Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][NH2:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([CH2:25][NH:26][C:34](=[O:35])[O:36][CH2:37][CH3:38])=[CH:14][CH:13]=2)=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CN)ccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NCc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a solution of crude tert-butyl[6-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.16 g) (Example 285) in tetrahydrofuran (2 mL) were added ethyl chloroformate (0.035 mL, 0.36 mmol) and triethylamine (0.050 mL, 0.36 mmol), and the mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water (4 mL) and concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 (v/v)) to give ethyl (3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)methylcarbamate (0.13 g, 87%) as pale yellow powder.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:19]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A solution (0.1 M) of 3-cyclohex-1-en-1-yl-1H-indole-6-carboxylic acid (prepared as described in International patent application publication WO2004/087714) in dry DMF was cooled to 0° C. and treated with K2CO3 (1.05 eq). A solution (3 M) of MeI (1.05 eq) in DMF was then added over 0.5 h, and the temperature was raised to 20° C. After 18 h, the reaction was quenched with aqueous HCl(1N) and diluted with EtOAc. The organic phase was separated and washed several times with aqueous HCl(1N), then with brine. The dried organics were concentrated to give the title compound (99%) as a solid; (ES+) m/z 256 (M+H)+.
Reaction SMILES: C(OC[C@@](NC(=O)C)(C)CCC1OC(Br)=CC=1)(=O)C.C1(CCC#C)C=CC=CC=1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH2:36][C@:37]([CH3:58])([CH2:40][CH2:41][C:42]1[O:43][C:44]([C:47]#[C:48][CH2:49][CH2:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54]C=2)=[CH:45][CH:46]=1)[CH2:38][OH:39]>>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH2:36][C@:37]([CH3:58])([CH2:40][CH2:41][C:42]1[O:43][C:44]([C:47]#[C:48][CH2:49][CH2:50][C:51]2[CH:52]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:45][CH:46]=1)[CH2:38][OH:39]
Reactant: C[C@](N)(CO)CCc1ccc(C#CCCCc2ccccc2)o1
Agent: C#CCCc1ccccc1
Agent: CC(=O)N[C@](C)(CCc1ccc(Br)o1)COC(C)=O
Agent: O=C(O)C(=O)O
Product: C[C@](N)(CO)CCc1ccc(C#CCCc2ccccc2)o1
Yield: 61 %

Procedure:
The title compound was synthesized in a yield of 61% using (2R)-1-acetoxy-2-acetylamino-2-methyl-4-(5-bromofuran-2-yl)butane obtained-in Reference example 6 and 4-phenylbut-1-yne as the starting materials by conducting successively the reactions similar to those mentioned in Examples (1a) and (1b).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C@@H:10]([C@@:14]2([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][C:23]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=3[F:31])[C:16]3[CH:32]=[CH:33][CH:34]=[CH:35][C:15]2=3)[C:11]([OH:13])=[O:12])[N:3]=1.C(N(CC)CC)C.Cl[CH2:50][C:51]([N:53]([CH3:55])[CH3:54])=[O:52]>CN(C=O)C.CC(=O)OCC>[CH3:54][N:53]([CH3:55])[C:51]([CH2:50][O:12][C:11](=[O:13])[C@@H:10]([O:9][C:4]1[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[C@@:14]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][C:23]2[C:28]([F:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=2[F:31])[C:16]2[CH:32]=[CH:33][CH:34]=[CH:35][C:15]1=2)=[O:52]
Reactant: CN(C)C(=O)CCl
Reactant: Cc1cc(C)nc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCC(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc32)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(O[C@H](C(=O)OCC(=O)N(C)C)[C@@]2(c3ccccc3)NCC(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
A solution of (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]di-azepin-5-yl]-acetic acid (150 mg, 0.266 mmol, Example 107) in DMF (5 ml) is treated with triethylamine (162 mg, 1.60 mmol) and 2-chloro-dimethylacetamide (162 mg, 1.38 mmol). The mixture is stirred at rt for 18 h before it is diluted with EA, washed twice with water, dried over MgSO4 and evaporated. The crude product is purified by chromatography on prep. tlc plates (DCM with 10% methanol) and crystallisation from diethyl ether/hexane to give (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid dimethylcarbamoylmethyl ester (151 mg) as a white powder. LC-MS1: tR=1.10 min, [M+1]+=648.15.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[C:24]1([CH:34]=O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)Cl>ClCCCl.C1COCC1>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([NH:13][C:14](=[O:22])[C:15]1[CH:16]=[CH:17][C:18]([NH:21][CH2:34][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:20]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([Br:12])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1ccc(N)cc1
Reactant: O=Cc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1ccc(NCc2cccc3ccccc23)cc1
Yield: 48 %

