Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:16][CH2:17][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:19][CH2:20]1
Reactant: ClCCN1CCCC1
Reactant: Cc1ccc2[nH]c(=O)c(C#N)c(N3CCN(C(=O)c4cccs4)CC3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2CCN1CCCC1
Temperature: 0 °C
Yield: 18.8 %

Procedure:
A solution of Compound 107 (1 g., 2.64 mmol), 1-(2-chloroethyl) pyrrolidine hydrochloride (2.24 g, 13.2 mmol), and potassium carbonate (3.64 g, 26.4 mmol) in DMF was heated overnight at 90° C. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried. The crude product was purified by flash chromatography eluting with 0-10% methanol in ethylacetate gradient to yield 236 mg (19%) of pale yellow solids. M.P. 139-143° C. 1H NMR (DMSO-d6): δ 1.67 (m, 4H), 2.41 (s, 3H), 2.53 (m, 4H), 2.61 (m, 2H), 3.01 (m, 2H), 3.62 (m, 4H), 3.93 (m, 4H), 4.30 (m, 2H), 7.16 (dd, J=3.4, 4.8 Hz, 1H), 7.49 (m, 2H), 7.60 (m, 1H), 7.69 (s, 1H), 7.80 (d, J=5.2 Hz, 1H). EIMS m/z 476 (M+1). Anal. (C26H29N5O2S) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][CH3:28])[C:22]=1[O:29][CH3:30].N1C=CC=CC=1.Cl.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>CN(C)C1C=CN=CC=1.C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:9]([F:12])([F:10])[F:11])[C:13]([F:14])([F:15])[F:16])[CH:5]=[C:4]([Br:18])[C:3]=1[NH:19][C:20]([C:21]1[C:22]([O:29][CH3:30])=[C:23]([N:27]([CH3:28])[C:39]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[O:46])[CH:24]=[CH:25][CH:26]=1)=[O:31]
Reactant: CNc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)c1OC
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1c(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1ccncc1

Procedure:
A solution of N-[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-2-methoxy-3-(methylamino)benzamide (0.600 g, 1.03 mmole), 4-dimethylaminopyridine (0.006 g) and pyridine (0.334 ml, 0.327 g, 4 mmole) in THF (11.4 ml) was treated with isonicotinoyl chloride hydrochloride (0.386 g, 2 mmole). The resulting white suspension was heated under reflux for 0.5 hour. The reaction mixture was filtered and the filtrate evaporated under reduced pressure. The residue was taken up in aqueous saturated sodium bicarbonate solution. The product was extracted with ethyl acetate and the organic phase was washed with brine and dried over sodium sulfate. The crude product was purified by column chromatography over silica gel using ethyl acetate 50%-cyclohexane 50% to yield the title compound corresponding to compound No. G14 of table G.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=O.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1>>[CH2:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:11]=[CH:12][C:13]([C:15]3[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:14][C:2]=2[Cl:1])[CH2:25][CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1Cl
Product: CC1NC(=O)NN=C1c1ccc(OCC(=O)NC2CCN(Cc3ccccc3)CC2)c(Cl)c1
Reaction time: 2.5 h
Yield: 69.5 %

Procedure:
0.5 g (1.53 mmole) of ethyl α-[2-chloro-4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetate (prepared as described in Example 5) was mixed with 0.58 g (3.06 mmole) of 4-amino-1-benzylpiperidine, and the mixture was stirred at 120°-130° C. for 2.5 hours. The mixture was then cooled, after which it was subjected to column chromatography through silica gel and eluted with methylene chloride containing 2% v/v ethanol to give 0.5 g of a pale yellow oil. Trituration of this oil with ethanol yielded crystals, which were then recrystallized from ethanol, to give 0.33 g of the title compound as pale yellow fine crystals melting at 190°-191° C.
Reaction SMILES: C(O)C.[SH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl.Br[CH2:14][CH2:15][NH2:16].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:16][CH2:15][CH2:14][S:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1
Reactant: NCCBr
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NCCSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.6 %

