Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCl)c(OC)c1
Temperature: 82.5 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 1.00 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 1.02 g (7.14 mmol) of 2-bromo-1-chloroethane, 0.83 g (6.04 mmol) of potassium carbonate, and 30 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85° C. for 8 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. To the concentrate was added 20 mL of n-heptane, to precipitate a crystalline product. The crystalline product was collected by filtration and dried under reduced pressure, to obtain 1.34 g (isolated yield: 97.8%) of methyl 4-(2-chloroethoxy)-3-methoxybenzoate as a white crystalline product.
Reaction SMILES: [O:1]=[C:2]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1.Cl[CH:24]([C:27]1([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[N:36]=[CH:35][CH:34]=[CH:33]3)[CH2:29][CH2:28]1)[CH:25]=O>C(O)(C)C.CO>[O:1]=[C:2]([N:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:24]([C:27]4([C:30]5[CH:31]=[C:32]6[C:37](=[CH:38][CH:39]=5)[N:36]=[CH:35][CH:34]=[CH:33]6)[CH2:29][CH2:28]4)=[CH:25][N:17]=3)[CH:16]=2)=[CH:7][CH:6]=1
Reactant: Nc1ncc(-c2ccc(OCC(=O)N3CCCC3)cc2)cn1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CO
Solvent: CC(C)O
Product: O=C(COc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1)N1CCCC1
Temperature: 90 °C

Procedure:
A mixture of 5-[4-(2-oxo-2-pyrrolidin-1-ylethoxy)phenyl]pyrimidin-2-amine (23.9 mg, 0.08 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (19.6 mg, 0.08 mmol) in isopropyl alcohol (0.4 mL) was heated at 90° C. overnight. The mixture was diluted with methanol, and purified by RP-HPLC (pH 10) to give the desired product. LCMS: (M+H)=490.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:40]2([CH3:41])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:42])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH2:34]I)[CH2:21][CH2:22][C@@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:9]1.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:40]2([CH3:41])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:42])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:34])[CH2:21][CH2:22][C@@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:9]1
Reactant: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](CI)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
By an alternative procedure, a mixture of 0.206 g. (0.00025 mole) of [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluoro-21-iodocholest-5-ene, 0.087 g. (0.00030 mole) of tri-n-butyltin hydride and 3 ml of tetrahydrofuran were stirred at 25° C. for 18 hr under an argon atmosphere. The mixture was evaporated to dryness and the residue was purified by chromatography on 0.06-0.20 mm silica gel to yield [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-ene, [α]D21 +7° (c 1, CHCl3).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4][OH:5].[OH-].[K+].Br[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([OH:28])=[C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:19]=1)=[O:17].Cl>O.CN1CCCC1=O>[C:24]([C:22]1[CH:23]=[C:18]([C:16](=[O:17])[CH2:15][O:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH:19]=[C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:21]=1[OH:28])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)=CCC/C(C)=C/COCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
A mixture of 9.6 g (62 mmol) of (E)-3,7-dimethyl-octa-2,6-dien-1-ol, 8.4 g (150 mmol) of potassium hydroxide and 20 ml of n-methylpyrrolidone are stirred for one hour at room temperature. Then 10.0 g (33 mmol) of 2-bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-ethanone is added in portions and stirring is continued at room temperature for 20 hours. After the addition of 30 ml of water the mixture is neutralized with 6N hydrochloric acid while cooling with an ice bath and then extracted with ethyl acetate. The organic phases are washed twice with brine, dried over sodium sulfate and evaporated. The residue is purified by column chromatography and crystallisation of the pure fractions from hexane gives 6.1 g (50%) of compound 116; m.p. 50° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:6]=[C:7]([NH:10]C(=O)C)[S:8][CH:9]=1)[CH3:3].[ClH:14]>CCO.O1CCOCC1>[ClH:14].[ClH:14].[CH3:1][N:2]([CH2:4][C:5]1[N:6]=[C:7]([NH2:10])[S:8][CH:9]=1)[CH3:3]
Reactant: CC(=O)Nc1nc(CN(C)C)cs1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CN(C)Cc1csc(N)n1
Temperature: 50 °C

Procedure:
Dissolved N-(4-dimethylaminomethyl-thiazol-2-yl)-acetamide (274 mg, 1.38 mmol) in 5 mL of EtOH. Added 2 mL of 4 M HCl in dioxane and heated at 50° C. for 16 h. LC-MS analysis indicated complete acetyl removal. Concentrated to give 274 mg of 4-dimethylaminomethyl-thiazol-2-ylamine dihydrochloride.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]([CH3:28])[CH2:26][CH3:27])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:2]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]([CH3:28])[CH2:26][CH3:27])=[O:22])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCBr
Reactant: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCCCOc1ccc(-c2ccc(C(=O)OCC(C)CC)cc2)cc1
Yield: 78.8 %

