Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:23])=[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])[C:5]([F:9])=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH:31]1([C:36](Cl)=O)[CH2:35][CH2:34][CH2:33][CH2:32]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[Cl:8][C:7]1[C:2]2[N:1]=[C:36]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:23][C:3]=2[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])=[C:5]([F:9])[CH:6]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(N)c2O)c1=O
Reactant: O=C(Cl)C1CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(C4CCCC4)oc23)c1=O
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
0.48 g of 3-[3-amino-4-chloro-6-fluoro-2-hydroxyphenyl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (from intermediate 7) was initially charged with 0.14 g of triethylamine in 30 ml of absolute xylene, and the mixture was, at 0° C., admixed dropwise with 0.18 g of cyclopentanecarbonyl chloride. After 10 minutes, the mixture was warmed to 20° C., 0.1 g of pyridinium p-toluenesulfonate was added and the mixture was heated at reflux for six hours. After cooling, the xylene phase was washed three times with 30 ml of water each time, dried over sodium sulfate and freed from the solvent under reduced pressure. The crude product was purified by medium pressure liquid chromatography (MPLC); mobile phase: cyclohexane/ethyl acetate (9:1). Yield: 0.27 g;
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25]([CH3:27])=[O:26])=[CH:9]2)=[N:6][CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=1B(O)O.[F-].[K+]>O1CCOCC1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[F:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=1[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25]([CH3:27])=[O:26])=[CH:9]2)=[N:6][CH:7]=1
Reactant: CS(=O)c1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: OB(O)c1cc(O)ccc1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Solvent: C1COCCO1
Product: CS(=O)c1cn(-c2ncc(-c3cc(O)ccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Bis(tri-tert-butylphosphine) palladium(0)(0.51 g, 1.0 mmol) was added under an argon atmosphere to a suspension of [1-(5-bromo-pyrimidin-2-yl)-3-methanesulfinyl-1H-indol-6-yl]-morpholin-4-yl-methanone (1.0 g, 2.0 mmol), 2-fluoro-5-hydroxyphenylboronic acid (0.625 g, 4.0 mmol) and potassium fluoride (0.29 g, 5.0 mmol) in dioxane (50 ml). The reaction mixture was stirred at 90° C. for 4 h and then filtered through a pad of celite. The filter was washed with dichloromethane (2×20 mL) and concentrated. The residue was purified by flash column chromatography [silica; dichloromethane with 2% methanol]. Light yellow solid. Yield: 0.44 g (46% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(Cl)Cl.OS([O-])(=O)=O.[K+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1ccc(Cl)cc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OCC(=O)O)C1
Reaction time: 2 h
Yield: 57.2 %

Procedure:
To the title compound from Step A (1.70 g, 4.40 mmol) in MeOH (10 mL) was added 4N NaOH (10 mL). After 2 h, CH2Cl2 was added and the mixture acidified with 1N KHSO4 (50 mL) then extracted with CH2Cl2 (2×). The combined organics were dried to give a 0.90 g (57%) of the title compound as a white solid that was used without further purification. MS (ESI): mass calcd. for C16H20ClNO6, 357.1; m/z found, 380.1 [M+Na]+. 1H NMR (400 MHz): 6.92 (dd, J=8.6, 2.3 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 6.59 (d, J=2.3 Hz, 1H), 4.92-4.86 (m, 1H), 4.67 (s, 2H), 4.31 (dd, J=9.9, 6.5 Hz, 2H), 4.07 (dd, J=10.0, 4.1 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: [OH-:1].[K+].[CH:3]1([N:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[CH:23][CH:22]=[CH:21]4)=O)=[C:11]([C:26]#[N:27])[C:10]([CH3:28])=[N:9]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.OO>O.CO>[CH:3]1([N:8]2[C:12]3=[N:13][C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[C:20]5[C:25]=4[N:24]=[CH:23][CH:22]=[CH:21]5)=[N:27][C:26](=[O:1])[C:11]3=[C:10]([CH3:28])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1nn(C2CCCC2)c(NC(=O)c2cccc3cccnc23)c1C#N
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1[nH]n(C2CCCC2)c2nc(-c3cccc4cccnc34)nc(=O)c1-2
Temperature: 25 °C
Yield: 19.3 %

