Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:44])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][C:21]=3[CH:35]([C:40]([O:42]C)=[O:41])[O:36]C(=O)C)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.C1COCC1.CO>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:44])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][C:21]=3[CH:35]([C:40]([OH:42])=[O:41])[OH:36])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COC(=O)C(OC(C)=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)c(C(O)C(=O)O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.2 %

Procedure:
A solution of (5S)-9-bromo-5-[p-tert-butoxycarbonylaminomethyl-o-(1-methoxycarbonyl-1-acetoxymethyl)phenylcarbamoylmethyl]-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (310 mg, 0.46 mmol) in a mixture of 1N aqueous sodium hydroxide (6 mL), THF (5 mL), and methanol (5 mL) was stirred for 6 h at room temperature. The mixture was concentrated to ca. 6 mL and acidified with 5% aqueous potassium hydrogen sulfate. The precipitates formed were collected and dried to give 276 mg of the title compound (97%).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[O:4]1.[C:21]1(C)[CH:26]=[CH:25][C:24]([S:27](O)(=O)=O)=[CH:23][CH:22]=1.C1(S)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:13]([N:10]1[CH2:9][CH2:8][C:5]2([O:4][CH:3]([CH2:2][S:27][C:24]3[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=3)[CH2:7][O:6]2)[CH2:12][CH2:11]1)[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC1COC2(CCN(CCc3ccccc3)CC2)O1
Agent: Sc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(CCN2CCC3(CC2)OCC(CSc2ccccc2)O3)cc1

Procedure:
2-hydroxymethyl-8-phenethyl-1,4-dioxa-8-azaspiro[4,5]decane (Compound 1, 50 gm, 0.18 mole) and Para Toluenesulfonic Acid (PTSA, 2 gm) were dissolved in toluene (350 ml) at room temperature. 20 gm of thiophenol was added drop wise to the above solution. The reaction was refluxed for 13 hrs at reflux temperature. The solvent was distilled off to get the light brown solid product with a melting point of 58° C. The yield of the product was 95%.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O)(=[O:3])[CH3:2].[CH:11]1([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:25]=[C:26]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[C:27]4[CH2:32][NH:31][CH2:30][C:28]=4[N:29]=3)=[CH:20][CH:19]=2)=[O:16])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][C:15](=[O:16])[NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:25]=[C:26]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[C:27]4[CH2:32][N:31]([C:8](=[O:10])[CH2:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH2:30][C:28]=4[N:29]=3)=[CH:22][CH:23]=2)[CH2:13][CH2:12]1
Reactant: CC(=O)NCCCC(=O)O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Product: CC(=O)NCCCC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 39 %

Procedure:
Method as example 127 using 4-acetamidobutanoic acid and (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) as starting materials. Purified by Prep HPLC at low pH to afford a white solid (46.5 mg, 0.089 mmol, 39%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[Cl-].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][Zn+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:20]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: FC(F)(F)c1cccc(C[Zn+])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1c(Cc2cccc(C(F)(F)F)c2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to procedure Z using 2,4-dichloro-5,7-difluoro-3-methylquinoline (350 mg, 1.411 mmol), Pd(PPh3)4 (163 mg, 0.14 mmol), 3-(trifluoromethyl)benzylzinc chloride (0.5M in THF, 2.96 mL, 1.48 mmol), and THF (3.5 mL). Purification by column chromatography (silica gel, 0-8% EtOAc in hexanes) gave 4-chloro-5,7-difluoro-3-methyl-2-(3-(trifluoromethyl)benzyl)-quinoline as a white solid. Mass Spectrum (ESI) m/e=372.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Cl:21][C:22]1[N:23]=[N:24][C:25](Cl)=[CH:26][C:27]=1[C:28]([C:30]1[CH:40]=[C:39]([CH3:41])[C:33]2[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=2[CH:31]=1)=[O:29].CCN(C(C)C)C(C)C>CN(C=O)C.[Cu]Br>[Cl:21][C:22]1[N:23]=[N:24][C:25]([N:15]2[CH2:14][CH2:13][CH:12]([N:9]3[CH2:10][CH2:11][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=4[NH:7][C:8]3=[O:18])[CH2:17][CH2:16]2)=[CH:26][C:27]=1[C:28]([C:30]1[CH:40]=[C:39]([CH3:41])[C:33]2[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=2[CH:31]=1)=[O:29]
Reactant: Cc1cc(C(=O)c2cc(Cl)nnc2Cl)cc2oc(=O)n(C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: [Cu]Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)c(Cl)nn3)CC1)C(=O)N2