Procedure:
To 30 ml of ethanol, 1.2 g of 4-mercaptophenol, 2.1 g of 2-bromoethylamine hydrochloride and 1.4 g of potassium carbonate were added, followed by stirring for 3 hours at room temperature. Water was added, and the resulting mixture was extracted with ethyl ether. The extract was dried over MgSO4 and the ethyl ether was distilled off under reduced pressure, whereby 1.7 g of the compound (7) were obtained (yield: stoichiometric).
Reaction SMILES: [NH2:1][C:2]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].CN1CCCC1=O.C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[N:36]=[C:35](Cl)[C:34]([Cl:38])=[CH:33][N:32]=1>>[Cl:30][C:31]1[N:36]=[C:35]([NH:1][C:2]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([NH:6][CH2:7][CH3:8])=[O:5])[C:34]([Cl:38])=[CH:33][N:32]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCNC(=O)c1cccc(F)c1N
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
Into a round bottom flask was added 2-amino-N-ethyl-3-fluoro-benzamide (2.00 g, 11.0 mmol) and N-methylpyrrolidinone (10 mL, 100 mmol). N,N-diisopropylethylamine (2.29 mL, 13.2 mmol) was added followed by 2,4,5-trichloro-pyrimidine (1.51 mL, 13.2 mmol) and the mixture was heated at 100° C. for 24 hours. The reaction mixture was then concentrated under reduced pressure and the residue was taken up in DCM (50 mL) and washed with water (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-70% EtOAc/hex as the eluting solvent. The product was placed in hexane and stirred overnight. The mixture was filtered to obtain 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide as a yellow solid (1.79 g, 50%). m.p.=233-234° C.; LCMS (m/e) 329 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.22 (s, 1H), 7.40-7.22 (m, 3H), 6.20-6.10 (m, 1H), 3.53-3.42 (m, 2H), 1.25 (t, 3H, J=7.3 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[N:10][N:9]([CH2:12][Si](C)(C)C)[C:8]=1[CH2:17][OH:18].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:12][N:9]1[C:8]([CH2:17][OH:18])=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:11]=[N:10]1
Reactant: C[Si](C)(C)Cn1nnc(-c2ccccn2)c1CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccccn2)c1CO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
To a solution of (5-pyridin-2-yl-3-trimethylsilanylmethyl-3H-[1,2,3]triazol-4-yl)-methanol (364 mg, 1.39 mmol) in THF (23 mL) was added water (50 μL, 2.78 mmol) and then tetrabutylammonium fluoride (1 M in THF, 1.66 mL, 1.66 mmol) added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 15 min. The resulting mixture was poured into water and then the THF was evaporated. The aqueous layer was then extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (161 mg, 61%) as an off white solid. MS: m/e=191.2 [M+H]+.
Reaction SMILES: [C:1]1([S:11](Cl)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].C(N(C(C)C)C(C)C)C.Cl.[Na+].[Cl-]>C(Cl)Cl>[C:1]1([S:11]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCCC1CCCCN1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCC1CCCCN1S(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
Naphthalene-1-sulfonyl chloride (13.7 g, 60.55 mmol) was added to a solution of methyl 4-(piperidine-2-yl)butanoate hydrochloride (2) (3.74 g, 20.2 mmol) in methylene chloride (143 ml). N-Ethyl-diisopropylamine (10.2 ml, 60.55 mmol) was then added dropwise. The reaction mixture was stirred overnight at room temperature. The completeness of the reaction was checked by means of TLC. When the reaction was complete, the reaction mixture was acidified with 1 M HCl (aqueous) and the aqueous phase was saturated with NaCl solution and then extracted 4× with methylene chloride. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. Purification via column chromatography (aluminium oxide; hexane/ethyl acetate 97.3→9:1) gave the desired product methyl 4-(1-(naphthalen-1-ylsulfonyl)piperidin-2-yl)butanoate 3 (4.95 g, 65%).
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.CN.[CH3:23][N:24]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[OH:1][C:2]1([C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:24][CH3:23])=[O:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CNC(=O)c1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
4-(8-Hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)benzoic acid (560 mg, 2 mmol), methylamine (1.2 mL, 2.0 M THF solution), BOP reagent (1.07 g, 2.4 mmol) and 0.8 mL (6 mmol) of triethylamine were dissolved in 15 mL of DMF at room temperature. The reaction mixture was stirred at r.t. overnight. Direct chromatography on silica gel (flash chromatography grade) with 50% ethyl acetate-hexane gave 410 mg (70%) of the desired product: 1H NMR (CDCl3) δ 7.76 (2H, d, J=11.2 Hz), 7.56 (2H, d, J=10.9 Hz), 5.01 (H, s), 3.90 (4H, s), 3.37 (3H, s), 2.80-2.75 (2H, m), 2.60-2.45 (2H, m), 1.95-1.90 (2H, m), 1.63-1.52 (2H, m); MS: 292 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[N:14]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[CH2:34]([N:31]1[C:26]2=[N:27][C:28]([CH2:29][CH3:30])=[C:23]([CH2:22][NH:21][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([NH:10][CH2:9][C:4]4[CH:3]=[C:2]([C:49]5[CH:48]=[CH:47][CH:46]=[C:45]([CH:43]=[O:44])[CH:50]=5)[C:7]([CH3:8])=[CH:6][CH:5]=4)=[O:12])[N:14]=3)=[O:20])[C:24]([NH:36][CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[C:25]2[CH:33]=[N:32]1)[CH3:35]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(Br)c2)n1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)n1
Temperature: 100 °C
Yield: 92.8 %

