Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:13]=2)[CH:10]=1.O1CCCC1.OS(C(F)(F)[F:37])(=O)=O.FN1C(Cl)=CC=CC1Cl.Cl>C(#N)C.C(OCC)(=O)C>[F:37][C:11]1[N:9]2[CH:10]=[C:5]([O:4][C:3]3[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:2]=3[F:1])[CH:6]=[CH:7][C:8]2=[N:13][C:12]=1[NH:14][C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: O=C(Nc1cn2cc(Oc3ccc([N+](=O)[O-])cc3F)ccc2n1)C1CC1
Agent: Cl
Agent: FN1C(Cl)=CC=CC1Cl
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(Nc1nc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cn2c1F)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.9 %

Procedure:
To a solution of N-[6-(2-fluoro-4-nitrophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (121.6 mg, 0.341 mmol) in acetonitrile (0.5 mL)/tetrahydrofuran (0.5 mL) was added 1-fluoro-2,6-dichloropyridine triflate (129 mg, 0.409 mmol), and the mixture was stirred at room temperature for 2 hr. Tetrahydrofuran, ethyl acetate and 1N hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=1/2→1/1) to give the title compound (15.2 mg, 12%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35]CC3C=CC=CC=3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:30]([OH:35])=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1nc2c(C)ccc(OCc3ccccc3)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2c(C)ccc(O)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
Prepared in analogous manner to Example 57 from tert.butyl 4'-[(2-n-butyl-4-methyl-7-benzyloxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and hydrogen in the presence of palladium hydroxide on carbon in methanol.
Reaction SMILES: C1(S([N:10]2[C:18]3[CH:17]=[C:16]([Cl:19])[CH:15]=[C:14]4[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([OH:26])=[O:25])[C:12]([C:13]=34)=[C:11]2[C:27]([O:29]C)=[O:28])(=O)=O)C=CC=CC=1.CO.[OH-].[Na+].OS([O-])(=O)=O.[K+]>C1COCC1>[Cl:19][C:16]1[CH:15]=[C:14]2[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([OH:26])=[O:25])[C:12]3=[C:11]([C:27]([OH:29])=[O:28])[NH:10][C:18]([CH:17]=1)=[C:13]23
Reactant: COC(=O)c1c2c3c(cc(Cl)cc3n1S(=O)(=O)c1ccccc1)CCC2CC(=O)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1CCc2cc(Cl)cc3[nH]c(C(=O)O)c1c23
Temperature: 25 °C
Reaction time: 19 h
Yield: 58.1 %

Procedure:
A solution of methyl 1-benzenesulfonyl-7-chloro-3-carboxymethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylate (143 mg, 0.328 mmol) in a mixture of THF (2 mL), MeOH (2 mL), and 5N NaOH (2 mL) was stirred for 19 h at room temperature, acidified to pH 3 with 5% KHSO4, and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over magnesium sulfate, and concentrated. The residue was rinsed with dichloroethane and dried in vacuo to give 56 mg of the title compound (58%): 1H NMR (DMSO-d6) δ12.58 (bs, 1H), 11.45 (s, 1H), 7.14 (d, 1H, J=1.0 Hz), 6.83 (d, 1H, J=1.0 Hz), 3.76 (m, 1H), 2.93 (mt, 1H, J=12.7 Hz), 2.78 (md, 1H, J=15.8 Hz), 2.64 (dd, 1H, J=15.3, 3.0 Hz), 2.35 (dd, 1H, J=15.5, 11.5 Hz), 2.08 (md, 1H, J=12.2 Hz), 1.87 (m, 1H).
Reaction SMILES: [C:1]([C:3](=[C:8](SC)[S:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH2:13]([NH2:15])[CH3:14]>C(COC)OC>[C:1]([C:3](=[C:8]([NH:15][CH2:13][CH3:14])[S:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)C(C#N)=C(SC)SC
Reactant: CCN
Solvent: COCCOC
Product: CCNC(SC)=C(C#N)C(=O)OC
Yield: 90 %