Procedure:
550 mg (2.00 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 610 mg (1.80 mmol) 6-(3.6-dichloro-pyridazine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one, 630 mg (4.39 mmol) copper(I)bromide and 430 mL (2.50 mmol) DIPEA in 5 mL DMF were stirred for 2 h at 110° C., then cooled and filtered. The filtrate was combined with 1 mL of a 1N aqueous hydrochloric acid solution and precipitated with 40 mL ice water. The precipitate was suction filtered, washed with water and dried. The solid was stirred with 120 mL DCM/MeOH (11:1), filtered through silica gel and washed with DCM/MeOH. The filtrate was evaporated down. The residue was triturated with diethyl ether, suction filtered and dried. A mixture of isomers was obtained which was further reacted.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:19][C:20]1[CH:42]=[CH:41][C:23]([C:24]([N:26]2[CH2:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[CH2:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:37]1[C:28]2[CH2:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH2:32][N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:5](=[O:6])[C:4]4[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=4)=[CH:42][CH:41]=3)=[O:25])[C:27]=2[CH:40]=[CH:39][CH:38]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A mixture of 314 mg of 3,4-dichlorobenzoyl chloride and 151 mg of triethylamine in 2 ml of methylene chloride is stirred while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 5 ml of methylene chloride is added. Stirring is continued for 2 hours. The reaction mixture is partitioned with water and the organic layer is washed 1N HCl, water, 0.5N NaOH and brine. The organic layer is dried with Na2SO4 and passed through a short pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.35 g of off-white crystalline solid, m.p. 238°-241° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N+:12]([O-])([OH:14])=[O:13]>O>[Br:1][C:2]1[C:3]([F:11])=[C:4]2[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1c(Br)cnc2[nH]ccc12
Solvent: O
Product: O=[N+]([O-])c1c[nH]c2ncc(Br)c(F)c12
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (0.100 g, 0.465 mmol, see Example 51) was added slowly to fuming HNO3 (5 mL) at 0° C. and stirred for 10 minutes. Ice was then added, followed by the addition of water. The resulting solid product was then filtered, and washed with water and dried to give 5-bromo-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (0.105 g, 86.8% yield).
Reaction SMILES: CN(C)CC[N:5](C)[C:6]1[CH:7]=[C:8]([N:14]2[C:18](S)=NN=[C:15]2[C:20]2C=C(C(C)C)C(O)=C[C:21]=2O)[CH:9]=[CH:10][C:11]=1OC>CO.CCOC(C)=O.[Pd]>[CH3:18][N:14]([CH2:15][CH2:20][CH3:21])[C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([NH2:5])[CH:7]=1
Reactant: COc1ccc(-n2c(S)nnc2-c2cc(C(C)C)c(O)cc2O)cc1N(C)CCN(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN(C)c1cccc(N)c1
Yield: 116.9 %

Procedure:
A solution of 9.0 g (40.1 mmol mmol) of (2-Methoxy-5-nitro-phenyl)-methyl-propyl-amine (4) in 200 mL of MeOH/EtOAc (1:1) containing 5% w/w of Pd—C (10%) was subjected to hydrogenation (1 atm, balloon) overnight. The contents of the flask were passed through a short pad of celite and washed with EtOAc. The filtrate was evaporated under reduced pressure to give 7.7 g (92%) of crude amine 4-Methoxy-N3-methyl-N3-propyl-benzene-1,3-diamine (5) of an oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:19][C:16]1[CH:17]=[CH:18][C:13]([NH2:12])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccc(N)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 87.2 %