Procedure:
(S)-3-(4-Bromo-phenyl)-2-{4-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid methyl ester (273 mg) was prepared from (S)-2-(4-amino-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (415 mg, 1.1 mmol) and 1-naphthaldehyde (0.331 mL, 2.4 mmol) according to Procedure G, except for the following: the reaction was done in 15 mL DCE and 5 mL THF, was allowed to stir for 15 min before NaBH(OAc)3was added, was treated with two additional equiv. NaBH(OAc)3 after 2 h, and an adapted work-up. After reaction completion, 100 mL of DCM was added and the organic washed with saturated sodium bicarbonate, dried over sodium sulfate, and evaporated. The crude material was triturated with MeOH.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:21])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[C:10]([F:22])[CH:9]=[CH:8][CH:7]=2)[CH3:3].CS(O[C@@H](C1OC2C(C(=O)C=1C1C=CC=C(F)C=1)=C(F)C=CC=2)C)(=O)=O.[N-:49]=[N+:50]=[N-].[Na+]>CN(C=O)C>[N:1]([C@@H:2]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:21])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[C:10]([F:22])[CH:9]=[CH:8][CH:7]=2)[CH3:3])=[N+:49]=[N-:50]
Reactant: C[C@@H](N)c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: C[C@@H](OS(C)(=O)=O)c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](N=[N+]=[N-])c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (S)/(R)-1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl methane sulfonate (0.900 g, 2.36 mmol) in DMF (18 ml), sodium azide (0.306 g, 4.72 mmol) is added and heated to 60° C. After 2 h, the reaction mass is quenched with water, extracted with dichloromethane, dried over sodium sulphate and concentrated. The crude product is column chromatographed with ethyl acetate:petroleum ether to afford the title compound as a brown liquid which is used as such in next step.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)[CH:3]=[N:4]2)[N:12]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cc(Br)cn3)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cnn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-pyrazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.11) (0.44 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.22 g, 1.0 mmol) according to the general procedure VI. Obtained as a yellow solid (0.027 g, 0.6%). MS (ISP) 451.1 [(M+H)+]; mp 206° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].S(=O)(=O)(O)O.[CH:14]([C:16]([CH3:18])=O)=[CH2:15].[OH-].[Na+]>C(O)(=O)C.O>[CH3:18][C:16]1[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=[CH:7][CH:6]=2)[N:4]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1Br
Reactant: C=CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccnc2c(Br)cccc12
Temperature: 90 °C

Procedure:
2-Bromoaniline (5.16 g, 30 mmol) dissolved in acetic acid and conc. sulfuric acid was treated with a solution of methyl vinyl ketone in acetic acid. The reaction mixture heated to 90° C. for 14 h. The cooled mixture was poured into water and basified with sodium hydroxide and extracted into EtOAc. The organics were dried over Na2SO4, and concentrated the purified by SGC (Combiflash 0-100% EtOAc: hexanes over 30 minutes) followed by recrystallization from hot hexanes furnished 4-methyl-8-bromoquinoline (2.3 g). 1H NMR (CDCl3) δ 8.92 (d, 1H), 8.08 (d,1H), 8.01 (d,1H), 7.45 (t,1H), 7.32 (d,1H), 2.71 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:11]1[N:12]=[N:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:15]([F:18])([F:17])[F:16])[CH:4]=2)=[CH:9][CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc(-c2ccc(F)c(C(F)(F)F)c2)n[nH]1
Product: Fc1ccc(-c2ccc(Cl)nn2)cc1C(F)(F)F

