Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](Cl)=[N:10][OH:11].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)#[CH:14]>O1CCCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:14]=[C:13]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[O:11][N:10]=1
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Reactant: C#Cc1ccc(C#N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cc(-c3c(Cl)cccc3Cl)no2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (2.67 g, 11.9 mmol) and 4-ethynylbenzonitrile (1.50 g, 11.9 mmol) were dissolved in anhydrous tetrahydrofuran (150 mL) and triethylamine (2.15 mL). The mixture was stirred at room temperature for 1 h then heated at reflux for 6 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 4-ethynylbenzonitrile. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 7:3 hexanes-ethyl acetate. The appropriate fractions were combined to give 3-(2,6-dichlorophenyl)-5-(4-cyanophenyl) isoxazole as a white solid, 0.58 g.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27]Cl)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].C(=O)([O-])[O-:32].[Na+].[Na+]>CS(C)=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:27]=[O:32])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4CCl)ccc3o2)n1
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4C=O)ccc3o2)n1
Temperature: 100 °C
Reaction time: 10 h
Yield: 50.6 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(2-chloromethylphenylmethoxy)benzofuran-2-yl]thiazole (1.56 g), sodium iodide (0.50 g) and sodium carbonate (0.83 g) in dimethylsulfoxide (15 ml) was stirred at 100° C. for 10 hours. After being cooled, the resulting mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and toluene (1:20). The fractions containing object compound were combined and concentrates under reduced pressure to give 4-tert-butyl-2-[5-(2-formylphenylmethoxy)benzofuran-2-yl]thiazole (0.75 g).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24](=[O:25])[CH:23]=[CH:22][O:21][C:20]=3[CH3:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24](=[O:25])[CH:23]=[CH:22][O:21][C:20]=3[CH3:26])[CH:13]=[N:12]2)[C:8]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: Cc1occc(=O)c1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Product: Cc1occc(=O)c1Oc1cnn(C(CC2CCCC2)C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)c(=O)c1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(2-methyl-4-oxo-4H-pyran-3-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 75) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(2-methyl-4-oxo-4H-pyran-3-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a white solid as a mixture of diastereomers (1.37 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:12][C:5]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)ccc1[N+](=O)[O-]
Yield: 38.6 %

Procedure:
A mixture of 20 g of 3-methoxy-4-nitrotoluene, 21.6 g of N-bromosuccinimide and 0.3 g of dibenzoyl peroxide in 120 ml of CCl4 is heated at reflux for 5 hours. The solvent is evaporated off under vacuum, the residue is taken up in water, extracted with DCM, washed with water, dried over Na2SO4 and evaporated under vacuum. 11.35 g of the expected product are obtained after crystallization from EtOH, mp=98° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]([C:21]3[C:22]([C:27]4[C:32](F)=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:34])=[N:23][O:24][C:25]=3[CH3:26])=[O:20])[CH2:13]2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CN(C)C=O>[Cl:34][C:28]1[C:27]2[C:22]3[C:21](=[C:25]([CH3:26])[O:24][N:23]=3)[C:19](=[O:20])[N:18]([CH:14]3[CH2:15][CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:13]3)[C:32]=2[CH:31]=[CH:30][CH:29]=1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)NC1CCCN(C(=O)CCCc2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCN(C(=O)CCCc3ccccc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.9 %

Procedure:
Dissolve 3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid[1-(4-phenyl-butyryl)-piperidin-3-yl]-amide (300 mg, 0.62 mmol) in N,N-dimethyl-formamide (4 mL) at ambient temperature under a nitrogen atmosphere. Add a solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 1.49 mL, 0.75 mmol) and stir for 20 min. at ambient temperature. Quench with water and follow by adding of solid sodium chloride. Extract with ethyl acetate and wash with water and dry over sodium sulfate. Concentrate and elute over silica gel to give 83 mg (29%) of the desired product. MS(ES): (M+1)+ 464.1, 466.1 m/z.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[OH:12].N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@H]1CCc2c(Br)ccc(F)c21
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c(Br)ccc(F)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol (6.8 g) and imidazol (5 g) are dissolved at 0° C. in N,N-dimethylformamide (NMP, 25 mL), treated with tert.-butyldimethylchlorosilane (6.3 g) and stirred for 2 hours at room temperature. Water is added and the mixture is stirred for 10 minutes. Then the mixture is partitioned between 1 M hydrochloric acid and ethyl acetate. The organic phase is dried (MgSO4) and concentrated to give the title compound. Yield: 9.25 g.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([S:12](=[O:33])(=[O:32])[NH:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([S:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=3[F:31])[N:15]=2)[CH2:8][CH2:7]1)C.[BH4-].[Li+]>C1COCC1>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][S:22][C:16]1[N:15]=[C:14]([NH:13][S:12]([N:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][OH:3])[CH2:7][CH2:8]2)(=[O:33])=[O:32])[CH:19]=[C:18]([O:20][CH3:21])[N:17]=1
Reactant: CCOC(=O)CN1CCN(S(=O)(=O)Nc2cc(OC)nc(SCc3cccc(F)c3F)n2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)N2CCN(CCO)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 24 using a mixture of {4-[2-(2,3-Difluoro-benzylsulfanyl)-6-methoxy-pyrimidin-4-ylsulfamoyl]piperazin-1-yl}-acetic acid ethyl ester (the product from example 86 step i) (0.31 g) lithium borohydride (1M solution in THF) (1.2 mL) in THF (5 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and NH4OAc/acetonitrile as the mobile phase) then titurated with Toluene, MeOH followed by DCM to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:16]([Cl:26])[CH:15]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[Cl:26][C:16]1[CH:15]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][C:22]([F:25])([F:24])[F:23]
Reactant: O=COc1ccccc1
Reactant: CC(c1ccc(OCC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Product: CC(c1ccc(OCC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2C(=O)Oc2ccccc2)C1=O
Yield: 59 %

