Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH:30]1([CH2:36][NH2:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:37][CH2:36][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCC1CCCCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCC3CCCCC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with cyclohexanemethylamine (0.026 mL, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(cyclohexylmethylaminomethyl)indol-2-yl]isoindolinone.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:13]([CH:22]([CH3:24])[CH3:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])=[C:4]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:3]=1.[C:32](Cl)(=[O:37])[CH2:33][C:34](Cl)=[O:35]>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[N:9]([CH2:10][C:11]([N:13]([CH:22]([CH3:24])[CH3:23])[C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[O:12])[C:32](=[O:37])[CH2:33][C:34](=[O:35])[N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: COc1ccc(N(C(=O)CNc2cc(F)c(F)cc2Nc2ccccc2)C(C)C)cc1
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3cc(F)c(F)cc32)C(C)C)cc1
Reaction time: 16 h
Yield: 35.9 %

Procedure:
A solution of 5.62 g 2-(4,5-difluoro-2-phenylamino-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, (13.2 mmol) in 50 mL of tetrahydrofuran is transferred to an addition funnel. A solution of 1.60 mL of malonyl dichloride (16.53 mmol, 1.25 equiv) in 50 mL tetrahydrofuran is transferred to a separate addition funnel. Each solution of each reagent is simultaneously added dropwise over 20 min. to 250 mL of tetrahydrofuran at ambient temperature under nitrogen with vigorous agitation. After stirring 16 hrs. at ambient temperature, the reaction mixture is concentrated in vacuo. The residue is purified on flash grade silica gel using 40-50% ethyl acetate in hexane. The appropriate fractions were combined, evaporated in vacuo, dried under high vacuum for 2 hrs., and then triturated with hexane. The hexane is removed in vacuo and the residual solid is dried under high vacuum to provide 2.340 g of 2-(7,8-Difluoro-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as an off-white solid: 1H NMR (300 MHz, CDCl3) δ7.37 (m, 7H), 7.15 (m, 1H), 7.01 (m, 2H), 6.76 (dd, 1H, J=7.8, 11.1), 5.04 (m, 1H), 4.36 (d, 1H, J=16.3), 4.00 (d, 1H, J=16.5), 3.89 (s, 3H), 3.62 (d, 1H, J=12.2), 3.54 (d, 1H, J=12.2), 1.14 (m, 6H); low resolution MS (FAB)m/e 494 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 120 °C
Yield: 53.9 %

Procedure:
To a solution of N-tert-butyloxycarbonylpiperazine (5 g) in anhydrous dimethylformamide (75 ml) containing triethylamine (7.4 ml), was added 1-fluoro-4-nitrobenzene (3.81 g). The solution was heated at 120° C. for 5 h then the solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was separated and the aqueous phase washed with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×50 ml), dried (Na2SO4) and evaporated in vacuo. The residue was triturated with ether and the resultant yellow solid filtered off. The solid was then chromatographed on silica gel, using a gradient elution of 0→1% methanol in dichloromethane to afford the title compound (4.45 g) as a yellow solid. 1H NMR (360 MHz, CDCl3) δ 1.49 (9H, s), 3.40-3.43 (4H, m), 3.59-3.62 (4H, m), 6.82 (2H, dd, J=9 and 1.8 Hz), 8.13 (2H, dd, J=9 and 1.8 Hz). MS (CI, NH3) 307 (M+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([OH:31])[CH:12]([N:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[N+:42]([O-:44])=[O:43]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]([O:31][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[N+:42]([O-:44])=[O:43])[CH:12]([N:16]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(C(O)CCOCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C(C(CCOCc1ccccc1)Oc1ccc(F)cc1[N+](=O)[O-])N(Cc1ccccc1)Cc1ccccc1
Reaction time: 3 h