Procedure:
N-[(3-Bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (1.86 g, 2.93 mmol), (3-formylphenyl)boronic acid (0.439 g, 2.93 mmol), potassium carbonate (1.215 g, 8.79 mmol), and Pd(Ph3P)4 (0.169 g, 0.147 mmol) were combined in three 10-20 mL Biotage microwave vials in 1,4-dioxane (27 mL) and water (9 mL). The vials were capped and the mixture was heated in the microwave at normal power at 100° C. for 15 min. The crude product was partitioned between EtOAc (200 mL) and water (70 mL). The phases were separated, and the organic phase was washed with water (2×50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated to give the crude residues. It was taken up in DCM and absorbed on Isolute® Sorbent and purified by a CombiFlash on a 120 g silica column eluted with 0-10% MeOH/DCM. Product fractions were combined and concentrated under vacuum to give (N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (1.85 g, 2.72 mmol, 93% yield)) as a white solid. LC-MS m/z 660 (M+H)+, 0.94 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:16][N:17]1[C:21](=[O:22])[CH2:20][CH:19]([C:23](O)=[O:24])[C:18]1([CH3:27])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:23]([CH:19]3[CH2:20][C:21](=[O:22])[N:17]([CH3:16])[C:18]3([CH3:27])[CH3:26])=[O:24])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CN1C(=O)CC(C(=O)O)C1(C)C
Reactant: Nc1cc(Cl)cc2c1[nH]c1cnccc12
Product: CN1C(=O)CC(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)C1(C)C
Yield: 68 %

Procedure:
The desired compound was prepared according to Method B from 6-chloro-9H-β-carboline-8-ylamine and 1,2,2-trimethyl-5-oxo-pyrrolidine-3-carboxylic acid in 68% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:34][CH3:35])=[C:7](/[CH:9]=[CH:10]/[C:11]([NH:13][C@@H:14]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[CH2:15][C:16](O)=[O:17])=[O:12])[CH:8]=1)#[N:2].C(N(C(C)C)CC)(C)C.[CH3:45][NH:46][CH2:47][CH2:48][OH:49].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C([O-])(O)=O.[Na+].FC1C=CC(OC2CCN(C[C@@H](C(=C)C(N)=O)CC(=O)N(CCO)C)CC2)=CC=1>CN(C=O)C.C(OC(=O)C)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:34][CH3:35])=[C:7](/[CH:9]=[CH:10]/[C:11]([NH:13][C@H:14]([CH2:15][C:16](=[O:17])[N:46]([CH2:47][CH2:48][OH:49])[CH3:45])[CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([O:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:24][CH2:25]2)=[O:12])[CH:8]=1)#[N:2]
Reactant: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CC(=O)O)CN1CCC(Oc2ccc(F)cc2)CC1
Reactant: CNCCO
Agent: C=C(C(N)=O)[C@@H](CC(=O)N(C)CCO)CN1CCC(Oc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CC(=O)N(C)CCO)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (R)-3-[(E)-3-(5-cyano-2-methoxy-phenyl)-acryloylamino]-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid (0.1 g, 0.21 mmol) in DMF (1 ml) is treated with diisopropylethylamine (0.108 ml, 0.62 mmol) and 2-methylamino-ethanol (0.02 ml, 0.248 mmol). To the solution is added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (0.117 g, 0.31 mmol) and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture is partioned between ethylacetate and saturated aqueous NaHCO3. The ethylacetate phase is washed with saturated brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 5:95 methanol/DCM) to afford (E)-3-(5-cyano-2-methoxy-phenyl)-.N.-((R)-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-1-{[(2-hydroxy-ethyl)-methyl-carbamoyl]-methyl}-ethyl)-acrylamide. [M-H] 537.02.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:26](=[O:28])[CH3:27])[CH2:20][C:19]2[C:18]([OH:21])=[C:17]3[C:8]([C:9](=[O:23])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]3=[O:22])=[C:7]([OH:24])[C:6]=2[CH:5]([OH:25])[CH2:4]1.C(O[C:33](=[O:35])[CH3:34])(=O)C.Cl>N1C=CC=CC=1>[C:26]([C:3]1([NH:2][C:33]([CH3:34])=[O:35])[CH2:20][C:19]2[C:18]([O:21][C:18](=[O:21])[CH3:17])=[C:17]3[C:8]([C:9](=[O:23])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]3=[O:22])=[C:7]([O:24][C:16](=[O:22])[CH3:15])[C:6]=2[CH:5]([O:25][C:9](=[O:23])[CH3:8])[CH2:4]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)C1(N)Cc2c(O)c3c(c(O)c2C(O)C1)C(=O)c1ccccc1C3=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NC1(C(C)=O)Cc2c(OC(C)=O)c3c(c(OC(C)=O)c2C(OC(C)=O)C1)C(=O)c1ccccc1C3=O
Temperature: 0 °C

