Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][N:19]3[CH2:22][C:21]([F:24])([F:23])[CH2:20]3)=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.CC(O)(C#C)C.[CH3:31][C:32]1[O:36][N:35]=[C:34]([C@:37]([OH:41])([C:39]#[CH:40])[CH3:38])[N:33]=1>>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:40]#[C:39][C@:37]([C:34]4[N:33]=[C:32]([CH3:31])[O:36][N:35]=4)([OH:41])[CH3:38])[CH:10]=3)[C:6]([CH2:18][N:19]3[CH2:22][C:21]([F:24])([F:23])[CH2:20]3)=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Nc1nccc(-n2nc(CN3CC(F)(F)C3)c3ccc(Br)cc32)n1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Agent: C#CC(C)(C)O
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(CN4CC(F)(F)C4)nn(-c4ccnc(N)n4)c3c2)no1

Procedure:
The title compound was prepared by the procedure described in Example 10-c by substituting 4-{6-bromo-3-[(dimethylamino)methyl]-1H-indazol-1-yl}pyrimidin-2-amine with of 4-{6-bromo-3-[(3,3-difluoroazetidin-1-yl)methyl]indazol-1-yl}pyrimidin-2-amine and 2-methyl-but-3-yn-2-ol with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol: 1H NMR (500 MHz, CDCl3) delta 2.09 (3H, s), 2.67 (3H, s), 3.73 (4H, t, J=12.06 Hz), 4.12 (2H, s), 4.80-5.13 (1 H, m), 5.51 (2H, s), 7.28 (1H, d, J=5.67 Hz), 7.37 (1H, dd, J=8.28, 1.02 Hz), 7.79 (1H, d, J=8.20 Hz), 8.30 (1H, d, J=5.67 Hz), 8.86 (1H, s); LC-MS: m/z=+467.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=1)[CH3:2].[O:20]1CCN(CCOC2C=CC(C(=O)CCC)=CC=2)CC1>>[O:20]1[CH2:2][CH2:1][N:3]([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])=[CH:11][CH:12]=2)[CH2:18][CH2:19]1
Reactant: CCCC(N)c1ccc(OCCN(CC)CC)cc1
Reactant: CCCC(=O)c1ccc(OCCN2CCOCC2)cc1
Product: CCCC(N)c1ccc(OCCN2CCOCC2)cc1
Yield: 70 %

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 25 except that 1-(4-(2-morpholinoethoxy)phenyl)butan-1-one (24) was used instead of 1-(4-(2-(diethylamino)ethoxy)phenyl)butan-1-one (21). This produced crude 28 (390 mg, 70%) as a light yellow oil: MS (ES+) m/z 279.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[NH:8][C:9](=[O:12])[NH:10][CH:11]=1)=[O:5])[CH3:2].[CH3:20]I>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[NH:8][C:9](=[O:12])[N:10]([CH3:20])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C1=CNC(=O)NC1c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CN(C)C(=O)NC1c1ccc(F)cc1
Temperature: 25 °C

Procedure:
4-(4-Fluoro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (6 g, from Preparation 1), CsCO3 (7.5 g) was added to 50 mL of DMF, followed by CH3I (1.5 mL). The mixture was heated at 60° for 18 hours, then cooled to room temperature and poured into ice water. The resulting precipitate was recovered by filtration and air-dried to give 5.6 g of 4-(4-fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)[CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[CH:33](=[O:36])[CH2:34][CH3:35].[Cl-].[NH4+]>>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:14]=[C:15]([CH:33]([OH:36])[CH2:34][CH3:35])[CH:16]=[CH:17][CH:18]=2)[CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc(Br)c1
Reactant: CCC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: CCC(O)c1cccc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: -30 °C
Yield: 57.4 %