Procedure:
8.00 g (19 mmol) racemic (2S,3R and 2R,3S)-5-Benzyloxy-2-dibenzylamino-3-hydroxy-pentanoic acid in 25 ml dimethylformamide were added at 0° C. to a suspension of 1.83 g (42 mmol) sodium hydride (55%) in 25 ml dimethylformamide. The suspension was stirred for 3 hours and then 6.67 g (42 mmol) 2,5-difluoro-nitrobenzene in 10 ml dimethylformamide were added. After stirring overnight the mixture was poured under ice water and the pH was adjusted to 1. Extraction with ethylacetate and chromatography on silicagel with heptane/ethylacetate (2:1 to 1:1) yielded 9.1 g (85%) racemic (2S,3R and 2R,3S)-5-benzyloxy-2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-pentanoic acid as yellow oil, MS m/e (%): 559.3 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].[H-].[Na+].Cl[C:17]1[C:22]([Cl:23])=[CH:21][C:20]([O:24][CH:25]([F:27])[F:26])=[CH:19][N:18]=1.O>CN(C)C=O>[Cl:23][C:22]1[C:17]([N:6]2[C:2]([CH3:1])=[C:3]([C:7]([F:13])([F:12])[C:8]([F:10])([F:9])[F:11])[N:4]=[CH:5]2)=[N:18][CH:19]=[C:20]([O:24][CH:25]([F:27])[F:26])[CH:21]=1
Reactant: Cc1[nH]cnc1C(F)(F)C(F)(F)F
Reactant: FC(F)Oc1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(F)(F)C(F)(F)F)ncn1-c1ncc(OC(F)F)cc1Cl
Reaction time: 0.33 h

Procedure:
To a solution of 0.5 g (2.5 m mol) of 5-methyl-4-pentafluoroethylimidazole in 5 ml of N,N-dimethyl formamide is added slowly 100 mg (2.5 m mol) of an oily sodium hydride (60%) while cooling with ice, followed by stirring at the same temperature for 20 minutes. After the reaction is completed, to the reaction mixture is added dropwise 0.50 g (2.5 m mol) of 2,3-dichloro-5-difluoromethoxypyridine, followed by stirring at room temperature for 9 hours. After the reaction is completed, the reaction mixture is poured into water, and extracted with ethyl acetate. Further, then the residue is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained product is subjected to silica gel chromatography to give 1-(3-chloro-5-difluoromethoxypyridin-2-yl)-5-methyl-4-pentafluoroethylimidazole.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C:14]1([C@@H:20]([CH3:23])[CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>O>[C:14]1([C@@H:20]([CH3:23])[CH2:21][NH:22][C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](CN)c1ccccc1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: c1ccncc1
Solvent: O
Product: C[C@@H](CNC(=O)c1cnc2ccccc2n1)c1ccccc1
Yield: 76.4 %