Procedure:
4.7 g of 6-bromo-1-hexene, 6.3 g of 2-methylbutyl 4'-hydroxybiphenyl-4-carboxylate, and 3.1 g of potassium carbonate were refluxed in 2-butanone for 20 hours. After the reaction, inorganic salt was removed by washing with water. After organic phase was dried over magnesium sulfate, the solvent was distilled out under reduced pressure. The resulting residue was purified by column chromatography to obtain 6.4 g of the objective ester compound. (Yield: 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=O)[CH:13]=[C:12]3[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:14]1[CH:13]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[CH:10]=2)[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccccc2)c2cc(C(c3ccc(Cl)cc3)n3ccnc3)ccc2[nH]1
Product: Clc1ccc(C(c2ccc3nc(Cl)cc(-c4ccccc4)c3c2)n2ccnc2)cc1
Yield: 85 %

Procedure:
A mixture of (±)-6-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-4phenyl-2(1H)-quinolinone (0.022 mol) in phosphoryl chloride (100 ml) was stirred and refluxed for 2 hours. The mixture was evaporated in vacuo, the residue was taken up in CH2Cl2 and basified with K2CO3 (10%). The organic layer was dried (MgSO4), filtered off and evaporated. The product was used without further purification, yielding 8 g (85%) of (±)-2-chloro-6-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-4-phenylquinoline (interm. 5).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:42]([CH:39]2[CH2:41][CH2:40]2)=[O:43])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:4])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(Cl)C1CC1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)C1CC1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure D using cyclopropanecarbonyl chloride. The final product was obtained in 79% yield.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C[CH2:31][N:32](CC)CC.CN.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:32][CH3:31])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: CCN(CC)CC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN
Solvent: ClCCl
Product: CNC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol), Et3N (157 mg, 1.56 mmol) and methyl amine (0.32 mL, 2.0 M solution in THF, 0.65 mmol) in DCM (5 mL), was added T3P (0.33 mL, 50 wt % solution in ethyl acetate, 0.52 mmol) and then stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 80 mg (78%) of the title compound as an off white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[CH3:24][S:25][CH2:26][CH2:27][C:28](Cl)=O.C(N(CC)CC)C.CS(O)(=O)=O.[OH-].[Na+]>O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:28]([CH2:27][CH2:26][S:25][CH3:24])=[N:15][C:14]=2[CH:16]=1
Reactant: CSCCC(=O)Cl
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CSCCc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 66.9 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (200 mg, 0.646 mmol) in tetrahydrofuran (5 mL) was added 3-(methylthio)propionyl chloride (98.5 mg, 0.711 mmol) and triethylamine (131 mg, 1.29 mmol), and this was stirred at room temperature for 7 hours. After the reaction was complete, water was added and this was extracted with ethyl acetate. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. To a solution of the residue obtained in dioxane (5 mL) was added methanesulfonic acid (0.5 mL), and this was heated to reflux for 3 hours. After the reaction was complete, 1M aqueous sodium hydroxide solution was added, and this was extracted with ethyl acetate. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude crystals that were purified by silica gel column chromatography to yield the title compound (170 mg, 67% yield) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]=3[CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.C(O)(=O)C(O)=O>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]=3[CH:12]=[N:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CNCc3[nH]c4ccccc4c32)cc1
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2cncc3[nH]c4ccccc4c23)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 63.1 %