Procedure:
Compound 78 (2.00 g; 5.78 mmol) was dissolved in tetrahydrofran (20 ml). While the solution was stirred at −30° C. under nitrogen atmosphere, n-butyl lithium in n-hexane (1.56 M: 3.70 ml; 5.77 mmol) was added dropwise, followed by stirring for 5 minutes. The mixture was cooled to −75° C., and propionaldehyde (1 ml) was slowly added dropwise thereto. The resultant mixture was brought to room temperature over 2 hours, and the reaction was stopped by dropwise addition of saturated aqueous ammonium chloride solution, followed by extraction with diethyl ether (100 ml). The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 1.08 g of the target compound as yellow oily matter (yield: 57.4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].[O:10]=[C:11]1[C:16](=[O:17])[N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][N:12]1[C:20]([NH:22][CH:23](O)[C:24]([OH:26])=[O:25])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O.O>[OH:9][C:4]1[C:5]([OH:6])=[CH:7][C:8]([CH:23]([C:24]([OH:26])=[O:25])[NH:22][C:20]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[C:16](=[O:17])[C:11]2=[O:10])=[O:21])=[C:2]([F:1])[CH:3]=1
Reactant: CCN1CCN(C(=O)NC(O)C(=O)O)C(=O)C1=O
Reactant: Oc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN1CCN(C(=O)NC(C(=O)O)c2cc(O)c(O)cc2F)C(=O)C1=O
Reaction time: 8 h

Procedure:
4-Fluorocatechol (3.06 g., 24 mmole) was added to a suspension of N-(2,3-dioxo-4-ethylpiperazin-1-ylcarbonyl)-2-hydroxyglycine (3.89 g, 15 mmole) in glacial acetic acid (13.5 ml) and concentrated sulphuric acid (1.5 ml). The mixture was stirred overnight, diluted with water (50 ml), adjusted to pH6 with saturated sodium carbonate and washed with ethyl acetate (2×50 ml). The aqueous solution was acidified to pH 2.5 and extracted with ethyl acetate (5×40 ml). The combined extracts were dried and evaporated to give the crude product, 6.10 g, as a foam.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[CH3:10]>>[CH:15]1[CH:16]=[CH:17][C:12](/[CH:9]=[CH:10]/[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:13][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccccc1
Product: O=C(/C=C/c1ccccc1)c1ccccc1

Procedure:
The compound was not synthesised according to the procedure of Example 1. Instead, an aldol condensation of equimolar amounts of benzaldehyde and acetophenone were first of all carried out to give 1,3-diphenylpropenone:
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]3[C:13]4[N:14]([CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:16][C:17]=3[C:18]([OH:20])=O)=[C:7]([F:24])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:55]([O:57][CH2:58][CH2:59][O:60][NH2:61])=[CH2:56]>C1COCC1>[CH:55]([O:57][CH2:58][CH2:59][O:60][NH:61][C:18]([C:17]1[CH:16]=[CH:15][N:14]2[CH:21]=[N:22][CH:23]=[C:13]2[C:12]=1[NH:11][C:8]1[CH:9]=[CH:10][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:6][C:7]=1[F:24])=[O:20])=[CH2:56]
Reactant: C=COCCON
Reactant: O=C(O)c1ccn2cncc2c1Nc1ccc(C2CCC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(C2CCC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
A suspension of 8-(4-cyclobutyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (154 mg, 0.46 mmol), EDCI (105 mg, 0.55 mmol), HOBt (74 mg, 0.55 mmol), DIPEA (0.19 mL, 1.14 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (52 mg, 0.50 mmol) in THF (2.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM (20 mL) and saturated aqueous NaHCO3. The organic layer was isolated then washed with water (20 mL), followed by brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The resultant gum was subjected to flash chromatography (Si-PPC, gradient 0% to 100%, ethyl actetate in cyclohexane) to afford the title compound as a brown gum (149 mg, 80%). LCMS (method B): RT=3.49 min, [M+H]+=411.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:16][CH2:17][OH:18])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:21][CH2:20][CH2:19][N:14]([CH2:15][CH2:16][CH2:17][OH:18])[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: OCCCN(CCO)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: OCCCN(CCO)C1CCNCC1
Reaction time: 15 h