Procedure:
A mixture 10 g. of 6-[4-nitro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone in 50 ml. of trifluoroacetic acid is reduced with hydrogen and palladium on carbon to give 6-[4-amino-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone. The preceding compound is converted to 6-[4-fluoro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone by the procedure described in J. Org. Chem., 26, 468 (1961). The preceding compound is reacted with phosphorus oxychloride as described in Example 47 to give 3-chloro-6-[4-fluoro-3-(trifluoromethyl)phenyl]pyridazine., which is reacted with formylhydrazine as described in Example 48 to give the product of the example.
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([C@@H:7]2[O:11][C@H:10]([CH2:12][O:13][P:14]([O:17][P:18]([O:21][CH2:22][C@H:23]3[O:27][C@@H:26]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH2:37])[C:31]=5[N:30]=[CH:29]4)[C@H:25]([OH:38])[C@@H:24]3[OH:39])([OH:20])=[O:19])([OH:16])=[O:15])[C@@H:9]([OH:40])[C@H:8]2[OH:41])[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH:2]=1.P([O-])([O-])([O-])=O.[I-].[Na+].[OH-].[Na+]>>[CH:34]1[N:35]=[C:36]([NH2:37])[C:31]2[N:30]=[CH:29][N:28]([C@@H:26]3[O:27][C@H:23]([CH2:22][O:21][P:18]([O:17][P:14]([O:13][CH2:12][C@H:10]4[O:11][C@@H:7]([N:5]5[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH2:2][CH:1]=[CH:6]5)[C@H:8]([OH:41])[C@@H:9]4[OH:40])([OH:16])=[O:15])([OH:20])=[O:19])[C@@H:24]([OH:39])[C@H:25]3[OH:38])[C:32]=2[N:33]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [Na+]
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Temperature: 23 °C
Reaction time: 13 h
Yield: 19.5 %

Procedure:
NAD+ (34.0 mg, 38.0 μmol) was placed in 2 mL of a 0.1 M phosphate buffer containing 0.07 M sodium iodide. The pH of this solution was adjusted to 8.1 with NaOH and then placed in an 80 mL Fisher-Porter bottle. The Fisber-Porter bottle was evacuated and refilled with argon three times then [Cl2Ru(TPPTS)2]2 (7.7 mg, 2.9 μmol) was added under a flow of argon. The Fisher-Porter bottle was evacuated and filled with 70 psi of H2 and stirred to 23° C. for 13.0 hr. The volatiles were removed under reduced pressure and a sample dissolved in D2O. To this was added 20 μl of trimethylsilylpropionate standard solution. 1H NMR integration shows that 7.4 μmole of NADH have been produced under these conditions.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13](=O)[C:14](=O)[CH3:15]>>[CH3:12][C:13]1[C:14]([CH3:15])=[N:11][C:6]2[C:7](=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: CC(=O)C(C)=O
Product: Cc1nc2ccc([N+](=O)[O-])cc2nc1C

