Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.[CH2:10]([OH:15])[C:11]#[C:12][CH2:13][CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:15][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[N:5]=[CH:4][N:3]=1
Reactant: Fc1ncnc(F)c1F
Reactant: CCC#CCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC#CCOc1ncnc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
0.5 g of 4,5,6-trifluoropyrimidine, 0.38 g of 2-pentyn-1-ol and 0.62 ml of triethylamine were added to 1 ml of toluene, then the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.53 g of 4,5-difluoro-6-(2-pentynyloxy)pyrimidine.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(OCC)C.[OH-].[Na+].[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>O>[OH:4][N:3]([CH3:2])[C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][CH3:12])=[CH:15][CH:16]=1)=[O:22]
Reactant: CNO
Reactant: CSc1ccc(N=C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CSc1ccc(NC(=O)N(C)O)cc1
Yield: 59.8 %

Procedure:
N-Methylhydroxylamine hydrochloride (1.1 g, 13 mmol) was dissolved in water (2 mL) then combined with diethyl ether (15 mL). The mixture was cooled in an ice bath then combined with a solution of sodium hydroxide (0.53 g, 13 mmol) in water (2 mL). The reaction mixture was allowed to stir for several minutes then 4-(methylthio)phenyl isocyanate (2.1 g, 13 mmol) was added dropwise via Pasteur pipette. A heavy white precipitate formed almost immediately. Diethyl ether (20 mL) was added and the reaction mixture was allowed to stir at ambient temperature overnight. The solid was isolated by filtration then recrystallized from 1,2-dichloroethane to afford 1.65 g of the desired product as a white crystalline solid, m.p. 146°-148° C. Analysis: Calculated for C9H12N2O2S: %C, 50.93; %H, 5.70; %N, 13.20; Found: %C, 50.82; %H, 5.63; %N, 13.11.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[CH2:9]([NH2:13])[CH2:10][CH2:11][CH3:12]>CN1CCCC1=O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:13][CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=1
Reactant: CCCCN
Reactant: Fc1cc(Br)ccn1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCCCNc1cc(Br)ccn1
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A solution of 4-bromo-2-fluoropyridine (2.0 g, 11.3 mmol) and n-butan-1-amine (752 mg, 10.3 mmol) in N-methyl-2-pyrrolidinone (NMP, 10 mL) was stirred at 100° C. for 1 hr. The reaction was allowed to cool to room temperature and diluted with DCM (50 mL), washed with water (10 mL*2). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (0-20% EtOAc-petroleum ether gradient elution) to afford the desired product (1.4 g, 45%). 1H NMR (300 MHz, CDCl3): 7.88 (d, J=5.4 Hz, 1H), 6.70 (d, J=5.4 Hz, 1H), 6.54 (s, 1H), 4.60 (br s, 1H), 3.26-3.19 (m, 2H), 1.63-1.56 (m, 2H), 1.46-1.39 (m, 2H), 0.96 (t, J=7.2 Hz, 3H). (R)-tert-butyl 1-(2-(butylamino)pyridin-4-yl)pyrrolidin-3-ylcarbamate. To a solution of 4-bromo-N-butylpyridin-2-amine (458 mg, 2 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (410 mg, 2.2 mmol) in anhydrous dioxane (12 mL) was added Pd2(dba)3 (200 mg, 0.22 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xant-phos) (200 mg, 0.24 mmol) and t-BuONa (576 mg, 6 mmol) under atmosphere of argen. The resulting reaction was stirred at 100° C. for 2 hrs and diluted with water (40 mL), extracted with DCM, The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (0-10% MeOH-DCM gradient elution) to afford the crude product (purity>70%). (R)-4-(3-aminopyrrolidin-1-yl)-N-butylpyridin-2-amine dihydrochloride. Crude product obtained above was dissolved in MeOH (6 mL) and ether solution of HCl gas (ca. 4N, 10 mL) was added. The resulting reaction was stirred at ambient temperature for 20 hrs. The reaction was concentrated under reduced pressure and purified by prep-HPLC to afford the desired product (50 mg, 6.7% yield in two steps). 1H NMR (300 MHz, CD3OD): 7.59 (d, J=7.5 Hz, 1H), 6.39 (d, J=6.9 Hz, 1H), 5.79 (s, 1H), 4.89 (m, 1H), 4.15 (m, 1H), 3.74-3.66 (m, 3H), 3.38-3.29 (m, 2H), 2.60-2.53 (m, 1H), 2.34-2.30 (m, 1H), 1.73-1.64 (m, 2H), 1.56-1.46 (m, 2H), 1.02 (t, J=7.5 Hz, 3H); LC-MS: m/z=235.2 [M+H]+, tR=0.92 min; HPLC: 100% (214 nm), 97% (254 nm), tR=4.84 min. The compounds in Example 255 through Example 297 were prepared using methods analogous to those described in Example 254.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:19]I>FC(F)(F)C([O-])=O.[Ag+].C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]([O:17][CH3:18])=[CH:11][C:12]([CH:13]=[O:14])=[C:15]([I:19])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C=O)c(I)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a mixture of 4-benzyloxy-3-methoxybenzaldehyde (10 g), silver trifluoroacetate (11.4 g) and methylene chloride (105 mL) was added iodine (13.1 g) at room temperature. After stirring for 2 hours, the mixture was passed through a layer of Celite (registered mark). The filtrate was washed with an aqueous solution of sodium hydrogen sulfite and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with methanol:water=4:1 to give the title compound (13.2 g).
Reaction SMILES: [I:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:18][C:19]([C:21]1[S:25][CH:24]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[I:1][C:2]1[C:3]([O:16][CH2:18][C:19]([C:21]2[S:25][CH:24]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[CH:22]=2)=[O:20])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CC1(C)CCC(C)(C)c2cc(I)c(O)cc21
Reactant: COC(=O)c1csc(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1csc(C(=O)COc2cc3c(cc2I)C(C)(C)CCC3(C)C)c1