Procedure:
13.3 g of 1-benzyl-4-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-piperidine are combined with 1.5 g of 10% palladium-charcoal in 150 ml of methanol and hydrogenated at ambient temperature for 18 hours under 5 bars of hydrogen. The catalyst is renewed after 8 hours and 15 hours. Then the catalyst is filtered off and the filtrate is freed from solvent in vacuo. 4-[(2-Hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-piperidine are obtained as an oil, which is used for the next reaction without any further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([O-:11])=[O:10])[CH:8]=1)#[N:2].[Na+].Br[CH2:35][CH:36]1[CH2:39][CH2:38][CH2:37]1>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([CH2:35][CH:36]2[CH2:39][CH2:38][CH2:37]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: BrCC1CCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)CC2CCC2)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
The reaction was carried out under argon. Sodium 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate (150 mg, 101 μmol; purity 32%) was suspended in DMF (1 ml). 1-(Bromomethyl)cyclobutane (164.1 mg) was then added, and the mixture was heated in a closed tube at 110° C. for 72 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a solid (40.2 mg, 75% of theory).
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.C[Si]([C:23]#[C:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:28]=[CH:29][CH:30]=1)(C)C.ClCCl.O>O1CCCC1>[C:24]([C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:28]=[CH:29][CH:30]=1)#[CH:23]
Reactant: C[Si](C)(C)C#Cc1cccc(-c2ccccn2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: C#Cc1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
Tetra-n-butylammonium hydroxide (22 cm3, 1 M in methanol) was added to a solution of (16) (1.87 g, 7.4 mmol) in tetrahydrofuran (20 cm3), and the solution was stirred at room temperature for 1 hour. Dichloromethane (20 cm3) and water (50 cm3) were added, and the layers were separated. The aqueous layer was extracted with dichloromethane (3×10 cm3). The combined organic extracts were washed with brine (50 cm3) and dried over magnesium sulfate, and the solvent was removed to leave an orange oil. The crude product was passed through a silica plug using dichloromethane: light petroleum (1:1) as eluent, and the solvent was completely removed to give (17) as a colourless oil (1.31 g, 99%).
Reaction SMILES: S[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.N1C(=O)C2NN=NC=2N=C1N.FC1N=C2C(NC=N2)=C(N)N=1>>[N:10]1[CH:2]=[C:3]2[C:7]([N:6]=[CH:5][NH:4]2)=[N:8][CH:9]=1
Reactant: Sc1ncnc2nc[nH]c12
Agent: Nc1nc(F)nc2nc[nH]c12
Agent: Nc1nc2nn[nH]c2c(=O)[nH]1
Product: c1ncc2[nH]cnc2n1

Procedure:
6-mercaptopurine, 8-azaguanine, 2-fluoroadenine
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([C:11]#[N:12])[CH:10]=[C:5]2[CH:4]=1.CO>C1COCC1>[F:15][C:2]([F:1])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1
Reactant: N#Cc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: C1CCOC1
Solvent: CO
Product: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (Intermediate 4, 1.48 g, 7.01 mmol) was dissolved in THF (59 mL), cooled in an ice bath and treated with a 1M solution of borane tetrahydrofuran complex (35.0 mL, 35.0 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. Methanol (59 mL) was added dropwise and the reaction mixture was stirred for 20 minutes at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in methanol (177 mL) and heated under reflux for 4 hours. The reaction mixture was allowed to cool to room temperature and passed down an SCX column (20 g) eluting with methanol, followed by 2M ammonia/methanol. Basic fractions were combined and evaporated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% 2M ammonia/methanol and DCM. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow solid (1.1 g);
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([O:10][C:24](=[O:27])[CH:25]=[CH2:26])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH3:2]
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Reactant: C=CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1CC(C)(CC)N(OC(C)c2ccccc2)C(C)(CC)C1C
Yield: 870.1 %

Procedure:
In analogy to example 1 were reacted 6,36 g (2 mmol) of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-ol with 1,81 g (2 mmol) of acryloyl chloride and 2,02 g (2 mmol) of triethylamine in toluene to give 6,5 g (87%) acrylic acid 2,6-di-ethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-yl ester as yellowish liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[C:10]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[C:10]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1NC(=O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2cccc(Cl)c2)ccc1C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-(3-chlorophenyl)-2-(4-fluorobenzamido)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 59 mg of 4-(3-chlorophenyl)-2-(4-fluorobenzamido)benzoic acid as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[N:11]([C:18](N2C=CN=C2)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[N:26]1([CH2:31][CH2:32][OH:33])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(O)(C(F)(F)F)=O.ClCCl>C1COCC1>[N:26]1([CH2:31][CH2:32][O:33][C:18]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)/[C:9](=[CH:8]/[C:3]3[NH:4][C:5]([CH3:7])=[CH:6][C:2]=3[CH3:1])/[C:10]2=[O:25])=[O:19])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Reactant: OCCN1CCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCCN3CCCC3)c3ccccc32)[nH]1
Yield: 14.8 %