Procedure:
To a mixture of 9-amino-9-acetyl-6,7,11-trihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione hydrochloride (550 mg) and anhydrous pyridine (10 ml), acetic anhydride (3 ml) was added thereto while cooling with ice water. The resultant mixture was heated at a temperature of 60° to 65° C. for 30 minutes. The reaction mixture was poured into 3% hydrochloric acid and extracted with chloroform. The chloroform extract was washed with water, a saturated sodium bicarbonate solution and water in order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography to give 9-acetyl-9-acetamino-6,7,11-triacetoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione. M.P., 276°-278° C.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=2)=[CH:9][CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+].CO>C(Cl)Cl>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=2)=[CH:11][CH:12]=1)#[CH:5]
Reactant: COc1cc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(C#Cc2cc(OC)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
Into a 100 ml round bottom flask was placed a mixture of 2.27 g (0.0068 mole) of 1-(trimethylsilylethynyl)-4-(3,5-dimethoxyphenylethynyl)benzene, 1.88 g (0.0136 mole) potassium carbonate, 30 ml of methanol and 30 ml of methylene chloride. The mixture was stirred at room temperature overnight under nitrogen. The dark brown suspension was filtered through an alumina bed to remove some color, and the still dark color filtrate was washed twice with water (30 ml each). The aqueous layers were combined and extracted twice with methylene chloride (20 ml each). The methylene chloride layers were combined and dried over anhydrous MgSO4, filtered and concentrated. 1.13 g of brown oil was obtained. The crude oil was purified by Preparative LC using 1:10 EtOAc:hexane as eluting solvent. 240 mg (13.5% yield) of yellow solid was obtained. 1HNMR: 3.20 ppm (s, 1H); 3.83 ppm (s, 6H); 6.50 ppm (t, 1H); 6.71 ppm (d, 2H); 7.50 ppm (s, 4H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[N:26][CH:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:57]([N:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][CH2:68]O)[CH2:62][CH2:61]1)(=[O:59])[CH3:58]>CN(C=O)C>[C:57]([N:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][CH2:68][O:36][C:30]2[CH:29]=[C:28]3[C:33]([C:24]([O:23][C:22]4[C:14]([F:13])=[C:15]5[C:19](=[CH:20][CH:21]=4)[NH:18][C:17]([CH3:37])=[CH:16]5)=[CH:25][N:26]=[N:27]3)=[CH:32][C:31]=2[O:34][CH3:35])[CH2:62][CH2:61]1)(=[O:59])[CH3:58]
Reactant: CC(=O)N1CCN(CCCO)CC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
Under nitrogen, diethyl azodicarboxylate (0.19 ml, 1.2 mmol) was added dropwise to a suspension of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.6 mmol), (prepared as described in Example 4), in DMF (4 ml) containing triphenylphosphine (0.31 g, 1.2 mmol) and 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.15 g, 0.9 mmol). After stirring for 2 hours at ambient temperature, the volatiles were removed under vacuum. The residue was purified by column chromatography eluting with methylene chloride, followed by ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (1/4/5) followed by methanol/methylene chloride (1/9). The fractions containing the expected product were combined and evaporated to give 7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline (0.11 g, 37%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[CH2:40]([O:42][CH:43]([O:48][CH2:49][CH3:50])[CH2:44][C:45](O)=[O:46])[CH3:41]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:40]([O:42][CH:43]([O:48][CH2:49][CH3:50])[CH2:44][C:45]([NH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:46])[CH3:41]
Reactant: CCOC(CC(=O)O)OCC
Reactant: CC(C)(C)OC(=O)NNc1c(N)cnc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(CC(=O)Nc1cnc2ccccc2c1NNC(=O)OC(C)(C)C)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate (9.01 g, 32.9 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (7.56 g, 39.4 mmol), 4-methylmorpholine (4.34 mL, 39.4 mmol), and 4-dimethylaminopyridine (0.200 g, 1.64 mmol) in pyridine (200 mL) was chilled in an ice-water under a nitrogen atmosphere. The mixture was treated drop-wise with a solution of 3,3-diethoxypropionic acid (6.40 g, 39.4 mmol) in pyridine (50 mL). The reaction was allowed to slowly come to ambient temperature and stirred overnight. After 15 h, the reaction mixture was concentrated under reduced pressure to yield a dark red solid. The solid was dissolved in chloroform (150 mL) and transferred to a separatory funnel. The organic solution was washed with 10% Na2CO3 aqueous solution (35 mL), water (2×35 mL), and brine (35 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 13.75 g of crude tert-butyl N′-[3-(3,3-diethoxypropionylamino)quinolin-4-yl]hydrazinecarboxylate as a dark red solid.