Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1)=O)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[Si]([N:58]=[N+:59]=[N-:60])(C)C>C1COCC1.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)[N:60]=[N:59][N:58]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-{[4-cyano-3-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (Intermediate 21, 65 g) in THF (300 mL) was added triphenylphosphine (161 g, 0.615 mol) and diisopropylazodicarboxylate (124 g, 0.615 mol) at 0° C. The reaction mixture was stirred for 30 minutes. Trimethylsilylazide (71.1 g, 0.615 mol) was added dropwise at room temperature and then heated to reflux for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with ice-water. The organic layer was separated and washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using an eluent of 20% ethyl acetate in petroleum ether to yield 1-[4-cyano-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl acetate (45 g).
Reaction SMILES: [C:1]([CH2:6][N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)([O:3][CH2:4][CH3:5])=[O:2].[Li]N(C(C)C)C(C)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:37]([CH:44]([CH3:46])[CH3:45])([CH2:40][CH2:41][CH2:42]I)[C:38]#[N:39])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:1]([CH:6]([N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:42][CH2:41][CH2:40][C:37]([C:31]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:29]([O:28][CH3:27])[CH:30]=1)([C:38]#[N:39])[CH:44]([CH3:46])[CH3:45])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CN=Cc1ccc(OC)c(OC)c1
Reactant: COc1ccc(C(C#N)(CCCI)C(C)C)cc1OC
Agent: [Li]N(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(CCCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C)N=Cc1ccc(OC)c(OC)c1

Procedure:
The resulting imine of formula 24 is then deprotonated using a suitable strong base, and allowed to react with a compound of formula 22 to produce a compound of formula 25 (step 2). For example, 1-(carboethoxy)methyliminomethyl-3,4-dimethoxybenzene (24) is suspended in a solution of LiNiPr2 in THF/HMPA at -78° C., then reacted with 2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-iodopropyl)acetonitrile (22) to produce N-[1-carboethoxy-5-(3,4-dimethoxyphenyl)-5-cyano-5-(isopropyl)pentyl]iminomethyl-3,4-dimethoxybenzene (25).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].[CH2:16](Br)[CH:17]=[CH2:18]>>[CH2:18]([O:14][C:13]([C:6]1[CH:7]=[C:8]([CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:9]([OH:11])=[O:10])=[O:15])[CH:17]=[CH2:16]
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: C=CCBr
Product: C=CCOC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
5-Nitroisophthalic acid (5 g) was converted to the mono allyl ester using one equivalent of allyl bromide (2 ml) using a similar method to that described in example 1. The required acid (2.7 g) was extracted from the organic phase with aqueous NaHCO3. The organic layer contained the di-allyl ester (2.7 g). The mono acid, 3-allyloxycarbonyl-5-nitrobenzoic acid, was obtained as a white solid. Nmr (CDCl3): 4.87 (d, 2H); 5.3-5.5 (q, 2H); 5.97-6.15 (m, 1H); 9.01 (t, 3H).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[C:19]#[CH:20])[CH3:16].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:2]([C:20]#[C:19][CH:18]([O:21][CH2:22][CH3:23])[O:17][CH2:15][CH3:16])=[CH:7][N:6]=1
Reactant: C#CC(OCC)OCC
Reactant: CCC(CC)Nc1nc(Cl)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(C#Cc1cnc(Cl)nc1NC(CC)CC)OCC
Temperature: 55 °C
Yield: 37.2 %

Procedure:
To a mixture of (5-Bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (420 mg, 1.5 mmol) and propiolaldehyde diethyl acetal (0.32 mL, 2.25 mmol) in DMF (6 mL) is added PdCl2(PPh3)2 (105 mg, 0.15 mmol) and CuI (28 mg, 0.15 mmol), followed by Et3N (0.42 mL, 3 mmol). The mixture is degassed and heated at 55° C. for 16 h. Then the mixture is cooled down to room temperature, diluted with EtOAc, washed with water and brine. The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, EtOAc:Heptane=5:95 to 40:60) to give 182 mg of the title compound as a light brown oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: NCCSCc1cccnn1
Reactant: CN=C=O
Product: CNC(=O)NCCSCc1cccnn1

Procedure:
By the same procedure of Example 24, 3-[(2-aminoethyl)thiomethyl]pyridazine is reacted with methyl isocyanate to give the title compound.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH3:19])[O:9][C:8]=1[CH3:20])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:9][C:8]([CH3:20])=[C:7]([CH:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:11]=2)=[C:13]([CH3:19])[CH:14]=1
Reactant: Cc1cc(F)ccc1-c1cc(C(Cl)CC(C)C)c(C)o1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(F)ccc1-c1cc(C(CC(C)C)Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)c(C)o1
Temperature: 80 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-5-(4-fluoro-2-methylphenyl)-2-methylfuran (442 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (451 mg), sodium carbonate (191 mg) and sodium iodide (270 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 50% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (188 mg, 26%).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:19]([O:21][C:22](=[O:32])[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:20].C(OCC)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:19]([O:21][C:22](=[O:32])[CH2:23][N:24]([C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:20]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C