Procedure:
A stirred mixture of 4-nitro-o-phenylenediamine (Fairmont) (105 g, 0.69 mole) and 2,3-butanedione (Aldrich) (59 g, 0.69 mole) in 1.5 L of SDA-32 was heated at reflux for 4 hours. The reaction mixture was let stand at room temperature overnight. The crystallized intermediate was chilled and collected to give after ether wash 62.9 g (44.9%) of known solid. The intermediate was used without further purification in step B.
Reaction SMILES: CC(C)([O-])C.[K+].CC(=[N:10][OH:11])C.F[C:13]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16].Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.CO.C(Cl)Cl.CCO>[NH2:16][C:15]1[C:14]2[CH:17]=[CH:18][C:19]([C:21]#[N:22])=[CH:20][C:13]=2[O:11][N:10]=1
Reactant: N#Cc1ccc(C#N)c(F)c1
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc2c(N)noc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1 M potassium tert-butoxide in THF (11.0 mL, 11.0 mmol) was added acetone oxime (0.824 g, 11.3 mmol) in one portion. After stirring for 20 min at room temperature, a solution of 2-fluoro-terephthalonitrile (1.48 g, 10.1 mmol) in THF (11 mL) was slowly added through a syringe. The reaction mixture warmed up and turned into a red solution. After stirring for 1.5 hrs at room temperature, the mixture was heated at 60° C. for 1 hr. The reaction was quenched with a mixture of saturated ammonium chloride solution and water (1:1, 10 mL). THF was removed by rotary evaporation. The reaction mixture was then partitioned between ethyl acetate (30 mL) and brine (20 mL). The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was then removed in vacuo to provide a yellow solid. The solid was then treated with a mixture of EtOH (22 mL) and HCl (1 N, 14 mL) at reflux for 1.5 hrs. After cooling to room temperature, the reaction mixture was basified with solid sodium carbonate and partitioned between ethyl acetate (100 mL) and water (20 mL). The aqueous layer was further extracted with ethyl acetate (2×25 mL). All organic layers were combined and extracted with water (3.25 mL), brine (30 mL) then dried over anhydrous sodium sulfate. Rotary evaporation of solvent afforded a light brown solid. LC/MS (ESI) showed the desired mass (M+H++CH3CN: 201.1). All crude was dissolved in minimum amount of MeOH/DCM (5:95) and loaded onto a silica column. The product was eluted with (2 M NH3 in MeOH)/DCM (5:95). A light brown solid was obtained (1.01 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][O:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:24][CH2:23]2)=[O:21])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][O:31][CH:32]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:24][CH2:23]2)=[O:21])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[OH:9]
Reactant: COCCOCOc1c(OC)cc(C=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1cc(C=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc(OC)c1O
Yield: 84.4 %

Procedure:
To a solution of 270 mg (0.45 mmol) of the amide compound in 5 ml of methanol was added 95 mg (0.5 mmol) of p-toluen esulfonic acid monohydrate,,and the mixture was heated and refluxed for 1 hour under argon atmosphere. The reaction mixture was concentrated by evaporation under reduced pressure, a saturated aqueous solution of sodium hydrcgencarbonate was added to the residue, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected tc silica gel column chromatography, eluted with chlcroform - methanol, to give 200 mg (0.38 mmol) of N-[3-(3,5-dimethoxy-4-hydroxyphenyl) 2-propenoyl]-N'-(3-benzhydroxypropyl)piperazine. Spectrophotometric data of the product support the structure shown below. ##STR93##
Reaction SMILES: ClC[C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1>C([O-])(O)=O.[Na+]>[N:4]1[CH:3]=[CH:11][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: ClCc1cn2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: c1ccn2ccnc2c1
Yield: 80 %

Procedure:
To saturated NaHCO3 (40 mL) was added the chlorhydrate form of 2-(chloromethyl)-imidazo[1,2-a]pyridine and the aqueous layer was extracted with AcOEt. The organic layers were combined and washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure to afford 877 mg of 2-chloromethyl)-imidazo[1,2-a]pyridine (Yield. 80%) as a brownish solid (M.P.: 8485° C.)
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:13][CH:12]=1)(=[O:10])[CH3:9].S(=O)(=O)(O)O>[Zn].C1C=CC=CC=1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:13][CH:12]=1)([OH:10])[CH3:9])[CH3:7]
Reactant: CC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Reactant: CCOC(=O)CBr
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1

Procedure:
A mixture of 20 g. of ethyl bromoacetate, 26.5 g. of 4-acetyl-3',4'-dichlorobiphenyl and 8 g. of zinc foil is added to 100 ml. of benzene and the mixture is stirred and heated under reflux for one hour. It is cooled and dilute sulfuric acid is added to decompose the alcoholate obtained. The organic phase is separated off and, after the customary work up, 3-(3',4'-dichloro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester is obtained.
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][C:15]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:9]1[CH2:10][O:11][CH2:12]2)C1C=CC=CC=1>CO.[Pd]>[C:21]([O:20][C:18]([NH:17][C:15]1([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:14][CH:13]2[NH:8][CH:9]([CH2:10][O:11][CH2:12]2)[CH2:16]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)CC1(NC(=O)OC(C)(C)C)CC2COCC(C1)N2Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1(NC(=O)OC(C)(C)C)CC2COCC(C1)N2
Reaction time: 12 h
Yield: 96 %