Procedure:
The title compound is prepared in 59% yield (50 mg, yellow oil) from 4-chloro-2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (70 mg, 0.17 mmol, Intermediate-29, single enantiomer) and phenyl formate (42 mg, 0.35 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[NH:21]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2)[C:22]([CH3:24])=[O:23]>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:28]3[C:27]4[C:31](=[CH:32][CH:33]=[C:25]([NH:21][C:22](=[O:23])[CH3:24])[CH:26]=4)[NH:30][C:29]3=[O:34])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(NC(C)=O)cc43)c(C)c2C1=O
Yield: 57.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-acetamino-1,3-dihydro-indol-2-one as starting materials to give N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide (52 mg, 57.9%) as a light yellow solid.
Reaction SMILES: CS[C:3]1N=C(Cl)C([N+]([O-])=O)=[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:15]=2)[N:4]=1.Cl.C(O[C:29](=O)[CH2:30][NH2:31])C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:24][N:22]([CH3:23])[C:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][C:5]1[N:4]=[CH:3][CH:29]=[CH:30][N:31]=1)=[O:21]
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cccc(C(=O)N(C)C)c2)n1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN(C)C(=O)c1cccc(Oc2ncccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-methylthio-4-chloro-5-nitro-6-(3-(dimethylaminocarbonyl)phenoxy)pyrimidine, a compound of formula (C), (3.0 g 8.14 mmol) in 80 mL of acetonitrile at 0° C. was added glycine ethyl ester hydrochloride, a compound of formula (D), (1.14 g, 8.14 mmol), followed by the addition of cesium carbonate (6.1 g, 18.7 mmol). The reaction mixture was allowed to warm to ambient temperature and then stirred for 2 hours. The volatiles were evaporated to yield 3.6 g of 2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-(dimethylaminocarbonyl)-phenoxypyrimidine, a compound of formula (E).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[O:23]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]1>>[CH3:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][CH3:13])[C:2]([O:28][CH:25]1[CH2:26][CH2:27][O:23][CH2:24]1)=[N:3][C:4]([NH:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1)=[CH:5]2
Reactant: OC1CCOC1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC3CCOC3)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from (1-Chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and tetrahydro-furan-3-ol to give [6,7-Dimethoxy-1-(tetrahydro-furan-3-yloxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 371(MH+).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([C@@H:9]2[CH2:12][C@H:11]([O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10]2)[CH:8]=1)([O-])=O.CCN(CC)CC.[C:31]1([CH2:41][C:42](O)=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>C(OCC)(=O)C.[Pd]>[C:31]1([CH2:41][C:42]([NH:1][C:4]2[N:5]=[CH:6][N:7]([C@H:9]3[CH2:12][C@H:11]([O:13][S:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[CH2:10]3)[CH:8]=2)=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](n3cnc([N+](=O)[O-])c3)C2)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](n3cnc(NC(=O)Cc4cccc5ccccc45)c3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
trans-Toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (Preparation 4, Step 2; 590 mg, 1.75 mmol) was mixed with 10% Pd on carbon (500 mg) in ethyl acetate (30 mL). The mixture was then reacted under 50 psi H2 at room temperature for 6 h. The mixture was filtered through celite into a flame-dried flask which was kept under a nitrogen atmosphere. Et3N (1.22 mL, 8.75 mmol) was added followed by 1-naphthylacetic acid (326 mg, 1.75 mmol) and tripropylphosphonic anhydride (1.1 mL, 1.7 M solution in ethyl acetate, 1.75 mmol). The mixture was stirred at room temperature for 1 h and was then diluted with ethyl acetate and was washed with water and brine. The organic layer was dried (MgSO4), was filtered, and was concentrated in vacuo The resulting residue was purified by silica gel chromatography (50:1 chloroform-methanol) to afford 600 mg (72% yield) of trans-toluene-4-sulfonic acid 3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl ester; 1H NMR (400 MHz, CDCl3) δ7.9 (m, 2H), 7.85 (m, 2H), 7.76 (d, J 8.3 Hz, 2H), 7.48 (m, 2H), 7.42 (m, 2H), 7.33 (m, 2H), 7.04 (s, 1H), 4.96 (m, 1H), 4.73 (m, 1H), 2.7 (m, 4H), 2.44 (s, 3H); MS (AP/Cl): 476.2 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:29][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4Cl)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(F)cc(-c3ccccc3Cl)c2O1