Procedure:
To potassium hydroxide (0.2 g, 3.0 mmol) in water (75 ml) cooled in an ice bath was added 1-cyclopentyl-3-methyl-4-cyano-5-(8-quinolinecarboxamido)-1H-pyrazole (2.05 g, 5.9 mmol) in methanol (30 ml) followed by 30% hydrogen peroxide (3.0 ml, 30 mmol). The reaction mixture was slowly warmed to room temperature and then refluxed for 24 hours. Additional potassium hydroxide (3.0 mmol) and 30% hydrogen peroxide (30 mmol) were added and the reaction mixture was refluxed for 1.5 hours. The reaction mixture was cooled in an ice-bath, the precipitated product was collected by filtration through a glass frit and was washed with water, then ether. Recrystallization from ethyl acetate afforded 0.2 g (10%) of 1-cyclopentyl-3-methyl-6-(8-quinolinyl)-pyrazolo[3,4-d]pyrimidin-4-one as yellow crystals, m.p.242°-244° C. when dried for 24 hours at 120° C. in high vacuum.
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25](O)[C:26]2[C:34]3[C:29](=[N:30][CH:31]=[C:32]([O:35][CH2:36][CH2:37][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH:33]=3)[NH:28][CH:27]=2)=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[N:38]1([CH2:37][CH2:36][O:35][C:32]2[CH:33]=[C:34]3[C:26]([CH2:25][C:22]4[CH:23]=[CH:24][C:19]([NH:7][CH2:8][C:9]5[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=5)=[N:20][CH:21]=4)=[CH:27][NH:28][C:29]3=[N:30][CH:31]=2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)c1ccc(C(O)c2c[nH]c3ncc(OCCN4CCOCC4)cc23)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: FC(F)(F)c1ccc(CNc2ccc(Cc3c[nH]c4ncc(OCCN5CCOCC5)cc34)cn2)cc1
Yield: 11.1 %

Procedure:
A mixture of (5-{Hydroxy-[5-(2-morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methyl}-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (24, 0.2 g, 0.3 mmol), triethylsilane (4 mL, 0.02 mol), and trifluoroacetic acid (2 mL, 0.02 mol) in acetonitrile (30 mL) was refluxed for 2 hours. After removal of solvent, the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the compound as a light yellow solid (25, 17 mg, 10%). MS (ESI) [M+H+]+=512.42.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:20]3[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:20]3[CH:21]=[CH:22][C:23]([CH2:24][NH:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)=[CH:26][CH:27]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Reactant: NCc1ccc(O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Oc1ccc(CNCc2ccc(-c3nc4ccn5cnnc5c4cc3-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-2 (0.05 g, 0.14 mMol) and 4-(aminomethyl)phenol (0.04, 0.35 mMol) in DMF (0.5 mL) was added acetic acid (0.04 mL, 0.7 mMol). After stirring for 2 hours at room temperature, sodium triacetoxyborohydride (0.06 g, 0.3 mMol) was added. After stirring overnight, the reaction was filtered through a syringe filter and purified on a C18 reverse phase HPLC to yield 19-1 as a solid. LC/MS (M+1) calculated: 458.5; observed: 458.3.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Br:11].CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:43][C:44]1[S:45][CH:46]=[CH:47][N:48]=1>CN(C=O)C.ClCCCl.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:43][C:44]2[S:45][CH:46]=[CH:47][N:48]=2)=[O:8])=[CH:4][C:3]=1[Br:11]
Reactant: Nc1ccc(C(=O)O)cc1Br
Reactant: Nc1nccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(C(=O)Nc2nccs2)cc1Br
Temperature: 60 °C