Procedure:
CBZ-L-Valine (12.6g, 0.05mol) was dissolved in CH2Cl2 (250mL) and the following reagents were added in equal molar amounts in the stated order; 4-Dimethylaminopyridine (DMAP), ethyl-N-(benzyl)glycinate and WSCDI. The reaction mixture was allowed to stir at room temperature over night. Evaporation of the solvent yielded a viscous semisolid which was treated with ethyl acetate and then IN HCl and separated. The organic extract was washed with 1N HCl followed by 5% aqueous Na2CO3 and saturated aqueous NaCl-solution. After drying over MgSO4, filtration and evaporation under reduced pressure afforded an oil (17.6 g) which ws used as is for saponification.
Reaction SMILES: C([N:4]1[C:8]2=[CH:9][C:10]3[C:11]([CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[CH:12][NH:13][C:14]=3[CH:15]=[C:7]2[CH2:6][CH2:5]1)(=O)C>C(O)C.[OH-].[Na+].O>[CH3:22][N:19]1[CH2:20][CH2:21][CH:16]([C:11]2[C:10]3[CH:9]=[C:8]4[NH:4][CH2:5][CH2:6][C:7]4=[CH:15][C:14]=3[NH:13][CH:12]=2)[CH2:17][CH2:18]1
Reactant: CC(=O)N1CCc2cc3[nH]cc(C4CCN(C)CC4)c3cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCC(c2c[nH]c3cc4c(cc23)NCC4)CC1
Yield: 61.4 %

Procedure:
To a stirred suspension of 1-acetyl-7-(1-methylpiperidin-4-yl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole (D5, 0.55 g, 1.85 mmole) in ethanol (10 ml) and 10% sodium hydroxide solution (10 ml) was added sodium hydroxide pellets (0.50 g) and the resultant mixture was heated at reflux under argon for 18 hours. The mixture was cooled, diluted with water (75 ml) and extracted with dichloromethane (5×30 ml). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to dryness. The residue was triturated with diethyl ether and the solid filtered off and dried in vacuo to afford the title compound as an off-white powder (0.29 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:25]([C:27]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=O.C(C1(C(OC)=O)CCC1)=O>>[O:22]1[CH2:23][CH2:24][CH:19]([O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:3][CH2:2][N:1]([CH2:25][C:27]5([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)[CH2:6][CH2:5]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21]1
Reactant: COC(=O)C1(C=O)CCOCC1
Reactant: c1cc(OC2CCOCC2)c2c(OCC3CCNCC3)noc2c1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OC5CCOCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 3-(piperidin-4-ylmethoxy)-4-(tetrahydro-2H-pyran-4-yloxy)-1,2-benzisoxazole (EXAMPLE 27, Step 1) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].Br[CH2:6][C:7]([NH:9][C:10]1[C:27]([OH:28])=[C:26]2[C:13]([CH2:14][CH:15]3[C:24]([C:25]2=[O:29])=[C:23]([OH:30])[C:22]2([OH:31])[CH:17]([CH:18]([N:37]([CH3:39])[CH3:38])[C:19]([OH:36])=[C:20]([C:33]([NH2:35])=[O:34])[C:21]2=[O:32])[CH2:16]3)=[C:12]([N:40]([CH3:42])[CH3:41])[CH:11]=1)=[O:8]>CN1C(=O)N(C)CCC1.C(#N)C>[CH3:39][N:37]([CH3:38])[C@H:18]1[C@H:17]2[C@:22]([OH:31])([C:23]([OH:30])=[C:24]3[C@H:15]([CH2:16]2)[CH2:14][C:13]2[C:26](=[C:27]([OH:28])[C:10]([NH:9][C:7](=[O:8])[CH2:6][NH:4][O:3][CH3:2])=[CH:11][C:12]=2[N:40]([CH3:41])[CH3:42])[C:25]3=[O:29])[C:21](=[O:32])[C:20]([C:33]([NH2:35])=[O:34])=[C:19]1[OH:36]
Reactant: CN(C)c1cc(NC(=O)CBr)c(O)c2c1CC1CC3C(N(C)C)C(O)=C(C(N)=O)C(=O)C3(O)C(O)=C1C2=O
Reactant: CON
Agent: Cl
Solvent: CC#N
Solvent: CN1CCCN(C)C1=O
Product: CONCC(=O)Nc1cc(N(C)C)c2c(c1O)C(=O)C1=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C[C@@H]1C2
Yield: 21.2 %