Procedure:
A solution of 3-iodo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ol (4 g, 12.1 mmol), methyl 5-bromoacetyl-3-thiophenecarboxylate (3.18 g, 12.1 mmol) and potassium carbonate (1.84 g, 13.3 mmol) in methyl ethyl ketone (100 ml), was heated under reflux for 4 h. The reaction medium was filtered and then concentrated in a rotary evaporator. The mixture was extracted with ethyl ether. The organic phase was washed with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[S:28][CH2:29][CH2:30]O)([CH3:21])[CH3:20])[C:13]3=[O:32])[C:9]([CH3:33])=[C:8]([F:34])[CH:7]=2)[CH2:3][CH2:2]1.[CH2:36]([N:38](CC)CC)C.CS(Cl)(=O)=O.CN>C(Cl)Cl.C(O)C>[CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH3:20])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[S:28][CH2:29][CH2:30][NH:38][CH3:36])[CH3:21])[C:13]3=[O:32])[C:9]([CH3:33])=[C:8]([F:34])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2SCCO)c1=O
Reactant: CCN(CC)CC
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCO
Product: CNCCSc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)cc(F)c2C)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Cyclopropyl-3-fluoro-5-{3-[(1-{2-[(2-hydroxyethyl)sulfanyl]phenyl}-1-methylethyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide (Example 320g, 0.15 g) was stirred in DCM (20 mL) and cooled to −40° C. before triethylamine (0.046 mL) and methanesulfonyl chloride (0.024 mL) were added. The reaction was warmed to room temperature and methylamine (40% in water) and ethanol (5 mL) were added. The reaction was then stirred for 18 h at 100° C. The reaction was concentrated in vacuo, then purified on SCX resin eluting with methanol (discarded) and flushing with 20% ammonia in methanol. The crude product was purified by preparative HPLC (Phenomenex Gemini column, eluent: 95-5% gradient of aqueous 0.2% aqueous ammonia in acetonitrile). The fractions containing the desired compound were evaporated to dryness to afford the title compound as a solid (3 mg).
Reaction SMILES: [N:1]1([C:6]2[CH:39]=[CH:38][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH:40]1[CH2:43][CH2:42][CH2:41]1>CN(C=O)C>[N:40]1([C:12]2[C:11]([CH2:10][C:9]3[CH:38]=[CH:39][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)=[C:20]([Cl:21])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]([C:30]4[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=4)([C:24]4[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=4)[OH:23])[CH:18]=3)[N:13]=2)[CH2:43][CH2:42][CH2:41]1
Reactant: C1CNC1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(N3CCC3)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Temperature: 100 °C

Procedure:
(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol (200 mg, 0.348 mmol, Intermediate 64), azetidine (199 mg, 3.48 mmol), and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature for 24 hours. The vessel was then cooled to room temperature and the solvent was removed by reduced pressure distillation. The residue was taken up into EtOAc, transferred to a separatory funnel and extracted twice with a saturated, aqueous NH4Cl solution. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to provide the title compound. MS (ESI): mass calcd. for C33H28Cl2N6O, 594.2. m/z found, 595.3 [M+H]+. 1H NMR (600 MHz, CDCl3) δ ppm 8.03 (d, J=2.1 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.70-7.67 (m, 2H), 7.61-7.56 (m, 2H), 7.45 (dd, J=8.8, 2.2 Hz, 1H), 7.32-7.27 (m, 4H), 7.24 (d, J=1.1 Hz, 1H), 7.20-7.14 (m, 2H), 6.43 (t, J=2.1 Hz, 1H), 6.33 (d, J=1.2 Hz, 1H), 4.30 (s, 2H), 4.14 (t, J=7.6 Hz, 4H), 3.35 (s, 3H), 2.27-2.17 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C[Al](C)C.O.O1CCO[CH2:34][CH2:33]1>CCCCCC.[Cu]Br>[C:1]([O:4][CH:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][C@@H:13]([CH2:33][CH3:34])[C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C1COCCO1
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=O)=CC[C@@H]32)C1
Agent: [Cu]Br
Agent: C[Al](C)C
Solvent: O
Solvent: CCCCCC
Product: CC[C@@H]1C[C@H]2[C@@H]3CC=C4CC(OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1C(C)=O
Temperature: 22 °C
Reaction time: 3 h