Procedure:
4-Amino-3-bromo-benzoic acid (18.5 mmol) was dissolved in DMF (10 mL) and 1,2-dichloroethane (80 mL). DIPEA (18.5 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (18.5 mmol), 1-hydroxybenzotriazole (18.5 mmol) and 2-aminothiazole (18.5 mmol) was added and the reaction mixture was stirred at 60° C. over night. The volume was reduced in vacuo, and water (60 mL) was added. The mixture was extracted with ethyl acetate, the organic phase was washed with NH4Cl (aq., sat.), dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography on silica using gradient elution (heptane/ethyl acetate).
Reaction SMILES: [OH:1][CH:2]([C:14]1[C:22]([CH2:23][O:24][C:25]2C=CC=C[CH:26]=2)=[CH:21][C:20]([CH3:31])=[C:19]2[C:15]=1[CH:16]=[CH:17][N:18]2S(C1C=CC(C)=CC=1)(=O)=O)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:5]=2[N:4]=1.C(N)CC(C)C.[OH-].[K+]>CCO.C(Cl)Cl>[CH2:25]([O:24][CH2:23][C:22]1[C:14]([CH:2]([OH:1])[C:3]2[NH:7][C:6]3[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:5]=3[N:4]=2)=[C:15]2[C:19](=[C:20]([CH3:31])[CH:21]=1)[NH:18][CH:17]=[CH:16]2)[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5cc(C#N)ccc5[nH]4)c(COc4ccccc4)cc(C)c32)cc1
Agent: CC(C)CCN
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCOCc1cc(C)c2[nH]ccc2c1C(O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(hydroxy(7-methyl-5-(phenoxymethyl)-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (130 mg, 0.23 mmol) in EtOH (3 mL), isoamylamine (101 mg, 1.15 mmol), and KOH (64.8 mg, 1.15 mmol) were added and the reaction stirred at 100° C. for 1.5 h under microwave irradiation. The reaction mixture was diluted with CH2Cl2 filtered through SiO2. The SiO2 cake was washed with a mixture of CH2Cl2/MeOH (c.a. 6/1). The organic solution was concentrated and purified by RP-HPLC (HC-A) to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3 with about 5 μL TFA) δ ppm 9.45 (br. s., 1H), 8.08 (s, 1H), 7.79 (d, J=8.60 Hz, 1H), 7.75 (dd, J=1.30, 8.60 Hz, 1H), 7.25 (dd, J=2.80, 3.00 Hz, 1H), 7.02 (s, 1H), 6.76 (s, 1H), 6.62 (dd, J=2.02, 3.03 Hz, 1H), 4.80 (d, J=10.86 Hz, 1H), 4.63 (d, J=10.86 Hz, 1H), 3.56-3.73 (m, 2H), 2.48 (s, 3H), 1.13 (t, J=6.95 Hz, 3H). HRMS calcd. for C21H20N4O2 (M+H)+ 361.1665. found 361.1658.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].[Br-].[CH2:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:13][CH3:14].[CH:34]([C@@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1)=O.[Cl-].[NH4+]>O1CCCC1>[CH:34](/[C@@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1)=[CH:12]/[CH2:13][CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C=O)CC1
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC/C=C\[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a mixture of 1.9 M sodium hexamethyldisilazane solution (in tetrahydrofuran, 2.1 ml) and anhydrous tetrahydrofuran (10 ml) was added n-propyltriphenyl-phosphonium bromide (1.52 g) at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was cooled to −78° C., and then a solution of t-butyl cis-4-formylcyclohexylcarbamate (900 mg) in anhydrous tetrahydrofuran (5 ml) was added thereto. The reaction mixture was gradually warmed to 25° C. and stirred overnight. To the reaction mixture was added saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, and then the solvent was removed in vacuo. After diethyl ether was added to the residue, the precipitate was filtered off and then the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 405 mg of t-butyl cis-4-[(Z)-1-butenyl]cyclohexylcarbamate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[Li]>C1COCC1>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:9]1[S:8][CH:12]=[CH:11][CH:10]=1
Reactant: [Li]c1cccs1
Reactant: BrCCCCCBr
Solvent: C1CCOC1
Product: BrCCCCCc1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a stirred solution of 1,5-dibromopentane (23.00 g, 0.1 mol) in THF (100 ml) at -60° C. under N2, was slowly added, during 30 min., 100 ml (0.10 mol) of a 1.0M solution of 2-thienyllithium in THF (Aldrich). Stirring was continued for 1 h at -60° C. After gradual warming to room temperature, the mixture was stirred for 2 h and slowly poured over a bed of ice (ca. 200 g). The organic layer was separated and the aqueous layer was extracted with Et2O (2×100 ml). The combined organic layer and the extracts were washed with saturated NaCl solution (2×75 ml), dried (MgSO4) and concentrated to a dark oil (23.13 g). Fractional distillation gave 12.34 g (53%) of 1-bromo-5-(2-thienyl) pentane as a colorless oil, b.p. 87°-88° C. (0.7 mm); nD23 1.5440.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6].O.[BH4-].[Na+].C(OCC)(=O)C>C1COCC1.CCCCCC>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][OH:6]
Reactant: COc1cc(Br)c(OC)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1cc(Br)c(OC)c(CO)c1
Yield: 100 %

Procedure:
A solution of 8.27 gm (33.75 mmol) of 3-bromo-2,5-dimethoxy benzaldehyde* in 40 ml THF and 20 ml water was cooled to 10° C. and treated portionwise with 3.83 gm (101.2 mmol) NaBH4. Stirring was maintained at ambient temperature until tlc analysis (silica gel; 1:4 ethyl acetate:hexane) indicated the absence of starting aldehyde. After 30 minutes the solvent was removed in vacuo and the residue was portioned between ethyl acetate and water. After washing with brine and drying (Na2SO4), the ethyl acetate extract was concentrated in vacuo to yield 8.34 gm (99%) of a white solid, mp 59°-60° C.; tlc (cited), Rf 0.12.
Reaction SMILES: [S:1]1[C:5]2C=CC=C[C:4]=2[N:3]=[C:2]1[NH2:10].[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>C(O)(=O)C>[CH3:15][C:13]1[N:10]=[C:2]2[S:1][CH:5]=[CH:4][N:3]2[C:11](=[O:16])[CH:12]=1
Reactant: Nc1nc2ccccc2s1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(=O)n2ccsc2n1
Yield: 40715.4 %

