Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[ClH:17].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][Cl:25])=[CH:20][CH:19]=1.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1C=CC=CC=1>[ClH:25].[ClH:17].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:7]2([CH2:24][C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[C:6]3[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:20][CH:19]=1
Reactant: ClCc1ccncc1
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(=O)c1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2

Procedure:
The title compound was prepared following the procedure of Example 1 from 5.0 g (24 mmole) of 2-acetylfluorene, 10 g of 4-picolylchloride hydrochloride, 120 ml benzene, 200 mg of benzyltriethylammonium chloride, and 20 ml of 50% sodium hydroxide by reaction solution at 20° for 17 hrs. The title compound was obtained after an acid-base wash and crystallization from benzene-hexane (Magnesol®), m.p., >300°. NMR (CDCl3, 200 MHz) δ: 2.68(S,3H), 3.46(S,4H), 6.44(d,J=5.9Hz,4H), 7.29-7.87(m,6H), 8.05(d,J=5.9Hz,4H), 8.22(d,1H). HRMS calculated for C27H22N2O: 390.1732 Found: 390.1720.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH3:13])[CH2:10][C@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.[NH4+].[Cl-].O>C1COCC1>[OH:15][CH2:14][C@@H:9]1[CH2:10][CH:11]([CH3:13])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: CC1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To a solution of (2S)-1-tert-butoxycarbonyl-4-methyl-pyrrolidine-2-carboxylic acid (26.6 g, 116.0 mmol) in THF (160 mL) is added 1 M borane in THF (243.6 mL, 243.6 mmol) at 0° C. The reaction mixture is stirred at rt overnight. Then a saturated aqueous solution of NH4Cl (50 mL) is carefully added (dropwise) at 4° C., followed by H2O (100 mL). The mixture is extracted with EtOAc and the organic phase is washed with H2O, dried over Na2SO4, filtered and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (0 to 20% EtOAc in Hexanes) to give tert-butyl (2S)-2-(hydroxymethyl)-4-methyl-pyrrolidine-1-carboxylate (23.5 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]1([C:18]2([C:24]#[N:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.O>ClCCl>[C:12]1([C:18]2([C:24]#[N:25])[CH2:19][CH2:20][N:21]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:22][CH2:23]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCC(C#N)(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
17.2 g (89.8 mmol) of 4-methylbenzenesulfonyl chloride dissolved in 150 mL of dichloromethane are added to a solution of 20 g (89.8 mmol) of 4-phenylpiperidine-4-carbonitrile and 28 mL of triethylamine in 200 mL of dichloromethane. The reaction mixture is stirred for 1 hour at room temperature. The reaction is stopped by adding 200 mL of water, and is then extracted with dichloromethane. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then taken up in diethyl ether and filtered off. 30.3 g of 4-phenyl-1-(toluene-4-sulfonyl)piperidin-4-carbonitrile in the form of a white powder are obtained in a yield of 99%.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:47][CH2:48][CH2:49][S:50]([CH3:53])(=[O:52])=[O:51].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:47][CH2:48][CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)CCCCl
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCCS(C)(=O)=O)c4cc(F)ccc34)nc12
Temperature: 65 °C
Yield: 76.9 %

Procedure:
To a solution of N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (60 mg, 0.1 mmol) in DMF (5 mL) was added 1-chloro-3-(methylsulfonyl)propane (19 mg, 0.12 mmol) followed by K2CO3 (42 mg, 0.3 mmol). The mixture was heated at 65° C. for 4 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (55 mg, 77%). The crude was used to the next step without further purification. LCMS: (M+H)+=715.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].[C:19]([O-])(O)=[O:20].[Na+]>C1COCC1>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:1][C:19]2=[O:20])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C([O-])O
Reactant: Cc1c(Br)cccc1NC(=O)c1ccccc1N
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2ccccc2c1=O
Yield: 97 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)benzamide (2.00 g, 6.55 mmol) in THF (50 mL) was treated with bis(trichloromethyl)carbonate[triphosgene] (2.92 g, 9.83 mmol) and heated at reflux for 60 min. The cooled mixture was treated with saturated aqueous NaHCO3, extracted with EtOAc, and the combined organic phases were washed twice with saturated NaHCO3, then with water, dried and concentrated. The residue was triturated with DCM to give a white solid which was collected by filtration. The residue from concentration of the filtrate was triturated with DCM to give additional white solid which was collected by filtration. The two solids were combined to give 3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione as a white solid (2.10 g, 97% yield). Mass spectrum m/z 331, 333 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 8.07 (dd, J=7.92, 1.32 Hz, 1H), 7.65-7.75 (m, 2H), 7.21-7.32 (m, 4H), 2.20 (s, 3H). 1H NMR (400 MHz, chloroform-d) δ 9.38 (br. s., 1H), 8.19 (dd, J=7.9, 1.1 Hz, 1H), 7.76-7.69 (m, 1H), 7.69-7.60 (m, 1H), 7.35-7.17 (m, 3H), 7.04-6.97 (m, 1H), 2.28 (s, 3H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccc(Cl)cc3)CC2)cc1-c1ccc(F)cc1