Procedure:
To a solution of 1.43 g (3.58 mmol) of 4-(p-methoxyphenyl)tetrahydro-β-carboline in 50 mL glacial AcOH was added 3.18 g (7.16 mmol) of Pb(OAc)4 with stirring at rt. After stiriing at rt for 40 min., 3.22 g (35.8 mmol) of oxalic acid was added. The resulting mixture was kept at rt for 1 h when yellow precipitate appeared. The yellow solid was filtered and the filtered cake was washed with MeOH. The solid product was suspended in 200 mL of H2O and 200 mL of CH2Cl2. The pH of the aqueous phase was adjusted to 7 by the addition of solid NaHCO3. The phases were separated and the aqueous phase was extracted 10×, 40 mL each, with CH2Cl2. The combined CH2Cl2 extracts were washed with 5% aqueous NaHCO3, dried (MgSO4) and concentrated to ~30 mL to precipitate out 0.62 g of product (63% yield), m.p. 235° C. (decomposed). Elemental Analysis Calcd for C18H14N2O: C,78.81; H,5.14; N,10.21. Found: C,78.68; H,5.27; N, 9.98.
Reaction SMILES: [F:1][C:2]([F:7])([CH2:5][OH:6])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:4][CH2:3][C:2]([F:7])([F:1])[CH2:5][O:6][S:16]([CH3:15])(=[O:18])=[O:17])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(F)(F)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(F)(F)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of 5 g (44.6 mmol) 2,2-difluoropropane-1,3-diol (prepared as described in J. Med. Chem. 1994, 37, 1857-1864) in DCM (50 mL) was added triethylamine (18.6 mL, 133.83 mmol) and methane sulphonyl chloride (6.9 mL, 89.22 mmol) at 0° C. and stirred for 1 h at 0° C. Thereafter the reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 2,2-difluoropropane-1,3-diyl dimethanesulfonate (9 g, 84%) which was used immediately in the next step.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][C:43]([Cl:49])=[C:44]([Cl:48])[CH:45]=3)[C:40]2=[O:50])[C:36](O)=[O:37])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][C:43]([Cl:49])=[C:44]([Cl:48])[CH:45]=3)[C:40]2=[O:50])[C:36]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2cc(Cl)c(Cl)cc2C1=O
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2cc(Cl)c(Cl)cc2C1=O
Yield: 35 %

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Step C; 248 mg; 0.70 mmol) and 2-aminothiazole (91 mg; 0.88 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 1, Step B) to provide (S)-3-Cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as a beige foam in 35% yield: EI-HRMS m/e calcd for C20H21Cl2N3O2S (M+) 437.0731, found 437.0725.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CN(Cc3ccccc3)CCO2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CN2CCOC(CN3CCNCC3)C2)cc1
Yield: 98.3 %

Procedure:
To a solution of tert-butyl 4-((4-benzylmorpholin-2-yl)methyl)piperazine-1-carboxylate (165 mg) in CH2Cl2 (5 ml) is added trifluoroacetic acid (1.0 ml), and the mixture is stirred over night. The solvent is removed under reduced pressure. The residue is dissolved in CH2Cl2 and washed with an aqueous solution of potassium carbonate (20%), dried (Na2SO4) and filtered, and the solvent is removed under reduced pressure to give 4-benzyl-2-(piperazin-1-ylmethyl)morpholine (119 mg). m/z(+) 276 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH:18]=[CH:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]2[CH:11]1[C:12](=[O:26])[NH:13][C:14]2=[O:25])([O-:3])=[O:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(O)C>C(C1C=CC=CC=1)(C)(C)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:15]2[C:11]=1[C:12](=[O:26])[NH:13][C:14]2=[O:25])([O-:3])=[O:2]
Reactant: O=C1NC(=O)C2C(c3ccccc3[N+](=O)[O-])C=CC(c3ccccc3)C12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(C)(C)c1ccccc1
Solvent: CCO
Product: O=C1NC(=O)c2c(-c3ccccc3[N+](=O)[O-])ccc(-c3ccccc3)c21

Procedure:
5.5 g (15.8 mmole) 1,3,3a,4,7,7a-hexahydro-4-(2-nitrophenyl)-1,3-dioxo-7-phenyl-2H-isoindole and 9.1 g (40.1 mmole) 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) are heated under reflux for 16 hours in 100 ml t-butylbenzene. The solvent is removed in a vacuum and the residue chromatographed on silica gel with toluene/ethyl acetate 3:1. The fraction with the Rf of 0.4 is isolated, stirred with a little hot ethanol, and the crystals formed after cooling are filtered off. After recrystallization from ethyl acetate, one obtains 1,3-dihydro-4-(2-nitrophenyl)-1,3-dioxo-7-phenyl-2H-isoindole in the form of colorless crystals of the mp 224°-226° C.
Reaction SMILES: ClC1C=CC=C[N:3]=1.S(=O)(=O)(O)O.Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])(=O)C.[NH4+]>COCCOCCOC>[NH2:3][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Clc1ccccn1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: COCCOCCOC
Product: Nc1ncccc1[N+](=O)[O-]