Procedure:
The compound of the example is prepared by the procedure of example 1 using 1.5 g of methoxyamine hydrochloride (neutralized by NaOH, extracted with methylene chloride), and 0.5 g of 9-(2-bromo-acetylamino)-4,7-bis-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide in 8 ml DMPU and 2.5 ml acetonitrile to give 0.1 g of the product.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(Br)c(N2CCNCC2)n1
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
A solution of 3-bromo-2-chloro-6-picoline (0.2 g), piperazine (0.083 g) and triethylamine (0.096 g) in acetonitrile (5 ml) was heated in the microwave apparatus: 30 min at 120° C. followed by 60 min at 150° C. and 30 min at 170° C. The mixture was concentrated and the product was purified by chromatography (SiO2, CH2Cl2=>CH2Cl2/CH3OH 4:1) to give 1-(3-bromo-6-methyl-pyridin-2-yl)-piperazine (0.05 g) as a light yellow solid.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N-].O.O.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([OH:27])(=[O:26])=[O:25]>CCOCC>[O:12]=[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][O:27][S:24]([C:17]1[C:18]([CH3:23])=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[CH3:15])(=[O:25])=[O:26]
Reactant: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Reactant: CCCCCCCC(=O)C=[N+]=[N-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCC(=O)COS(=O)(=O)c1c(C)cc(C)cc1C
Yield: 69 %

Procedure:
A 1.0 g quantity of 1-diazo-2-nonanone is dissolved in 30 ml of ether, and 2.0 g of 2,4,6-trimethylbenzenesulfonic acid dihydrate is slowly added to the solution at room temperature. The same procedure as in Example 1 is thereafter repeated to give 1.4 g of 2-oxononanyl-2,4,6-trimethylbenzene sulfonate in the form of a colorless transparent oil (Compound 77). Yield 69.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2I)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([Sn](CCCC)(CCCC)[C:27]1[O:28][C:29]2[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32][C:30]=2[CH:31]=1)CCC.C(OCC)(=O)C>CN(C=O)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>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:27]2[O:28][C:29]3[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32][C:30]=3[CH:31]=2)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Cc1c(Nc2c(I)cncc2C#N)cc(Cl)c2[nH]ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2cc(C=O)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(C=O)ccc3o2)cc(Cl)c2[nH]ccc12
Temperature: 110 °C
Yield: 82.2 %

Procedure:
To a stirred solution of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-iodonicotinonitrile (405 mg, 1 mmol) in DMF (7 mL) was added 2-(tributylstannyl)-1-benzofuran-5-carbaldehyde (609 mg, 1.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.1 mmol) under nitrogen atmosphere, the reaction mixture was heated at 110° C. for 1.5 h and cooled to room temperature and ethyl acetate was added to the resulting mixture. The organic phase was washed with water, saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated and the residue was purified by flash column chromatography (ethyl acetate/hexane) to give 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-(5-formyl-1-benzofuran-2-yl)nicotinonitrile as a yellow solid (351 mg, 82%). HPLC retention time: 12.4 min.(g); and MS: 427.3 (M+H).
Reaction SMILES: [C:1]([NH:24][CH:25]([CH3:35])[CH2:26][NH:27]C(=O)OC(C)(C)C)(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:27][CH2:26][CH:25]([NH:24][C:1](=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22])[CH3:35]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(C)CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(C)CN
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a solution of tert-butyl 2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropylcarbamate (2.10 g, 4.34 mmol) in DCM (100 mL) at 0° C. was slowly added TFA (30 mL). The mixture was stirred (0° C., 2 h), warmed to RT and stirred (16 h). The mixture was basified to pH=10 with saturated aqueous Na2CO3 and extracted with EA (2×200 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford (4Z,7Z,10Z,13Z,16Z,19Z)-N-(1-aminopropan-2-yl)docosa-4,7,10,13,16,19-hexaenamide (1.60 g, 98%) as a light yellow oil. Mass calculated for C25H40N2O=384.6; found: [M+H]+=385.2.
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:11][Si:12](Cl)([CH3:14])[CH3:13]>CCCCCC.CCOCC>[CH3:11][Si:12]([CH3:14])([CH3:13])[C:7]1[O:6][CH:10]=[CH:9][N:8]=1
Reactant: c1cocn1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1ncco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
n-Butyllithium (28.5 ml of a 2.54M solution in hexane) was added to a -78° solution of oxazole (5.0 g) in ether (150 ml). The resulting solution was stirred at -78° for 30 min, followed by the addition of trimethylsilyl chloride (7.86 g), and the mixture allowed to warm to room temperature. The reaction mixture was distilled and the fraction with a boiling point of about 130° was collected to afford 2-trimethylsilyl oxazole (5.12 g); MS, m/e=142(M+1), 91, 73.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:28]=[C:27]4[C:18]([N:19]5[CH:24]([C:25](=[O:29])[NH:26]4)[CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:28]=[C:27]4[C:18]([N:19]5[CH:24]([C:25](=[O:29])[NH:26]4)[CH2:23][N:22]([CH3:30])[CH2:21][CH2:20]5)=[N:17][CH:16]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCNCC12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN2c3ncc(CN4CCN(c5ccc(Cl)cc5)CC4)cc3NC(=O)C2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 3.2 %