Procedure:
The title compound was prepared (0.075 g, 52%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.19 g, 0.44 mmol) and methylamine (0.136 g, 4.40 mmol). mp 141-143.
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][CH:5]=1)[CH2:2][CH3:3].Br[CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][O:13]1>>[CH2:1]([C:4]1[S:8][C:7](=[NH:9])[N:6]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:5]=1)[CH2:2][CH3:3]
Reactant: BrCC1CCCO1
Reactant: CCCc1cnc(N)s1
Product: CCCc1cn(CC2CCCO2)c(=N)s1

Procedure:
A mixture of 5-propylthiazol-2-amine and 2-(bromomethyl)tetrahydrofuran were processed using the method described in Example 2A to afford the title compound. MS (ESI) m/z 227 (M+H)+.
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=1[C:14]([NH:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:20]([NH:22][CH:23]1[CH2:25][CH2:24]1)=[O:21])=[O:15].C(O)(=O)C>C(O)C>[CH:23]1([NH:22][C:20](=[O:21])[C:19]2[CH:26]=[CH:27][C:28]([CH3:29])=[C:17]([N:16]3[C:14](=[O:15])[C:13]4[C:12](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:11]=[CH:1]3)[CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccccc1N
Reactant: CCOC(OCC)OCC
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccccc2c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Triethylorthoformate (0.15 ml) was added to a stirred mixture of 3-[(2-aminobenzoyl)amino]-N-cyclopropyl-4-methylbenzamide (0.093 g) and glacial acetic acid (0.017 ml) in ethanol (10 ml). The mixture was heated to 80° C. and stirred for 16 hours. The reaction mixture was evaporated, dissolved in ethyl acetate (50 ml) and washed with a saturated NaHCO3 solution (100 ml). The organic phase was dried over magnesium sulphate, filtered then concentrated in vacuo onto silica gel (0.1 g). The residue was purified by column chromatography (isolute silica 20 g column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using a gradient of 10% iso-propanol/iso-hexane through to 50% iso-propanol/iso-hexane to give the title compound as a white solid (0.062 g); NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.68 (m, 2H), 2.14 (s, 3H), 2.84 (m, 1H), 7.52 (d, 1H), 7.62 (t, 1H), 7.78 (d, 1H), 7.84 (d, 1H), 7.89 (m, 2H), 8.21 (m, 1H), 8.30 (s, 1H), 8.41 (d, 1H); Mass Spectrum: M+H+ 320.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:30](Cl)=[O:31])=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20]=[CH:21][CH:22]=3)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccnc2ccccc12
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccnc2ccccc12

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin4-amine and quinoline4-carbonyl chloride were combined to provide N4-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]4-quinolinecarboxamide as a white crystalline solid, m.p. 214.5-215.2° C. 1H NMR (300 MHz, DMSO-d6) δ 8.89 (d, J=4.3 Hz, 1H), 8.76 (t, J=5.6 Hz, 1H), 8.24 (s, 1H), 8.10-8.01 (m, 3H), 7.78 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.64 (dd, J=8.4, 1.1 Hz, 1H), 7.56 (ddd, J=8.3, 6.9, 1.4 Hz, 1H), 7.44 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 7.34 (d, J=4.3 Hz, 1H), 7.24 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 6.60 (broad s, 2H), 4.68 (t, J=6.9 Hz, 2H), 3.38 (q, J=7.0 Hz, 2H), 2.00 (m, 2H), 1.63 (m, 2H); MS (EI) m/e 410.1860 (410.1855 calcd for C24H22N6O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.[CH:25]12[O:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]2.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]3[OH:31])[CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1
Reactant: C1CCC2OC2C1
Reactant: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCNC3)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCN([C@@H]2CCCC[C@H]2O)C3)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(2-chlorophenyl)-2-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 2, 500 mg, 1.33 mmol), cyclohexene oxide (1.34 mL, 13.3 mmol), and trietylamine (0.55 mL, 3.99 mmol) in ethanol (14 mL) was heated at reflux for 20 h. The solution was cooled to rt, and evaporated. The residue was purified by silica gel column, eluting with 3:1 to 2:1 hexanes:ethyl acetate. The product, racemic trans-2-[1-(2-chlorophenyl)-2-(4-methoxyphenyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]cyclohexanol, was isolated as a pale yellow solid (398 mg, 63%). LC-MS m/z (MH+) 437.1, retention time 2.45 min (method 1).
Reaction SMILES: [CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[N:6][N:5]=1)([CH3:3])[CH3:2].OO.C([O-])([O-])=[O:20].[K+].[K+]>>[CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]([NH2:14])=[O:20])=[CH:11][CH:10]=2)=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1nnc(-c2ccc(C#N)cc2)o1
Agent: OO
Agent: [K+]
Product: CC(C)c1nnc(-c2ccc(C(N)=O)cc2)o1
Yield: 1544.4 %