Procedure:
108 mg (60%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-(4-chlorophenyl)piperazine (98 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][C:12]1[C:13]([CH3:23])=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[Cl:11][C:12]1[C:13]([CH3:23])=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10])[OH:22]
Reactant: Cc1c(Cl)ccc2c1C(=O)C(=O)N2
Reactant: COc1ccc(Cl)cc1Br
Product: COc1ccc(Cl)cc1C1(O)C(=O)Nc2ccc(Cl)c(C)c21
Yield: 71.7 %

Procedure:
With 4.75 g of 2-bromo-4-chloro-1-methoxy benzene and 1.96 g of 5-chloro-4-methyl-1H-indol-2,3-dione as starting materials, 2.43 g of the title compound (yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[CH2:24]([O:26][C:27]([CH:29]1[C:33](=[O:34])[CH2:32][N:31]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:30]1)=[O:28])[CH3:25]>O>[CH2:24]([O:26][C:27]([CH:29]1[CH:33]([OH:34])[CH2:32][N:31]([C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH2:30]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1O
Temperature: 32 °C
Reaction time: 24 h
Yield: 41.4 %

Procedure:
To a solution of sucrose (3 g) in distilled water (40 mL) was added Baker's yeast (2 g). The suspension was heated at 32° C. for 1 h. The content of the flask was then poured into a flask containing ketoester 71 (2.9 g, 9.88 mmol, dissolved in 4 mL of methanol). Stirring was continued at 32° C. for 24 h after which additional sucrose (3 g) in warm (40° C.) distilled water was added. After 48 h, the suspension was filtered through a pad of Celite. The pad was washed with water and the aqueous layer was extracted with ethyl acetate (3×250 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to flash chromatography (30% EtOAc/Hexane) to afford alcohol 73 (1.2 g, 41%).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]1[CH2:11][CH2:10][N:9](C(OCCCC)=O)[CH2:8][CH2:7]1)(=[O:4])=[O:3].[ClH:19]>ClCCl.CO>[ClH:19].[NH:9]1[CH2:8][CH2:7][CH:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:11][CH2:10]1
Reactant: CCCCOC(=O)N1CCC(NS(C)(=O)=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)NC1CCNCC1
Reaction time: 2 h
Yield: 96.3 %

Procedure:
In a dried reaction flask, butyl 4-(methylsulfonamido)piperidine-1-carboxylate (2.53 g, 9.1 mmol) was dissolved in a mixed solvent of dichloromethane (20 mL) and methanol (5 mL). A dried HCl gas was passed thereto at room temperature for 2 hr, and a white solid was formed. The mixture was filtered and washed with dichloromethane and anhydrous ethyl ether, and dried to obtain a white powdery solid (1.88 g) in a 96.3% yield.
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH:16]=[O:17])[CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1C1(C=O)CCNCC1.BrCCC1C=CC=CC=1.Cl>CN(C=O)C.CO.CCOC(C)=O.O>[ClH:1].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)=[O:17])=[CH:21][CH:20]=1
Reactant: Cc1ccccc1C1(C=O)CCNCC1
Reactant: O=CC1CCN(CCc2ccccc2)CC1
Agent: BrCCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C(=O)C2CCN(CCc3ccccc3)CC2)cc1
Temperature: 100 °C
Reaction time: 23 h