Procedure:
To a solution of 1-fluoro-2-methyl-4-nitrobenzene (2.02 g, 13.0 mmol) and 4-amino-3-nitrophenol (2.22 g, 14.4 mmol) in DMF (20 mL) was added cesium carbonate (5.28 g, 16.2 mmol). After heating to 60° C. for 10 hours, the mixture was diluted with water (100 mL) and filtered. The precipitate was washed with water and air-dried to provide the product (3.28 g, 87%) as dark solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:8]([OH:10])=O)=[CH:5][NH:6][CH:7]=1)#[N:2].Cl.CN.O[N:15]1[C:19]2C=CC=CC=2N=N1.Cl>O1CCCC1.C(N(CC)CC)C>[CH3:19][NH:15][C:8]([C:4]1[C:3]([C:1]#[N:2])=[CH:7][NH:6][CH:5]=1)=[O:10]
Reactant: On1nnc2ccccc21
Reactant: N#Cc1c[nH]cc1C(=O)O
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)c1c[nH]cc1C#N
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a solution of 4-cyano-1H-pyrrole-3-carboxylic acid (0.034 g), methylamine hydrochloride (0.034 g), triethylamine (0.084 g) and 1-hydroxybenzotriazole (0.034 g) in tetrahydrofuran (2.5 mL) was added N-ethyl—N′-3-dimethylaminopropylcarbodiimide (0.058 g) at room temperature, and this mixture was stirred at same temperature overnight. This reaction mixture was poured into 1 mol/L hydrochloric acid, and this mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give the title compound (0.035 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:19])=[O:11].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:19])(=[O:28])=[O:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc[n+]([O-])c1S(=O)Cc1c(Cl)cccc1Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc[n+]([O-])c1S(=O)(=O)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.1 %

Procedure:
To 8.0 g (0.03 mole) of 2[(2,6-dichlorophenyl)methylsulfinyl]-3-methyl-pyridine-N-oxide (See Example 29 above) in 150 ml of chloroform were added 10 g (0.05 mole) of metachloroperbenzoic acid. The mixture was stirred at room temperature for 24 hours, and then was washed with 20% K2CO3, and then with aqueous NaHSO3 until no peroxides were present. The chloroform layer was dried with Na2SO4 and then the mixture was filtered and the solvent removed on a steam bath. The residue was taken up in ether and filtered to give 2 g of solid, having a melting point of 215-218° C. The elemental analysis for C,H,N; the infrared, and the NMR all supported the proposed structure.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[C:22]([F:28])[CH:21]=1.C(N(CC)CC)C>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[C:22]([F:28])[CH:21]=4)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cc2cc(C3CCCCC3)ccc2o1
Reactant: O=Cc1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2cc3cc(C4CCCCC4)ccc3o2)cc1F
Yield: 65.9 %

Procedure:
A mixture of 5-cyclohexylbenzofuran-2-ylboronic acid (75 mg, 0.30 mmol), 4-bromo-2-fluorobenzaldehyde (48 mg, 0.24 mmol), triethylamine (1.1 mL, 7.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (12 mg, 0.05 mmol) in ethanol (11 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was treated with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo (the aqueous work-up is optional). Purification by silica gel chromatography on ISCO system gave the title compound (51 mg, 49% yield). 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.00-7.97 (m, 2H), 7.46 (s, 1H), 7.43 (d, 2H), 7.32 (s, 1H), 7.25 (d, 1H), 2.62 (m, 1H), 1.95-1.77 (m, 4H), 1.58-1.56 (m, 4H), 1.46-1.44 (m, 2H). MS (ESI) m/z: Calculated: 322.27; Observed: 323.2 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH2:11]([NH2:13])[CH3:12].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[CH2:7][NH:13][CH2:11][CH3:12]
Reactant: CCN
Reactant: O=Cc1cc(Br)ccc1I
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNCc1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 5-bromo-2-iodo-benzaldehyde (5.0 g, 16.1 mmol) in MeOH (20 mL) was added ethylamine (2M in MeOH; 16 mL, 24.0 mmol), followed by acetic acid (1.0 mL, 17.8 mmol), and the mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (2.0 g, 31.8 mmol) was then added over 5 minutes, and the reaction was stirred at room temperature over the weekend. The mixture was concentrated and partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to give the title compound.
Reaction SMILES: C(=O)(O)O.[OH:5][CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH2:7][NH2:8].[CH2:16]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=2[CH3:33])=[CH:23][CH:22]=1)[C:17]([CH3:19])=O>>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH:6]([OH:5])[CH2:7][NH:8][CH:17]([CH3:19])[CH2:16][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH2:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=2[CH3:33])=[CH:25][CH:26]=1
Reactant: CC(=O)COc1ccc(C2=C(C)NC(=O)CC2)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: O=C(O)O
Product: CC1=C(c2ccc(OCC(C)NCC(O)c3cccc(Cl)c3)cc2)CCC(=O)N1