Procedure:
A reaction mixture containing 3-[1-(3,5-dimethyl-1h-pyrrol-2-yl)-meth-(z)-ylidene]-1-(imidazol-1-ylcarbonyl)-1,3-dihydro-indole-2-one (166 mg, 0.5 mmol), 2-pyrrolidin-1-yl-ethanol (115 mg, 1.0 mmol), and TFA (0.13 mL, 1.5 mmol) in 2 mL of THF, and 2 mL of dichloromethane gave 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-pyrrolidin-1-yl-ethyl ester (28 mg, 15%) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ 12.56 (s, br, 1H, N-1′), 7.80–7.86 (m, 2H), 7.64 (s, 1H, H-vinyl), 7.16–7.20 (m, 2H), 6.10 (s, 1H, H-4′), 4.46 (t, J=5.47 Hz, 2H, CH2), 2.83 (m, br, 2H, CH2), 2.56 (m, br, 4H, CH2×2), 2.36 (s, 3H, CH3), 2.33 (s, 3H, CH3), and 1.69 (m, br, 4H, CH2×2).
Reaction SMILES: [CH:1]1([C:4]2[NH:26][C:7]3=[N:8][C:9]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:11]=[C:6]3[CH:5]=2)[CH2:3][CH2:2]1.N#N.[H-].[Na+].Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].Cl>CN(C=O)C.O>[CH:1]1([C:4]2[N:26]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:7]3=[N:8][C:9]([C:19]4[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=4)=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:11]=[C:6]3[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCCCCCBr
Reactant: Cc1ccc(-c2nc3cc(C4CC4)[nH]c3nc2-c2ccc(C)cc2)cc1
Agent: Cl
Agent: N#N
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCn1c(C2CC2)cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Cyclopropyl-2,3-di-p-p-tolyl-5H-pyrrolo[2,3-b]pyrazine (step 5) (189 mg, 0.557 mmol) in anhydrous DMF (3 ml) degassed with N2 was treated with NaH (60% in mineral oil) (24.50 mg, 0.612 mmol). After stirring at RT for 30 minutes, ethyl 7-bromoheptanoate (0.119 ml, 0.612 mmol) was added and stirring continued for 2 hours. The mixture was diluted with water (50 ml) and the pH was adjusted to pH 1 using 2M HCl. The resulting mixture was extracted with DCM (×3) and the combined organic extracts were concentrated under reduced pressure. Purification of the crude product by chromatography on silica eluting with 0-10% EtOAc in iso-hexane afforded the titled compound as a yellow oil;
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3Br)[N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30](=[O:32])[CH3:31]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH:30]([OH:32])[CH3:31])[N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(Cc3ccccc3)CC2)c2c(Br)cccc21
Reactant: CC=O
Solvent: C1CCOC1
Product: CC(O)c1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
A solution of tert-butyl 1′-benzyl-4-bromospiro[indoline-3,4′-piperidine]-1-carboxylate (0.700 g, 1.53 mmol) in THF (10 mL) at −78° C. was treated by the dropwise addition of 1.6M in hexanes n-BuLi (0.673 ml, 1.68 mmol). The mixture was stirred at −78° C. for 30 minutes, and acetaldehyde (0.129 mL, 2.30 mmol) was added neat and stirring was continued an additional 30 minutes at −78° C. The reaction was then stirred at room temperature for 1.5 hours. The reaction was quenched by the addition of saturated NH4Cl, and the reaction was extracted with EtOAc. The combined organics were washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (20 then 50-70% EtOAc/Hexane) to yield pure tert-butyl 1′-benzyl-4-(1-hydroxyethyl)spiro[indoline-3,4′-piperidine]-1-carboxylate (0.491 g, 76%). LCMS (APCI+) m/z 423.2 [M+H]+; Rt=3.66 min
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[O:18][C:19]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:20]=4[C:21]=3[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]=2)[C:8]=1[Br:33])C.[OH-].[K+]>C1COCC1.O>[Br:33][C:8]1[C:9]2[C:14](=[CH:13][C:12]([C:17]3[O:18][C:19]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:20]=4[C:21]=3[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:5][C:4]([OH:34])=[O:3]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)OCC)ccc3c2)oc2ccc(Cl)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)O)ccc3c2)oc2ccc(Cl)cc12
Yield: 88.5 %