Procedure:
To a suspension of 2-cyano-3,3-bis(methylthio)-2-propenoic acid, methyl ester (8.12 g, 1 eq) in dimethoxyethane (14 mL) was added a solution of ethylamine (2.16 g, 1.2 eq.) in dimethoxyethane (6.5 mL). The suspension turned to solution, and a white solid began to precipitate. After about 10 min the solvent was removed and the residue was filtered with diethyl ether to yield 2-cyano-3-ethylamino-3-methylthio-2-propenoic acid, methyl ester (7.2 g): mp 86°-88° C.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([S:32][CH3:33])[CH:27]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:33][S:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2
Reactant: CSc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CSc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 79 %

Procedure:
Following procedures as described in Example 219, mix 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (1 equivalent), 4,4,5,5-tetramethyl-2-(3-methylsulfanyl-phenyl)-[1,3,2]dioxaborolane (1.25 equivalents), 2N Na2CO3 (2 equivalents) and tetrakistriphenylphosphine palladium (0.05 equivalents)in a suitable solvent. Purify the product by silica gel chromatography to obtain a 79% yield of the title compound. MS(ES)=329(+)
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.[B:14](OC)([O:17]C)[O:15]C.Cl.[K+].[Br-]>CCCCCC.CCOCC>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([B:14]([OH:17])[OH:15])=[CH:9][CH:8]=1
Reactant: Brc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of butyllithium (21.2 mmol, 15%, 13.3 ml) in hexane was slowly added to a solution of 1,4-dibromobenzene (21.2 mmol, 5.0 g) in ether (86 ml) at -40° C. under argon. The mixture was allowed to warm to room temperature and was stirred for further 2 h. The mixture was transferred into a solution of freshly distilled trimethyl borate (63.3 mmol, 7.2 ml) in ether (172 ml) at -60° C. under argon. The mixture was allowed to warm to room temperature and refluxed for further 20 h. Aqueous hydrochloric acid (2M, 127 ml) was added, and the aqueous phase was separated and extracted with ether (90 ml). The solvent was removed from the combined organic layers and petroleum ether was added. A colourless solid was recovered by filtration (ca 5 g). Further purification was carried out by column chromatography over silica (64 g), with toluene (200 ml) as an eluent to remove by-products. Elution with ether (300 ml) produced a pure product.(2.0 g, 48%); m.p. 282°-283° C., Rf (ether), 0.42; νmax (KBr, cm-1) 3020 (Ph), 1580 (Ph), 830 (Ph); δH (250 MHz, CDCl3) 4.63 (2H, s, OH), 7.64 (2H, d, J 6.6, 3,5-PhH), 8.05 (2H, d, J 6.6, 2,6-PhH).
Reaction SMILES: Br[C:2]1[C:14]([O:15][CH2:16][CH3:17])=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[O:18][CH2:19][CH3:20].[Li]CCCC.[B:26](OC)([O:29]C)[O:27]C>C1COCC1>[C:9]([O:8][C:6]([C:5]1[CH:13]=[C:14]([O:15][CH2:16][CH3:17])[C:2]([B:26]([OH:29])[OH:27])=[C:3]([O:18][CH2:19][CH3:20])[CH:4]=1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCOc1cc(C(=O)OC(C)(C)C)cc(OCC)c1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)OC(C)(C)C)cc(OCC)c1B(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 4-bromo-3,5-diethoxybenzoate (1 g) in THF (20 ml) was added n-BuLi (1.6M in hexane, 3.6 ml) at −78° C. under argon atmosphere and stirred at the same temperature for 1 h. To the mixture was added B(OMe)3 (777 ul) at −78° C. and the mixture was allowed to warm up to at room temperature. After stirring for further 1 h, the mixture was poured into ice-HCl aq., extracted with EtOAc, washed with brine and dried over sodium sulphate. After filtration and concentration, the residue was purified by silicagel column chromatography (hexane/EtOAc) to give the title product as a colorless solid.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:11]=[C:12]([S:21](Cl)(=[O:23])=[O:22])[CH:13]=[C:14]([CH:17]([CH2:19][CH3:20])[CH3:18])[C:15]=2[OH:16])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Br.[Br:26][CH2:27][CH2:28][NH2:29].C(N(CC)CC)C>C(#N)C>[N:1]1[N:2]([C:10]2[CH:11]=[C:12]([S:21]([NH:29][CH2:28][CH2:27][Br:26])(=[O:23])=[O:22])[CH:13]=[C:14]([CH:17]([CH2:19][CH3:20])[CH3:18])[C:15]=2[OH:16])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: NCCBr
Reactant: CCC(C)c1cc(S(=O)(=O)Cl)cc(-n2nc3ccccc3n2)c1O
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(C)c1cc(S(=O)(=O)NCCBr)cc(-n2nc3ccccc3n2)c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.9 %