Procedure:
5-[4-[2-[(3-Chloro-β-hydroxyphenethyl)amino]propyloxy]phenyl]-3,4-dihydro-6-methyl-2(1H)-pyridinone was prepared as a 1:1 mixture of diastereoisomers, m.pt. 99°-104° C., from 2-hydroxy-2-(3-chlorophenyl)ethanamine carbonate (0.58 g) and 3,4-dihydro-5-(4-acetonyloxyphenyl) 6-methyl-2(1H)-pyridinone (0.75 g) in an analogous manner to the compound described in Example 38.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15][C@@H:16]2[O:33][C@H:32]([CH2:34][O:35]C(=O)C)[C@H:27]([O:28]C(=O)C)[C@H:22]([O:23]C(=O)C)[C@H:17]2[O:18][CH2:19][CH:20]=[CH2:21])[C@@H:8]([CH2:39][O:40]C(=O)C)[O:7][C@@H:6]1Cl)(=O)C.[CH3:45][OH:46]>>[CH2:19]([O:18][C@@H:17]1[C@@H:22]([OH:23])[C@@H:27]([OH:28])[C@@H:32]([CH2:34][OH:35])[O:33][C@H:16]1[O:15][C@@H:9]1[C@@H:8]([CH2:39][OH:40])[O:7][C@@H:6]([O:46][CH3:45])[C@H:5]([OH:4])[C@H:10]1[OH:11])[CH:20]=[CH2:21]
Reactant: C=CCO[C@H]1[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](Cl)O[C@@H]2COC(C)=O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CO
Product: C=CCO[C@H]1[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](OC)O[C@@H]2CO)O[C@H](CO)[C@H](O)[C@@H]1O
Reaction time: 48 h
Yield: 67 %

Procedure:
Chloride 3 (4.4 g, 6.74 mmol) was dissolved in dry MeOH and left at room temperature for two days. The mixture was neutralized with Dowex 50W (H+) resin, the suspension was filtered and the filtrate was crystallized from EtOH to give 4 (1.8 g, 67%), [α]D−1.8° (c 0.2, H2O), m.p. 22-223° C.; 1H NMR (D2O) δ 5.99 (m, 1H, Hc), 5.36 (m, 1H, Hb), 5.28 (m, 1H, Ha), 4.49 (d, 1H, J1′,2′=7.9 Hz, H-1′), 4.41 (d, 1H, J1,2=8.0 Hz, H-1), 4.34 (m, 1H, Hd), 4.26 (m, 1H, He), 3.99 (broad d, 1H, H-6a), 3.83-3.62 (m, 8H, H-3, H-4, H-5, H-6b, H-3′, H-5′, H-6′a, H-6′b), 3.58 (s, 3H, Me), 3.4dd, 1H, J2′,3′=10.0 Hz, H-2′), 3.32 (m, H-2). Calc'd for C16H28O11 (396.38) C, 48.48; H, 7.12. Found C, 48.47, H, 7.12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[CH2:21]([C:23]1[C:24](=[O:30])[NH:25][C:26](=[S:29])[NH:27][CH:28]=1)[CH3:22].CCN(C(C)C)C(C)C>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:29][C:26]3[NH:27][CH:28]=[C:23]([CH2:21][CH3:22])[C:24](=[O:30])[N:25]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Reactant: CCc1c[nH]c(=S)[nH]c1=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c[nH]c(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46 %