Procedure:
(4-Methylphenyl)[1-(2-phenylethyl)-4-piperidinyl -methanone HCl. A mixture containing 4-(methylphenyl)(4-piperidinyl)methanone (10.5 g, 0.052 mol), 2-bromoethyl benzene (11.1 g, 0.06 mol, 8.2 ml) in dry DMF 125 ml was stirred at 100° C. for 23 h. The cooled reaction mixture was poured into H2O (600 ml) and extracted with toluene (4×200 ml). The extracts were washed with H2O (2×100 ml) saturated aqueous NaCl (100 ml) and dried over MgSO4. The mixture was filtered and the filtrate concentrated to a solid residue which was dissolved in dry Et2O and filtered. The filtrate was treated with a solution of HCl (0.052 mol) in CH3OH/EtOAc (9:20, 29 ml . The mixture was cooled and filtered to give a light tan powder. The solid was recrystalized twice from EtOH/Et2O to give (4-methylphenyl)[1-(2-phenylethyl)-4-piperidinyl]-methanone hydrochloride, which contains 0.4 mol of water of hydration and melts at 261°-263° C.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][CH:11]([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:12][CH2:13][N:14](CC1C=CC=CC=1)[CH3:15])C1C=CC=CC=1.Cl>CO.[Pd]>[CH3:1][NH:8][CH2:9][CH2:10][CH:11]([N:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1)[CH2:12][CH2:13][NH:14][CH3:15]
Reactant: CN(CCC(CCN(C)Cc1ccccc1)N1CCCC1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNCCC(CCNC)N1CCCC1
Temperature: 50 °C
Reaction time: 14 h
Yield: 77.8 %

Procedure:
To a solution of N,N′-dibenzyl-N,N′-dimethyl-3-(1-pyrrolidinyl)-1,5-pentanediamine (249.1 mg, 0.657 mmol) in methanol (3.0 mL) were added concentrated hydrochloric acid (0.33 mL, 4.0 mmol) and 10% palladium on charcoal (50.0 mg), and the mixture was stirred at 50° C. for 14 hours under hydrogen. Insoluble materials were removed by filtration through a membrane filter, and the filtrate was concentrated under reduced pressure. The residue was adsorbed on an alumina column, and eluted with methanol-chloroform (1:4). The eluate was concentrated under reduced pressure to afford the title compound as a colorless oil (101.9 mg, yield: 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:12]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH:9]([Br:12])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)c1cccc(Cl)c1
Reactant: BrBr
Product: CC(Br)C(=O)c1cccc(Cl)c1
Reaction time: 5.5 h

Procedure:
To 1 mole of m-chloropropiophenone heated to 60±5° C., bromine was added dropwise under stirring. The reaction temperature was kept at 60±5° C. during the addition of bromine, and kept for 5.5 hours after the addition. m-Chloro-α-bromopropiophenone (compound of formula (II)) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]2[NH:19][C:18](=[O:20])[C:17]3=[CH:21][N:22]=[CH:23][N:16]3[N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[I:29]I>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]2[NH:19][C:18](=[O:20])[C:17]3=[CH:21][N:22]=[C:23]([I:29])[N:16]3[N:15]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CC1c1nn2cncc2c(=O)[nH]1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CC1c1nn2c(I)ncc2c(=O)[nH]1
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of compound 5 (1.0 g, 3.24 mmol) in dry THF (70 mL) was added n-BuLi (2.5 M, 2 mL) dropwise at −78° C. over 30 minutes. The reaction was stirred at −45° C. for 30 minutes. Then a solution of iodine in THF (20 mL) was dropwise added at −78° C. over 10 minutes. The resulting mixture was stirred at 0° C. for 2 hours. The reaction was quenched with saturated aqueous Na2S2O3 solution (10 mL). Then the reaction mixture was diluted with EtOAc (200 mL), and washed with brine (50 mL×2). The separated organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluted by PE/EtOAc=10:1 to 2:1) to afford compound 6 (930 mg, 66% yield) as a white solid. LC-MS: m/z 435.99 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 7.89 (s, 1H), 7.37˜7.26 (m, 5H), 3.82 (d, J=12.4 Hz, 1H), 3.59 (d, J=12.4 Hz, 1H), 3.42˜3.38 (m, 1H), 2.98 (d, J=8.4 Hz, 1H), 2.82˜2.81 (m, 1H), 2.55˜2.51 (m, 1H), 2.45˜2.42 (m, 1H), 1.96˜1.92 (m, 1H), 1.22 (d, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:18][CH3:19])([C:14]([O:16]C)=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.O.O.[OH-].[Li+]>O1CCCC1.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:18][CH3:19])([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@]1(C(=O)OC)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC[C@]1(C(=O)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 30.8 %