Procedure:
Prepared from 2-quinoxaloyl chloride (0.47 g, 2.4 mmol), (R)-2-phenyl-1-propylamine (0.30 g, 2.2 mmol), pyridine (5 mL), and water (50 mL) yielding 0.49 g (76%) of (172):
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:34][CH3:35])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].C1C=C(Cl)C=C(C(OO)=[O:45])C=1>ClCCl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:34]([CH3:35])=[O:45])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2cc(C(=O)Nc3nccs3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide (262 mg, 0.50 mmol) in dichloromethane (10 mL) was added mCPBA (116 mg, 0.75 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Then the reaction mixture was applied to flash chromatography to afford the titled compound 256 mg (95%). LC-MS m/z 541 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20]C(C)(C)C)=[O:19])=[CH:16][CH:15]=3)=[CH:7][CH:8]=2)[NH:3]1.[Br:27]Br.[Br-].[K+]>C(O)(=O)C>[Br:27][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:12][CH2:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)[NH:3][C:2](=[O:1])[CH2:11][CH2:10]2
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)c1ccc(COc2ccc3c(c2)NC(=O)CC3)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1CCc2cc(Br)c(OCc3ccc(C(=O)O)cc3)cc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a suspension of tert-butyl 4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoate (550 mg, 1.56 mmol) in glacial acetic acid (5 mL) was added dropwise a solution of bromine (800 mg, 5.00 mmol) and potassium bromide (595 mg, 5.0 mmol) in acetic acid (10 mL) under an atmosphere of dry N2, and the mixture stirred at room temperature for 1 hour. The reaction mixture was warmed to 60° C. for 18 hours, then cooled, and the solvent evaporated under reduced pressure. The residue was poured slowly into water (40 mL) with stirring, diethyl ether (3 mL) was added, and the mixture sonicated, filtered, the solid thus obtained was washed with saturated sodium carbonate (30 mL), water (50 mL), diethyl ether (10 mL), and dried under reduced pressure to afford 4-((6-bromo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoic acid (334 mg, 0.89 mmol, 57%). LCMS mz 375.9 (M−H) and 377.9 (M+H), anal HPLC >91% in purity, 1H NMR (400 MHz; CD3CN) δ8.25 (bs, 1H); 8.09 (d, J=8.6 Hz, 2H); 7.65 (d, J=8.6 Hz, 2H); 7.42 (s, 1H); 6.62 (s, 1H); 5.26 (s, 2H); 2.91 (m, 2H); 2.53 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].I[CH3:17]>CN(C=O)C.C1CCN2C(=NCCC2)CC1>[CH3:17][O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:15]
Reactant: CI
Reactant: O=C(O)/C=C/C(=O)c1ccc(Cl)c(Cl)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)/C=C/C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
To an ice cooled solution of (E)-4-(3',4'-dichlorophenyl)-4-oxo-2-butenoic acid (2.4 g, 0.01 mol) in dry DMF (80 mL), DBU (1.5 mL, 0.01) was added dropwise on stirring, under nitrogen atmosphere. To the resulting stirred solution iodomethane (3.1 mL, 0.05 mol) dissolved in dry DMF (20 mL) was added dropwise over 20 min. The resulting solution was stirred at 0° C. for 1 hour and 3 hours at room temperature. The resulting reaction mixture was poured into ice-water on stirring, and the precipitate was filtered, washed with water and then with hexane. Recrystallization from diisopropyl ether/hexane provided the pure ester (2.2 g, 86%), pale yellow needles, mp. 108-109°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1)#[CH:2].[CH3:13][O:14][C:15](=[O:45])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:33]=[C:32]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:31]=[C:30](Br)[CH:29]=2)=[CH:20][C:19]=1[CH3:44]>CN(C=O)C.C(N(CC)CC)C.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.[Cu]I>[CH3:13][O:14][C:15](=[O:45])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:29]=[C:30]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][CH:4]=3)[CH:31]=[C:32]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:33]=2)=[CH:20][C:19]=1[CH3:44]
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCCCC3)c2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCCCC3)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of 1-ethynyl-4-trifluoromethyl-benzene (300 mg, 1.77 mmol), (4-{3-[3-bromo-5-(3-piperidin-1-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (100 mg, 0.2 mmol, example 3), Pd(PPh3)4 (22 mg, 0.02 mmol), CuI (10 mg, 0.055 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 50 min at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using ethyl acetate/methanol mixtures to give (2-methyl-4-{3-[3-(3-piperidin-1-yl-prop-1-ynyl)-5-(4-trifluoromethyl-phenylethynyl)-phenyl]-prop-2-ynyloxy}-phenoxy)-acetic acid methyl ester in 30 mg (26%) yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCBr
Reactant: Oc1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1ccccc1F
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of 2-fluorophenol (1) (15 g), 3-bromopropanoic acid (20 g) and NaOH (11 g) was refluxed in 50 mL of water. The solution was cooled to room temperature and acidified to pH 2 with 3 M HCl. The resulting precipitate was isolated by filtration to yield 9.27 g of title compound as a white solid. The filtrate was extracted three times with EtOAc to yield 2.5 g of less pure compound (2).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C(N(CC)CC)C.[Br:15][CH2:16][C:17](Cl)=[O:18]>C(OCC)C>[Br:15][CH2:16][C:17]([N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[O:18]
Reactant: O=C(Cl)CBr
Reactant: CCCNCCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a mixture of dipropylamine (10.1 g), triethylamine (10.1 g) and anhydrous diethyl ether (80 ml) is added dropwise a solution of bromoacetyl chloride (15.8 g) in anhydrous diethyl ether (40 ml) while the temperature of the mixture is kept at -40° C. After addition, the temperature is gradually raised, and the mixture is stirred at room temperature for one hour. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure, and purified by distillation under reduced pressure to give the desired compound (14 g), b.p. 100-103° C./1 mmHg.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([CH2:11][CH:10]3[CH2:12][CH2:13][CH:7]2[CH2:8][CH2:9]3)[CH2:2]1.C([O-])(=O)C.[Na+].[Cl:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>CC(C)=O.O>[Cl:19][CH2:20][CH2:21][C:22]([N:1]1[CH2:6][CH2:5][CH2:4][C:3]2([CH2:11][CH:10]3[CH2:12][CH2:13][CH:7]2[CH2:8][CH2:9]3)[CH2:2]1)=[O:23]
Reactant: O=C(Cl)CCCl
Reactant: C1CNCC2(C1)CC1CCC2CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(CCCl)N1CCCC2(CC3CCC2CC3)C1