Procedure:
The title compound was prepared according to the procedure described in step1 of Intermediate-59 by using 4-(5-isopropyl-1,3,4-oxadiazol-2-yl)benzonitrile (0.500 g, 2.34 mmol), 50% H2O2 (5.0 mL), K2CO3 (0.097 g, 0.070 mmol) to afford 0.250 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 1.3 (s, 3H), 1.35 (s, 3H), 3.33 (m, 1H), 7.56 (br s, 1H), 8.06 (s, 4H), 8.16 (br s, 1H); MS (m/z): 232.30 (M+H)+.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]([NH:9][C:10]1[C:11]([CH3:19])=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8])(=O)C.N1CCCC1.Cl>CO>[SH:4][CH2:5][CH:6]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]([NH:9][C:10]1[C:11]([CH3:19])=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8]
Reactant: CC(=O)SCC(CC(C)C)C(=O)Nc1cccc(C(=O)O)c1C
Agent: Cl
Solvent: C1CCNC1
Solvent: CO
Product: Cc1c(NC(=O)C(CS)CC(C)C)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
3-[(2-Acetylthiomethyl-4-methylpentanoyl)amino]-2-methylbenzoic acid (compound of Example 175) (3 g), 70% aqueous methanol (30 ml) and pyrrolidine (2.2 g) are mixed, and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is adjusted to pH 3.0 with 10 hydrochloric acid, and methanol is distilled off under reduced pressure. The precipitated crystals are separated by filtration and dissolved in 50% aqueous acetonitrile and purified by a column chromatography using Diaion HP-20 (eluant, water-acetonitrile). The fractions containing the desired compound are collected and acetonitrile is distilled off under reduced pressure, and the precipitated crystals are separated by filtration to give the title compound (2 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][NH:10][C:3]=12.[C:11]([O:15][C:16](=[O:35])[NH:17][CH:18]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:19](=[O:26])[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:14])([CH3:13])[CH3:12]>C1(C)C(C)=CC=CC=1>[C:11]([O:15][C:16](=[O:35])[NH:17][CH:18]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:19](=[O:26])[N:20]1[CH2:21][CH2:22][N:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[CH:9][NH:10][C:3]=23)[CH2:24][CH2:25]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCNCC1
Reactant: Clc1ccnc2cc[nH]c12
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccnc3cc[nH]c23)CC1
Yield: 7.9 %

Procedure:
To a solution of 7-Chloro-1H-pyrrolo[3,2-b]pyridine (40 mg, 0.262 mmol) in xylene (4 mL) and TEA (1 mL) was added [1-(4-chlorobenzyl)-2-oxo-2-piperazin-1-yl-ethyl]-carbamic acid tert-butyl ester (0.1 g, 0.27 mol). The mixture was refluxed for 6 days. The solvent was removed under vacuum and the residue was subject to purification by HPLC to afford {1-(4-chlorobenzyl)-2-oxo-2-[4-(1H-pyrrolo[3,2-b]pyridin-7-yl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester (10 mg, 8%). 1H NMR (CDCl3, 400 Hz) δ 11.81 (s, 1H), 7.95 (d, J=6.4 Hz, 1H), 7.40 (s, 1H), 7.15 (d, J=8.00 Hz, 2H), 6.46 (d, J=6.8 Hz, 2H), 5.42 (d, J=8.4 Hz, 1H), 4.82 (d, J=7.2 Hz, 1H), 3.87-3.28 (m, 8H), 2.98 (d, J=6.4 Hz, 2H), 1.41 (s, 9H). MS (ESI+) [M+H]+ 484.