Procedure:
To a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]-1-ethylcyclopent-2-ene-1-carboxylate (4.80 g, 17.8 mmol)) in a mixture of tetrahydrofuran (100 mL), methanol (100 mL) and water (20 mL) was added lithium hydroxide, monohydrate (1.2 g, 28.6 mmol) and the mixture was refluxed overnight. The organic solvents were evaporated. The aqueous layer was then acidified with 6N HCl to about pH 4 and extracted with methylene chloride three times. The combined extracts were dried, filtered, and concentrated to give a mixture of cis/trans isomers (2.93 g, cis/trans=7:1) as a light yellow solid. This solid was dissolved in EtOAc (4.0 mL) with heating and diluted with hexanes (100 mL) to give a clear solution. This solution was allowed to cool to room temperature slowly over 1 h and then maintained at −25° overnight. The cis-isomer was crystallized and dried to provide the desired product (1.40 g, 31%) as a white solid. MS calculated for C13H21NO4: (M+H) 256.2.2; found 156.1 (M+H-Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](O)=[O:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1.[NH2:30][CH2:31][CH2:32][OH:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([NH:30][CH2:31][CH2:32][OH:33])=[O:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2cccc(C(=O)O)c2)c2ccc(Cl)cc2F)ccc1=O
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2cccc(C(=O)NCCO)c2)c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 207, step 2, 3-(1-(4-chloro-2-fluorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)benzoic acid (example 320, step 4) was coupled with 2-aminoethanol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a colourless foam, MS (ESI+): m/z=457.3 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:20])([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[CH3:11])[C:6](=[O:21])[C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:28](O)(=[O:30])[CH3:29]>O>[C:28]([O:1][N:2]=[CH:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:11])([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[CH3:20])[C:6](=[O:21])[C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(c1cc(Cl)cc(Cl)c1)N1COC(C=NO)=C(c2ccccc2)C1=O
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)ON=CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cc(Cl)cc(Cl)c2)CO1
Yield: 94 %

Procedure:
A mixture of 6-hydroxyiminomethyl-3-[1-methyl-1-(3,5-dichlorophenyl)ethyl]-5-phenyl-2,3-dihydro-4H-1,3-oxazin-4-one (Compound No. 135, 0.60 g) and anhydrous acetic acid (2 ml) was stirred at room temperature for 4 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was rinsed with saturated saline solution, and dried with magnesium sulfate. The solvent was removed by evaporation, and the crude product was purified by silica gel chromatography to afford the captioned compound (0.54 g, yield 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[N:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:26](=[O:39])[CH:25]=[CH:24]4)=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:11])[F:10]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[C:26](=[O:39])[CH:25]=[CH:24]4)=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:11])[F:10]
Reactant: C[Si](C)(C)CCOCn1c(=O)ccc2cc(C=Cc3cnc(Nc4ccc(OC(F)F)c(Cl)c4)nc3)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(=O)ccc2cc(CCc3cnc(Nc4ccc(OC(F)F)c(Cl)c4)nc3)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.8 %

Procedure:
To 6-(2-(2-((3-chloro-4-(difluoromethoxy)phenyl)amino)pyrimidin-5-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one (0.1 g, 0.175 mmol) in ethyl acetate (10 mL) was added Pd/C (0.186 g, 1.751 mmol) and the reaction mixture was stirred at room temperature under an atmosphere of H2 gas for 12 hours. The reaction mass was filtered through celite and the filtrate was concentrated to give 6-(2-(2-(3-chloro-4-(difluoromethoxy)phenylamino)pyrimidin-5-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one (0.075 g, 74%). LCMS (ES-API), RT: 2.56 m/z 575.2 (M+H).
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[NH:21][N:20]=2)=[CH:14][C:10]=1[C:11]([OH:13])=O.Cl.[CH:31]1([O:36][CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CC(N(C)C)=O>[CH:31]1([O:36][CH:37]2[CH2:42][CH2:41][N:40]([C:11]([C:10]3[CH:14]=[C:15]([CH:16]=[CH:17][CH:9]=3)[CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22](=[O:29])[NH:21][N:20]=3)=[O:13])[CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCC(OC2CCNCC2)C1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1)N1CCC(OC2CCCC2)CC1
Temperature: 20 °C
Reaction time: 72 h
Yield: 39.2 %

Procedure:
Triethylamine (0.298 ml, 2.14 mmol) was added in one portion to 3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1b) (200 mg, 0.71 mmol), 4-(cyclopentyloxy)piperidine hydrochloride (121 mg, 0.71 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (352 mg, 0.93 mmol) in DMA (2 ml) at 20° C. under air. The resulting mixture was stirred at 20° C. for 3 days. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (120 mg, 39% yield); 1H NMR (400.132 MHz, DMSO) δ 1.22-1.86 (11H, m), 3.00-3.20 (2H, m), 3.25-3.43 (2H, m), 3.52-3.56 (1H, m), 3.91-4.05 (2H, m), 4.35 (2H, s), 7.20 (1H, d), 7.31 (1H, s), 7.34-7.40 (2H, m), 7.80-7.89 (2H, m), 7.96 (1H, d), 8.26 (1H, d), 12.57 (1H, s); m/z (LC-MS, ESI+), RT=2.18 (M+H 432.1)