, and the residue was purified through CombiFlash using 0-10% ethyl acetate in hexane to provide ethyl 3-bromo-5-chloropyridine-4-carboxylate as pale yellow oil (5.84 g, 85% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.35 (t, 3H), 4.45 (q, 2H), 8.82 (s, 1H), 8.87 (s, 1H); M+265.5.
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[S:7][CH:8]=1)[CH3:3].C([Li])CCC.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.[Cl-].[Na+].O>[OH:31][C:28]1([C:8]2[S:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[C:4]=2[CH:2]([OH:1])[CH3:3])[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(O)c1csc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1c(C2(O)CCN(C(=O)OC(C)(C)C)CC2)sc2ccccc12
Temperature: 0 °C
Reaction time: 6 h
Yield: 87.1 %

Procedure:
Scheme IA, Step A: To a solution of 3-(1-hydroxyethyl)benzo[b]thiophene (2.036 g, 11.4 mmol) in tetrahydrofuran (75 mL) at −78° C. was added a solution of n-butyllithium (15.7 mL, 25.1 mmol, 1.6 M in hexanes). The solution was warmed to 0° C. for one hour then recooled to −78° C. A solution of 1-t-butyloxycarbonyl-4-piperidone (2.503 g, 12.6 mmol) in tetrahydrofuran was added dropwise and the mixture was warmed to 20° C. After stirring for 6 hours at 20° C. the mixture was diluted with brine and extracted 3 times with ethyl acetate. The combined organics were dried over sodium sulfate then filtered and evaporated. The residue was purified using silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent) to give 3.75 g (87%) of the intermediate title compound as a yellow amorphous solid. FDMS m/e=378 (M++1).
Reaction SMILES: [CH3:1][C@@H:2]([NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:3]([OH:5])=[O:4].[H-].[Na+].[CH3:16]I>O1CCCC1>[CH3:1][C@@H:2]([N:6]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH3:16])[C:3]([OH:5])=[O:4]
Reactant: CI
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
To 48 ml of a solution of Boc-D -Ala-OH (3.0 g, 15.9 mmol) in tetrahydrofuran (THF) was added 60% sodium hydride (1.9 g, 47.6 mmol) under ice-cooling and the mixture was stirred for 10 minutes. Then, methyl iodide (7.9 ml, 127 mmol) was added and the mixture was further stirred at room temperature for 22 hours. The reaction mixture was then concentrated under reduced pressure, ice-cooled, acidified with 10% citric acid-H2O, and extracted with ethyl acetate. The extract was washed with saturated NaCl-H2O, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane and the crystal crop was washed with hexane to provide the title compound. Yield 3.07 g (94.8%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)([Cl:17])=O.C1(C)C=CC=CC=1>C1COCC1>[Cl:17][C:6]([OH:5])=[O:7].[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cl
Agent: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (201 mg, 1.0 mmol) in THF (2 mL) was added a 20% solution of phosgene in toluene (358 μL, 1.7 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:31])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C=NC1CCCCC1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)NC1CCCCC1
Yield: 48 %

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) was reacted with cyclohexyl isocyanate (780 mg, 5.51 mmol) to provide 1.02 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-cyclohexylurea as a solid, m.p. 179-180° C. Analysis: Calculated for C23H32N6O2.0.75 H2O: % C, 63.06; % H, 7.71; % N, 19.18. Found: % C, 62.74; % H, 7.57; % N, 19.16.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:26][C:16]3=[C:17]4[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:25])[CH2:18]4)(=O)=O)=CC=1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.O>CS(C)=O>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][CH2:11][CH:12]2[O:26][C:16]3=[C:17]4[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:25])[CH2:18]4)=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(C)c4c(c3O2)CC(=O)N4)cc1
Reactant: NCc1ccc(F)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)C3)OC(CNCc1ccc(F)cc1)CO2
Temperature: 90 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-6-methyl-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (0.28 g, 0.72 mmole) and 4-fluorobenzylamine (0.45 g, 3.6 mmole) were combined in 10 ml of dry DMSO and heated to 90° C. for 4 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 35% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an orange semisolid. Column chromatography on silica gel using 1% methanol/CH2Cl2 as eluant gave the free base of the title compound as a brown oil. This was crystallized from isopropanol with the addition of fumaric acid (0.20 g, 1.7 mmole) to give 0.06 g of the (S) enantiomer of the title compound as a beige solid fumarate, m.p. 233-234° C.