Procedure:
A solution of 1,3-benzothiazol-2-amine (20 g, 0.133 mmol), ethyl acetoacetate (25.96 g, 0.199 mmol) and acetic acid (150 ml) was reacted together according to the procedure described in Intermediate 3, Step 1 to afford 9 g of the desired product as a pale yellow solid; 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 6.15 (s, 1H), 6.95 (d, J=4.8 Hz, 1H), 7.94 (d, J=4.8 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.I[CH2:12][CH2:13][O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][O:14][CH2:13][CH2:12][O:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2ccsc12
Reactant: COCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1cccc2ccsc12

Procedure:
To a solution of 7-hydroxy-benzo[b]thiophene (Boot, J. R.; Brace, G.; Delatour, C. L.; Dezutter, N.; Fairhurst, J.; Findlay, J.; Gallagher, P. T.; Hoes, I.; Mahadevan, S.; Mitchell, S. N.; Rathmell, R. E.; Richards, S. J.; Simmonds, R. G.; Wallace, L.; Whatton, M. A.; Bioorganic & Medicinal Chemistry Letters (2004), 14(21), 5395-5399; 1.0 g, 6.6 mmol) in acetone (15 mL) was added 2-iodoethyl methylether (Ubichem, CAS: 4296-15-5, 2.47 g, 13.2 mmol) and potassium carbonate (1.84 g, 13.2 g). The reaction mixture was stirred at reflux for 16 h, quenched with ice/water, and extracted with ethyl acetate. The organics were washed, dried and concentrated. The residue was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain 7-(2-methoxy-ethoxy)-benzo[b]thiophene (1.29 g) as a colourless oil. MS (ISP): m/209.1 (M+H)+
Reaction SMILES: [CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[S:20][C:19]([C:21]4([C:26]([OH:28])=[O:27])[CH2:25][CH:24]=[CH:23][CH2:22]4)=[CH:18][CH:17]=3)[C:7]3=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.[C:29]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:29]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[S:20][C:19]([C:21]4([C:26]([OH:28])=[O:27])[CH2:25][CH:24]=[C:23]=[CH:22]4)=[CH:18][CH:17]=3)[C:7]3=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C)c2nc(C3CC3)n(Cc3ccc(C4(C(=O)O)CC=CC4)s3)c2n1
Agent: NS(=O)(=O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1cc(C)c2nc(C3CC3)n(Cc3ccc(C4(C(=O)O)C=C=CC4)s3)c2n1
Temperature: 40 °C
Yield: 58.3 %

Procedure:
A mixture of 1-[5-(2-cyclopropyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)thiophen-2-yl]cyclopenten-3-ene carboxylic acid (Example 3) (500 mg, 1.27 mmol) and 1,1-carbonyl diimidazole (250 mg, 1.27 mmol) in THF (25 ml) was heated under reflux for 3 hours, then a solution of benzenesulfonamide (242 mg, 1.6 mmol) and DBU (243 mg, 1.6 mmol) in THF (2.0 ml) was added. The reaction mixture was heated at 40° C. for 19 hours, cooled to 23° C. and concentrated in vacuo. The residue was dissolved in water and acidified with 10% aqueous NaH2PO3. The aqueous mixture was extracted with EtOAc (3×25 ml). The combined extracts were dried and concentrated in vacuo. The crude residue was chromatographed on SiO2 gel using 2% MeOH/EtOAc to give 406 mg of the title compound (60% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([N:6]([CH:13]1[CH2:19][CH2:18][CH2:17][CH:16]([Cl:20])[CH2:15][C:14]1=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C([BH3-])#N.[Na+].[CH3:26][NH:27][CH3:28].Cl.CNC>CO>[Cl:1][CH2:2][CH2:3][C:4]([N:6]([CH:13]1[CH2:19][CH2:18][CH2:17][CH:16]([Cl:20])[CH2:15][CH:14]1[N:27]([CH3:28])[CH3:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: O=C1CC(Cl)CCCC1N(C(=O)CCCl)c1ccccc1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C)C1CC(Cl)CCCC1N(C(=O)CCCl)c1ccccc1