Procedure:
Following the procedure described in Step 4 of Example 6, [1-bromo-6-(5-chloro-3-pentanoyl-benzofuran -2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester (0.25 g, 0.46 mmol) was hydrolyzed with potassium hydroxide (0.300 g, 5.36 mmol) in THF (10 mL) and water (10 mL). Crystallization from ethyl acetate afforded the title compound as an off-white solid (0.21 g), mp 130-132° C. Mass spectrum (−APCl, [M−H]−) m/z 513, 515, 517. 1HNMR (400 MHz, DMSO-d6): δ13.25 (br s,1H), 8.48 (d,1H, J=1.5 Hz), 8.25 (d, 1H, J=9.0 Hz), 8.14 (d, 1H, J=9.0 Hz), 8.04 (d, 1H, J=2.2 Hz), 7.99 (dd, 1H, J=9.0, 1.8 Hz), 7.79 (d, 1H, J=8.8 Hz), 7.52-7.48 (m, 2H), 5.03 (s, 2H), 2.72 (t, 2H, J=7.3 Hz), 1.56-1.48 (m, 2H), 13H, 1.17-1.07 (m, 2H), and 0.70 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C25H20BrClO5: Calculated: C, 58.22; H, 3.91; N, 0.00. Found: C, 58.24; H, 3.73; N, 0.03.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][C:11]1([OH:14])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:25]>C1COCC1>[CH2:15]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][C:11]1([O:14][CH3:25])[CH2:12][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OC1(CCN(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(CCN(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.3 %

Procedure:
Treat a 0° C. solution of 1-(2-(dibenzylamino)ethyl)cyclopropanol (3 g, 10.6 mmol) in THF (50 mL), under N2, portion wise with NaH (60%, 0.85 g, 21.3 mmol), stir at 0° C. for 0.5 h, add iodomethane (1.82 g, 12.8 mmol) drop wise, warm to RT and stir for 3 h. Cool the mixture to 0° C., quench with satd. NH4Cl and partially concentrate. Extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate and purify via silica gel chromatography to afford the title compound (1.2 g, 38%). 1H NMR (400 MHz, CDCl3): δ 7.39-7.21 (m, 10H), 3.60 (s, 4H), 3.12 (s, 3H), 2.65 (t, J=8 Hz, 2H), 1.75 (t, J=8 Hz, 2H), 0.68-0.65 (m, 2H), 0.34-0.31 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)=[O:8].[Br-:18].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[Br:18][C:5]1[S:4][C:3]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: CCCc1ccc(C(=O)c2sccc2C)cc1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCc1ccc(C(=O)c2sc(Br)cc2C)cc1
Temperature: 50 °C
Yield: 64.4 %

Procedure:
To a solution of (3-methylthiophen-2-yl)(4-propylphenyl)methanone (44, 1.12 g, 4.58 mmol) in acetic acid (4.67 mL) was added pyridinium tribromide (3.67 g, 11.5 mmol). The reaction mixture was heated to 50° C. for 3 hours. After cooling to room temperature, the mixture was poured into water (50 mL) and extracted with EtOAc (100 mL). The organic phase was dried over MgSO4 and evaporated under vacuum. The residue was further purified by silica column chromatography (Biotage) to provide (5-bromo-3-methylthiophen-2-yl)(4-propylphenyl)methanone (45, 0.95 g, 2.95 mmol, 64%).