Procedure:
A mixture of 1-chloro-4-{[4-(chloromethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (65 mg, 0.202 mmol), 5-ethyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (47.4 mg, 0.304 mmol) and DIPEA (0.163 mL, 0.933 mmol) in DCE (3.0 mL) was sealed in a vessel and stirred at room temperature for 5 min, then was heated with a microwave condition at 80° C. for 30 min. After cooling, the reaction was quenched with water, extracted with EA, the combined organic layers were dried with sodium sulfate, concentrated, and purified via MDAP to afford the title compound (41 mg, 45.9% yield). LCMS: rt=3.94 min, [M+H+]=441
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[C@@H:19]3[CH2:23][C@H:22]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])[C@@H:21]([OH:29])[C@H:20]3[OH:30])=[C:12]([NH:31]C(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)[N:11]=2)[CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[C@@H:19]3[CH2:23][C@H:22]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])[C@@H:21]([OH:29])[C@H:20]3[OH:30])=[C:12]([NH2:31])[N:11]=2)[CH:9]=1)=[O:4]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(-n4cc(C(=O)NC)cn4)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(N)nc(-n4cc(C(=O)NC)cn4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A cooled (0° C.) solution of 1-[6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid methylamide (0.08 g, 0.122 mmol) in dry dichloromethane (4 ml) is treated slowly with trifluoroacetic acid (2 ml). The reaction mixture is stirred at room temperature for 48 h and then concentrated in vacuo. The residue was co-evaporated with chloroform three times to remove excess trifluoro acetic acid and purification of the crude product by preparative HPLC affords the title compound. LC-MS (0.1% formic acid, acetonitrile): (MH+ 430.28)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>>[OH:9][CH2:8][C:6]1[CH:7]=[C:2]([NH:1][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(CO)c1
Product: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])c(CO)c1

Procedure:
N-(3-Hydroxymethyl-4-nitrophenyl)-2-methylacrylamide was prepared as described in Example 1a starting from (5-Amino-2-nitrophenyl)methanol and methacryloyl chloride. 1H NMR (400 MHz, DMSO-d6): 1.97 (3H, s), 4.85 (2H, d, J=5.2 Hz), 5.56 (1H, t, J=5.2 Hz), 5.61 (1H, s), 5.90 (1H, s), 7.93 (1H, dd, J=9.0 Hz, J=2.1 Hz), 8.11 (1H, d, J=9.0 Hz), 8.20 (1H, d, J=2.1 Hz), 10.32 (1H, s).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>CS(C)=O.O>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:1]2[CH2:5][CH2:4][NH:3][C:2]2=[O:6])=[CH:18][CH:17]=1
Reactant: O=C1NCCN1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN1Cc1ccc(Cl)cc1
Reaction time: 1.3 h
Yield: 92 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 300 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of potassium carbonate, 10 g (0.06 mole) of potassium iodide and 40.5 g (0.25 mole) of 4-chlorobenzyl chloride. The reaction mixture was heated to 100° over 0.3 hours, held at 100° with rapid stirring for 1.3 hours and poured into 1.3 l of water. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 150 ml of water, dried over magnesium sulfate for 3 hours and filtered. The filtrate was concentrated to dryness to give 49 g (92%) a light yellow oil which crystallized.
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>O>[C:3]1([N:2]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[NH:16][C:17]2=[O:18])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC1CCCCC1=O
Agent: Br
Solvent: O
Solvent: c1ccncc1
Product: O=c1[nH]c2c(n1-c1ccccc1)CCCC2
Temperature: 125 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
A mixture of 1.94 g (0.01 mol) of 2-aminocyclohexanone hydrobromide, 1.19 g (0.01 mol) of phenyl isocyanate and 4 ml of pyridine is stirred at 125° C. for 4 hours. Water is added, the mixture is stirred until crystallization is obtained, drained, washed with water and dried. The compound is purified by flash chromatography on silica, eluting with a 95:5 CH2Cl2/CH3OH mixture. 0.7 g of product is recovered. Yield=33% (m.p.=224° C.).