Procedure:
The 3,4-dichloro-N-[2-oxocycloheptyl]propionanilide from Part C above is treated with sodium cyanoborohydride and dimethylamine-dimethylamine hydrochloride in methanol in the presence of 3A molecular sieves; the resulting mixture is worked up under basic pH conditions and the organic residue is chromatographed (column) on silica gel to isolate the cis isomer of 3,4-dichloro-N-[2-(dimethylamino)cycloheptyl]propionanilide.
Reaction SMILES: C(OCC)(=O)CCC.CCC(O)CC.[C:15]([O:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])(=[O:19])[CH2:16]CC>C(O)C>[C:15]([O:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])(=[O:19])[CH3:16]
Reactant: CCCC(=O)OC(CC)CC
Solvent: CCCC(=O)OCC
Solvent: CCO
Solvent: CCC(O)CC
Product: CCC(CC)OC(C)=O

Procedure:
These reactions were also studied with unsymmetrical esters. The reaction of ethyl butyrate with 3-pentanol in the presence of 1 mol % of 1 under refluxing toluene led to 75% conversion of ethyl butyrate with the formation of 73% of 3-pentyl butyrate as the exclusive product (entry 16). Traces of 3-pentyl acetate, resulting from reaction with the formed ethanol, were also observed. The remaining ethanol probably evaporated from the reaction mixture under the reflux conditions. Similarly, the reaction of methyl hexanoate with cyclohexanol results in 42% conversion after 17 h with the formation of 42% of cyclohexyl hexanoate (entry 17).
Reaction SMILES: [CH:1]1([N:7]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:26][N:27]([CH3:37])[S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29]>>[CH3:26][N:27]([CH3:37])[S:28]([N:31]1[CH2:36][CH2:35][N:34]([CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C@H:18]3[CH2:19][CH2:20][C@H:21]([CH3:24])[CH2:22][CH2:23]3)=[O:9])=[N:15][CH:14]=2)[CH2:33][CH2:32]1)(=[O:29])=[O:30]
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(C=O)s2)C2CCCCC2)CC1
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Agent: Cl
Product: CN(C)S(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)[C@H]3CC[C@H](C)CC3)s2)CC1

Procedure:
Prepared in 62% (326 mg) yield as described in general procedure (B) from trans-1-cyclohexyl-3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea (349 mg, 1.0 mmol) and piperazine-1-sulfonic acid dimethylamide hydrochloride (230 mg, 1 mmol).
Reaction SMILES: OC(C(F)(F)F)=O.C([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH:16]1[CH2:21][N:22]1[C:27](=[O:28])[C:26]([OH:29])=[C:25]2[C:30](=[O:42])[N:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH2:32][CH2:33][N:24]2[C:23]1=[O:43])C1C=CC=CC=1>C(O)C.[Pd]>[F:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:31]2[CH2:32][CH2:33][N:24]3[C:23](=[O:43])[N:22]([CH2:21][CH:16]4[CH2:17][O:18][CH2:19][CH2:20][NH:15]4)[C:27](=[O:28])[C:26]([OH:29])=[C:25]3[C:30]2=[O:42])=[CH:40][CH:39]=1
Reactant: O=C1c2c(O)c(=O)n(CC3COCCN3Cc3ccccc3)c(=O)n2CCN1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: O=C1c2c(O)c(=O)n(CC3COCCN3)c(=O)n2CCN1Cc1ccc(F)cc1
Reaction time: 8 h

Procedure:
7-[(4-Benzylmorpholin-3-yl)methyl]-2-(4-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione TFA salt (921 mg, 1.86 mmol, from Example 16) was dissolved in degassed ethanol (10 mL) under nitrogen and 10% palladium on carbon (92 mg) was added. The flask was evacuated and purged with hydrogen three times using a vacuum line and a hydrogen gas balloon. The reaction was stirred overnight under a hydrogen gas atmosphere. The reaction was filtered through a thin pad of celite, washing with degassed ethanol. The filtrate was concentrated to a yellow solid which was triturated with methanol. The solids were collected by vacuum filtration to give the desired product as a white powder. 1H NMR (400 MHz, d6 DMSO) δ 11.9 (s, 1H), 8.96 (bs, 2H), 7.39 (m, 2H), 7.22 (m, 2H), 4.72 (s, 2H), 4.13 (m, 1H), 3.84-4.02 (m, 5H), 3.52-3.70 (m, 5H), 3.27 (m, 1H), and 3.05 (m, 1H). HRMS (FT-ICR C19H21FN4O5+H)=405.1572; calculated 405.1569.