Procedure:
A general synthesis route begins with 2-chloropyridine which is nitrated in the presence of sulfuric acid to make 2-chloro-3-nitropyridine. This material is reacted with ammonium acetate in the presence of diglyme at about 160° C. to form 2-amino-3-nitropyridine which is reduced to form 2,3-diaminopyridine. The 2,3-diaminopyridine is reacted with 2-thiophenecarboxylic acid in the presence of polyphosphoric acid at about 125° C. to prepare 2-(2-thienyl)imidazolo [4,5]pyridine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4C(OC(C)(C)C)=O)[CH2:12][C:13]([O:15]C)=[O:14])=[N:8][C:7]=2[CH:36]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CO.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH2:12][C:13]([OH:15])=[O:14])=[N:8][C:7]=2[CH:36]=1)#[N:2]
Reactant: COC(=O)CC(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C)c2[nH]ccc2c1C(CC(=O)O)c1nc2cc(C#N)ccc2o1
Temperature: 65 °C

Procedure:
(±)-tert-Butyl 4-(1-(5-cyanobenzo[d]oxazol-2-yl)-3-methoxy-3-oxopropyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 148-A) (0.3 g, 0.613 mmol) was dissolved in MeOH (6 ml). cesium carbonate (0.998 g, 3.06 mmol) was added and the reaction was heated at 65° C. for 2.5 hours. The reaction was then cooled to room temperature and treated with 1 N HCl until pH=˜3. The mixture was then diluted with DCM and passed through a phase separator, concentrated and purified via preparative HPLC (HC-B) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (br. s., 1H) 8.34 (t, J=1.14 Hz, 1H) 7.58-7.92 (m, 2H) 7.22 (t, J=2.78 Hz, 1H) 6.77 (s, 1H) 6.22 (dd, J=3.03, 1.89 Hz, 1H) 5.39 (dd, J=9.85, 4.67 Hz, 1H) 3.72 (s, 3H) 3.57 (dd, J=16.67, 9.98 Hz, 1H) 2.74 (dd, J=16.67, 4.67 Hz, 1H) 2.44 (d, J=0.63 Hz, 3H). HRMS calcd. for C21H17N3O4 (M+H)+ 376.1297. found 376.1290.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[CH:10]2)=[CH:7][C:6]([CH3:17])=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=2[O:29][CH3:30])[N:4]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.O.[Na+].[Cl-]>[CH3:1][O:2][C:3]1[C:8]([N:9]2[C:13]([C:14]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:16])=[CH:12][N:11]=[CH:10]2)=[CH:7][C:6]([CH3:17])=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][C:19]=2[O:29][CH3:30])[N:4]=1
Reactant: COc1cc(OC(F)(F)F)ccc1-c1nc(OC)c(-n2cncc2C(=O)O)cc1C
Reactant: C1COCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(OC(F)(F)F)ccc1-c1nc(OC)c(-n2cncc2C(=O)N2CCOCC2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-3H-imidazole-4-carboxylic acid (0.2 g, 0.50 mmol), morpholine (0.04 mL, 0.47 mmol) and N,N diisopropylethyl amine (0.1 mL, 0.5 mmol) in CH2Cl2 (5 mL) is treated with benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (0.20 g, 0.50 mmol) and stirred at room temperature overnight. The resulting mixture is diluted with CH2Cl2 (50 mL) and water (50 mL) and saturated aqueous NaCl (50 mL). The organic portion is dried over Na2SO4, filtered and concentrated. Purification by preparative TLC (8% methanol-CH2Cl2) gives {3-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-3H-imidazole-4-yl}-morpholin-4-yl-methanone (Compound 6) as a white solid. TLC Rf 0.45 (elution with 8% methanol-methylene chloride).
Reaction SMILES: C(OC1C=C(C=CC=1OC(C)C)/C=[N:8]/[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)C.[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([O:36][CH:37]([CH3:39])[CH3:38])[C:30]([F:35])=[C:31]([CH:34]=1)[CH:32]=O)[CH3:25].NC1C=CC(C#N)=CC=1>>[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([O:36][CH:37]([CH3:39])[CH3:38])[C:30]([F:35])=[C:31]([CH:34]=1)/[CH:32]=[N:8]/[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[CH3:25]
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)ccc1OC(C)C
Reactant: CCOc1cc(C=O)c(F)c(OC(C)C)c1
Agent: N#Cc1ccc(N)cc1
Product: CCOc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(OC(C)C)c1

Procedure:
According to the procedure for Intermediate 1.1, Intermediate 7.2 (3.13 g, 13.8 mmol) and 4-aminobenzonitrile (1.63 g, 13.8 mmol) afforded 4.45 g of Intermediate 7.3 as a yellow solid.