Procedure:
An amount of 2.0 g (0.0112 mole) of spiro[bicyclo [2.2.2]octane-2,3'-piperidine] is added, with ice cooling and with stirring, to a suspension of 2.4 g of sodium acetate in 30 ml of acetone and 10 ml of water; there is then added dropwise to the formed mixture at 0°-5° 1.8 g (0.014 mole) of 3-chloropropionyl chloride. An addition is subsequently made to the mixture, at 0°-5°, of 70 ml of water, whereupon the reaction product precipitates in liquid form. The mixture is extracted three times with 50 ml of methylene chloride each time. The methylene chloride extracts are washed separately in each case once with saturated sodium bicarbonate solution and twice with water; they are then dried over sodium sulphate and afterwards concentrated in vacuo (ca. 12 Torr) to obtain 1'-(3-chloropropionyl)-spiro[bicyclo[2.2.2]octane-2,3'-piperidine].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[N+:18]([O-])=O)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][C:9]=2[NH2:18])[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc(C(F)(F)F)cc2N)CC1

Procedure:
To 1-Methyl-4-(2-nitro-4-trifluoromethyl-phenyl)-piperazine (1.46 g, 5.05 mmol) in dry MeOH (50 mL) was added Pd/C (10%, 535 mg). H2 gas was bubbled through the solution at room temperature overnight with vigorous stirring. The reaction mixture was filtered through celite to provide, after concentration, the desired product as a white solid. MS (M+H)+=260; Calc'd 259.28 for C12H16F3N3.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25]1([CH:28]=O)[CH2:27][CH2:26]1>CN(C)C(=O)C>[CH:25]1([CH:28]=[N:1][N:2]2[C:7](=[O:8])[C:6]([C:9]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[S:11](=[O:20])(=[O:19])[N:10]=3)=[C:5]([OH:21])[C:4]3[S:22][CH:23]=[CH:24][C:3]2=3)[CH2:27][CH2:26]1
Reactant: O=CC1CC1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=CC1CC1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
The product of Example 268D (0.15 g, 0.41 mmol) was reacted with cyclopropanecarbaldehyde (1.0 g, 14 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 120° C. for 90 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.104 g, 60%).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:20])#[N:2].[Li+:21].[OH-].Cl>C1COCC1.O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([O-:16])=[O:15])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:20])#[N:2].[Li+:21]
Reactant: COC(=O)Cc1cncn1Cc1ccc(C#N)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(Cn2cncc2CC(=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 1-(4-cyano-3-fluoro-benzyl)imidazol-5-ylacetate from Step C (260 mg, 0.95 mmol) in THF (5 mL) and water (1 mL) was added LiOH (40 mg, 0.95 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, then the solution was adjusted to pH 7 with 1 N aq. HCl and concentrated to dryness in vacuo to provide the titled product as a white solid which was sufficiently pure for use in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:33][CH2:20][C:13]1[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2nncs2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(F)cc1Cl
Yield: 50 %

Procedure:
Ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.76 g, 2 mmol) was reacted with NBS (0.36 g, 2 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.46 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[O:37](C1C=CC(C(=O)C)=CC=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][C:3]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:2][CH:7]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(Oc5ccccc5)cc4)ccc3c1)n2C1CCCCC1
Yield: 31 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(4-phenoxy-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in Ethanol (506 μL, 0.64 mmol) to produce the title compound (42 mg, 31% yield).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([NH2:21])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30](O)=[O:31])[CH2:25][CH2:24]1>>[C@@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:21][C:30](=[O:31])[CH2:29][N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: CN1CCN(CC(=O)O)CC1
Product: CN1CCN(CC(=O)Nc2cccc3nc(N[C@H]4CCc5ccccc54)ccc23)CC1

Procedure:
The title compound, light yellow oil, MS: m/e=416.4 (M+H+), was prepared in accordance with the general method of example 32 from (R)—N2-indan-1-yl-quinoline-2,5-diamine (example 16) and commercially available (4-methyl-piperazin-1-yl)-acetic acid.