Procedure:
3.56 g (10 mmol) of 3-acetoxy-pregna-5,16-dien-20-one is dissolved in 20 ml of dioxane at 20° C. and mixed with 143.3 g (1 mmol) of copper(I) bromide. 11 ml (11 mmol) of a 1 molar solution of trimethyl aluminum in hexane is added to the reaction at room temperature under nitrogen atmosphere and, after completion of the addition, stirred for 3 hours more at 22° C. For hydrolysis of the reaction solution, 1 ml of water dissolved in 5 ml of dioxane is carefully added to the reaction. It is stirred for 10 minutes more and the inorganic precipitate is filtered off with dioxane and washed again. The dioxane solution is concentrated by evaporation on a rotary evaporator and the residue is chromatographed on silica gel with ethyl acetate/hexane as eluent. After concentration by evaporation of the fractions, 1.72 g of 3-acetoxy-16α-ethyl-pregn-5-en-20-one (45% of theory) of a melting point of 114.9° C. is obtained.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[IH:16].CS[C:19]1[C:27]2[CH:28]=[CH:29][CH:30]=[C:25]3[C:26]=2[C:21](=[CH:22][CH:23]=[CH:24]3)[N:20]=1.C([O-])(=O)C.[Na+]>C(O)C>[IH:16].[C:1]1([C:7]2[N:8]([CH2:12][CH2:13][CH2:14][NH:15][C:19]3[C:27]4[CH:28]=[CH:29][CH:30]=[C:25]5[C:26]=4[C:21](=[CH:22][CH:23]=[CH:24]5)[N:20]=3)[CH:9]=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSC1=Nc2cccc3cccc1c23
Reactant: NCCCn1ccnc1-c1ccccc1
Agent: CC(=O)[O-]
Agent: I
Agent: [Na+]
Solvent: CCO
Product: c1ccc(-c2nccn2CCCNC2=Nc3cccc4cccc2c34)cc1

Procedure:
A mixture of 4.0 g of 3-(2-phenyl-1H-imidazol-1-yl)propanamine, 6.5 g of 2-(methylthio)benz[cd]indole hydroiodide, 1.8 g of sodium acetate and 250 ml of ethanol was reacted as described in Example 11. The crude product was recrystallized from a mixture of ethanol and isopropanol giving 3.8 g of the desired product, mp 153° C.-155° C.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[Cl:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1B1OC(C)(C)C(C)(C)O1>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[C:22]([C:29]4[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=4[Cl:27])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Reactant: CC1(C)OB(c2ccc(F)cc2Cl)OC1(C)C
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccccc3-c3ccc(F)cc3Cl)cc2s1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.20 g, 0.42 mmol) and 2-(2-chloro-4-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.18 g, 0.71 mmol) to afford 0.072 g (35%). LC/MS, Retention time 4.98 min; (m/z): calcd for C25H24ClFN4OS: 483.0; found: 483.0.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[NH2:13][C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[CH:17]=[CH:16][CH:15]=1>CO.C(O)(=O)C>[C:14]1([N:13]=[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:13][C:14]3[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[CH:17]=[CH:16][CH:15]=3)[CH3:11])[N:5]=2)[CH3:2])[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Nc1cccc2c1CCCC2
Solvent: CC(=O)O
Solvent: CO
Product: CC(=Nc1cccc2c1CCCC2)c1cccc(C(C)=Nc2cccc3c2CCCC3)n1
Reaction time: 48 h
Yield: 29.6 %

Procedure:
Chemicals 2,6-Diacetylpyridine (1.0 g, 6.1 mmol) and 1-amino-5,6,7,8-tetrahydronaphthalene (3.6 g, 24.5 mmol) were dissolved in a round-bottom flask, to which 50 ml of anhydrous methanol were added. Three drops of glacial acetic acid were added, and the flask was sealed. After stirring the solution for two days, a yellow solid was collected and re-crystallized from methanol to give 760 mg (30%) of the desired ligand for catalyst 3. H NMR (C6D6) δ 8.48 (d, 2), 7.30 (t, 1), 7.10 (m, 2), 6.85 (d, 2), 6.56 (d, 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][O:11][C:13]2[CH:23]=[C:17]3[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]3[C:15](=[O:24])[N:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCCc1ccc(Cl)c(Cl)c1
Product: CN1CCCn2c1cc(OCCc1ccc(Cl)c(Cl)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from 2-(3,4-dichlorophenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C>>[C:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Yield: 81.5 %