Procedure:
To a solution of 7-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-1,3,4,10a-tetrahydro-2H,9H-2,4-a,5,9-tetraaza-phenanthren-10-one (139 mg, 0.337 mmol) in DMF (3.4 mL) cooled to 0° C. was added potassium carbonate (233 mg, 1.683 mmol) and methyl iodide (2 M in THF, 0.168 mL). The reaction was stirred 1 h at 0° C. and filtered through celite. The filtrate was purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (4.6 mg, 3.2%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.59 (s, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.15-7.28 (m, 2H), 7.01 (d, J=2.0 Hz, 1H), 6.85-6.97 (m, 2H), 4.17-4.30 (m, 1H), 3.88 (dd, J=10.6, 3.3 Hz, 1H), 3.37 (s, 2H), 3.14-3.20 (m, 1H), 3.06-3.14 (m, 4H), 2.84 (d, J=11.6 Hz, 1H), 2.74 (td, J=12.4, 3.0 Hz, 1H), 2.44-2.48 (m, 4H), 2.26 (s, 3H), 1.91-2.02 (m, 2H). [M+H] calc'd for C22H27ClN6O, 427; found, 427.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2[CH:45]=[CH:46][CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CCC[C@H](N)C1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][C@H:44]5[CH2:45][CH2:46][CH2:47][NH:48][CH2:43]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CCCNC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (S)-1-Boc-3-aminopiperidine. The final compound was purified by reverse phase HPLC and basified to give the free base. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml) and purified the product using preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.95 (m., 14H) 2.40 (t, J=7.38 Hz, 2H) 2.80 (br. s., 1H) 2.96 (br. s., 1H) 3.33 (s, 3H) 3.81 (br. s., 1H) 3.94 (s, 3H) 4.06 (t, J=13.64 Hz, 2H) 4.45 (m, 1H) 7.34-7.55 (m, 2H) 7.90 (s, 1H) 8.03 (d, J=7.58 Hz, 1H) 8.21 (s, 1H) 8.26 (d, J=8.34 Hz, 1H). [M+H] calculated for C27H35F2N7O3, 544. found 544.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)#[N:2].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]([C:22]2[C:30]3[CH:29]=[N:28][CH:27]=[N:26][C:25]=3[N:24]([C:31]3([CH2:34][O:35]C4CCCCO4)[CH2:33][CH2:32]3)[CH:23]=2)=[O:21])[CH:17]=[N:18][CH:19]=1.CCCP(O)(O)=O.C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:20]([C:22]3[C:30]4[CH:29]=[N:28][CH:27]=[N:26][C:25]=4[N:24]([C:31]4([CH2:34][OH:35])[CH2:33][CH2:32]4)[CH:23]=3)=[O:21])[CH:15]=2)=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: Nc1cncc(C(=O)c2cn(C3(COC4CCCCO4)CC3)c3ncncc23)c1
Agent: CCCP(=O)(O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CC(=O)Nc2cncc(C(=O)c3cn(C4(CO)CC4)c4ncncc34)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
(4-Cyano-phenyl)-acetic acid (6.1 mg, 0.04 mmol) was added to a solution of (5-Amino-pyridin-3-yl)-{7-[1-(tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-methanone (15 mg, 0.04 mmol) (Preparation 251) in THF (1 mL). Then 1-propylphosphonic acid cyclic anhydride (0.07 mL, 0.11 mmol) and triethylamine (0.02 mL, 0.13 mmol) were added and the mixture was stirred at 25° C. for 4 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over sodium sulphate and evaporated in vacuo. The crude was dissolved in methanol (1 mL), PTSA (5 mg) was added and stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with dichloromethane (5×5 mL). The combined organic layer was washed with brine (5 mL), dried over sodium sulphate and evaporated in vacuo. The crude material was purified by preparative TLC (dichloromethane:methanol 95:5) to afford the title compound as a white solid in 58% yield, 10 mg.