Procedure:
A mixture of ethyl 2-[9-benzyl-7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetate (0.7 g, 1.67 mmol), 10% Pd/C (0.5 g) in methanol (20 mL) was stirred for 12 hours under 1 atm H2. Filtration followed by removal of the residue gave ethyl 2-[7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetate 146a, which was used in next step without purification. Yield: 96%. MS: calc'd (MH+) 329, measured (MH+) 329.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=3)[C:6]=2[N:7]=1.[CH3:22][NH2:23]>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][CH3:22])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=3)[C:6]=2[N:7]=1
Reactant: CN
Reactant: FC(F)(F)c1ccc(C2CCc3c(Cl)nc(Cl)nc32)cn1
Solvent: CN1CCCC1=O
Product: CNc1nc(Cl)nc2c1CCC2c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.2 %

Procedure:
To a solution of 2,4-dichloro-7-(6-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (33 mg, 0.099 mmol) in NMP (Volume: 5 mL) was added methanamine (0.247 mL, 0.494 mmol). The reaction mixture was stirred at room temperature for 2 h. The product was partitioned between ethyl acetate & water. The organic layers were combined and dried in vacuum to afford 2-chloro-N-methyl-7-(6-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (8 mg, 0.024 mmol, 24.64% yield). LC-MS (M+H)+=329.0.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].[C:17]1([CH2:23]C[Mg]Cl)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+].O>C1COCC1>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[CH2:5][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Cl[Mg]CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(CCc1ccccc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 12 (21.93 g, 97 mmole) in absolute THF (180 ml) was added dropwise to a 1M solution of phenylethyl magnesium chloride in THF (242 ml, 242 mmole) under argon and while cooling with ice, and stirred for 20 hours at RT. To work up the reaction mixture saturated ammonium chloride solution (100 ml) and water (100 ml) were added while cooling with ice and the mixture was extracted with diethyl ether (3×100 ml). The organic phase was washed with water and saturated sodium chloride solution, dried, and concentrated by evaporation.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]([CH2:19][CH2:20][NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[C:7](=[O:18])[CH2:8][N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11])C.[OH-].[Li+].Cl>C1COCC1.O>[N+:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[S:22]([NH:21][CH2:20][CH2:19][N:6]([C:7](=[O:18])[CH2:8][N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11])[CH2:5][C:4]([OH:34])=[O:3])(=[O:24])=[O:23])([O-:33])=[O:32]
Reactant: CCOC(=O)CN(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)Cn1cc(C)c(=O)[nH]c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(CC(=O)N(CCNS(=O)(=O)c2ccccc2[N+](=O)[O-])CC(=O)O)c(=O)[nH]c1=O
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
To a solution of N-[2-(2-Nitro-benzenesulfonylamino)-ethyl]-N-[(thymin-1-yl)-acetyl]-glycine ethyl ester (1.00 g, 2.0 mmol) in THF (10 ml,) was added a solution of lithium hydroxide (210 mg, 5 mmol) in water (10 mL) at 10° C. After stirring for 1.5 h, the reaction mixture was acidified to pH=2˜3 by adding 1 N HCl solution. The precipitated solid was filtered off, washed with water, and dried in vacuo to give the tilted product as a white solid (896 mg, 95%). 1H-NMR (500 MHz; DMSO-d6) δ 11.30 (s, 0.6H), 11.27 (s, 0.4H), 8.22˜7.85 (m, 5H), 7.31 (d, 0.6H), 7.23 (d, 0.4H), 4.63 (s, 1.2H), 4.45 (s, 0.8H), 4.19 (s, 0.8H), 4.16 (q. 0.8H), 3.93 (s, 1.2H), 3.47 (t, 1.2H), 3.34 (t, 0.8H), 3.20 (q, 1.2H), 3.04 (q. 0.8H), 1.75 (s, 3H).