Procedure:
Prepared according to Method E from 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol), pivaloyl chloride (0.148 mL, 1.2 mmol) and N,N-diisopropylethyl-amine (0.21 mL, 1.2 mmol) to give 0.31 g of the title compound as a white solid, mp 105° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[CH:40]([CH3:42])[CH3:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:40]([CH3:42])[CH3:41])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: CC(C)I
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(F)cc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(F)cc3)c(OC(C)C)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of [8-chloro-3-(4-fluorobenzyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.020 g), N,N-dimethylformamide (1.0 mL), potassium carbonate (0.020 g) and 2-iodopropane (0.050 g) was stirred at room temperature for 2 days. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:9 by volume) to afford title compound as a light brown oil, 0.024 g.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[N:17]=[N:18][C:19]([C:23]([CH3:29])([CH3:28])[C:24]([O:26]C)=O)=[C:20](O)[N:21]=3)=[N:14][N:13]([CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[C:10]2=[N:11][CH:12]=1.[NH3:39]>C(#N)C>[F:6][C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[N:17]=[N:18][C:19]4[C:23]([CH3:29])([CH3:28])[C:24](=[O:26])[NH:39][C:20]=4[N:21]=3)=[N:14][N:13]([CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:34])([F:36])[F:35])[C:10]2=[N:11][CH:12]=1
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(CCC(F)(F)C(F)(F)F)c3ncc(F)cc23)nc1O
Reactant: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncc(F)cc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.172 ml of phosphoryl chloride were added to 290 mg (0.606 mmol) of the compound from Example 17A, and the mixture was stirred at RT overnight. The reaction mixture was dissolved in 40 ml of acetonitrile and, with ice-cooling, stirred into 27 ml of concentrated aqueous ammonia solution (33% strength). The mixture was stirred at room temperature for 2 days. The mixture was then concentrated. The residue was taken up in water and ethanol and treated in an ultrasonic bath. A precipitate was formed, which was filtered off with suction and washed with water, ethanol and then with diethyl ether. DMF was added to this residue, acetonitrile and water were added and the mixture was then once more filtered off with suction. The precipitate was washed with acetonitrile and water and then dried under high vacuum. This gave 149 mg of the title compound (52% of theory, purity 94%).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][NH2:39])[NH:13]2)=[O:11])[CH2:4][O:3]1.C(N(CC)CC)C.[C:50](Cl)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.Cl>O1CCCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][NH:9][C:10]([CH:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][NH:39][C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[NH:13]1)=[O:11]
Reactant: CC(C)(CCN)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(CCNC(=O)c1ccccc1)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F

Procedure:
In a manner similar to the method described in Examples 122a and 122b, rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide (80 mg, 0.13 mmol) prepared in Example 121a was reacted with triethylamine and benzoyl chloride (22 mg, 0.16 mmol) in tetrahydrofuran, followed by the reaction with aqueous HCl solution in tetrahydrofuran to give rac-(2R,3S,4R,5S)-5-(4-benzoylamino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (57 mg, 90%)
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].Cl[C:8]([O:10][CH2:11][CH:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9].O>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>[C:8]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])([O:10][CH2:11][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[C:24]1=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:9]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Yield: 90.1 %

Procedure:
To a solution of L-alanine (1.78g, 20 mmol) in 10% Na2CO3 (53 ml) was added dropwise (within 50 min) with stirring and ice bath cooling a solution of 9-fluorenylmethyl chloroformate (5.17g, 20 mmol) in dioxane (40 ml). The mixture was stirred for 1 hr at 0° and 15 hr at 5°, poured into H2O (1.5 liters) and extracted with ether (2 x). The aqueous layer was cooled in an ice bath, acidified with concentrated HCl to pH 2-3 (white precipitate) and extracted with EtOAc (3 × 500 ml). The organic phase was washed with H2O, dried (MgSO4), filtered, and evaporated. Ether-petroleum ether was added to the residue which crystallized while being kept at 5°. The crude product (5.94g, 95.5%) was recrystallized from methanol-petroleum ether to yield colorless crystals of Fmoc-L-alanine (5.61g, 90.2%), mp 144.5°-145.5° ; [α]D25 = - 11.7° (c 1, CH3OH); tlc, Rf 0.8 (A), 0.3 (B); uv max (CH2Cl2) 267 nm (ε18,950), 290 (5,280), 301 (6,200).