Procedure:
To a stirred suspension of 3-benzotriazol-2-yl-5-sec-butyl-4-hydroxybenzenesulfonyl chloride (14.19 g, 0.0388 mol) and 2-bromoethylamine hydrobromide (8.44 g, 0.0412 mol) in acetonitrile (100 g) at 0-5° C. under nitrogen was added dropwise a solution of triethylamine (8.05 g, 0.0796 mol) in acetonitrile (60 g). When the addition was complete, the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was suction filtered and the filter cake was washed with acetonitrile (20 g). The filtrate was spin-evaporated and the residue was suspended in water (130 g). The suspension was suction filtered and the filter cake was dried to give 10 g of 3-benzotriazol-2-yl-N-(2-bromoethyl)-5-sec-butyl-4-hydroxy-benzenesulfonamide as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3]([CH3:7])([CH3:6])[CH:4]=O.[CH2:9]([NH2:11])[CH3:10]>>[CH3:1][N:2]([CH3:8])[C:3]([CH3:7])([CH3:6])[CH2:4][NH:11][CH2:9][CH3:10]
Reactant: CN(C)C(C)(C)C=O
Reactant: CCN
Product: CCNCC(C)(C)N(C)C

Procedure:
Prepared by General Procedure A from 2-(dimethylamino)-2-methylpropanal and ethylamine to get the title compound as colorless oil. 1H NMR (300 MHz, CDCl3) δ 2.63 (q, 2H), 2.50 (s, 2H), 2.19 (s, 6H), 1.11 (t, 3H), 1.01 (s, 6H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]([C:17]3[N:18]=[CH:19][N:20]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])[CH:21]=3)=[C:15]([CH3:31])[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1>>[CH:1]1([NH:4][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([N:20]3[CH:21]=[C:17]([C:16]4[C:12]([C:8]5[CH:9]=[CH:10][CH:11]=[C:6]([F:5])[CH:7]=5)=[N:13][O:14][C:15]=4[CH3:31])[N:18]=[CH:19]3)[CH:23]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Product: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)NC3CC3)c2)cn1
Yield: 38 %

Procedure:
As described for Example 71c, cyclopropylamine was converted, using 3-{4-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid (100 mg, 0.28 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (42 mg, 38%) which was obtained as an off-white solid. MS: m/e=403.0 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:17].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Br:1][CH2:2][C:3]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:17])[N:7]([CH3:6])[CH2:16]2)=[O:4]
Reactant: O=C(Cl)CBr
Reactant: CN1Cc2ccccc2NC1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CN1Cc2cc(C(=O)CBr)ccc2NC1=O
Temperature: 25 °C

Procedure:
Bromoacetyl chloride (4.8 g) is added dropwise to a stirring solution of 3,4-dihydro-3-methyl-2(1H)-quinazolinone (2.5 g) and anhydrous aluminum chloride (4.9 g) in carbon disulfide (50 ml) under nitrogen. The reaction mixture is refluxed for five hours, cooled to RT and the carbon disulfide decanted. The residue is treated with hydrochloric acid (6N) and the acidic residue poured into ice water, stirred and filtered. The filtered solid is washed with water and dried in vacuo, affording the desired product, which is used in the next step without further purification, M.P. 190°-200° C. (dec).
Reaction SMILES: C(S([NH:7][C:8]([CH:18]1[CH2:20][CH2:19]1)([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O)(C)(C)C.O1CCOCC1>Cl.C(OCC)(=O)C>[NH2:7][C:8]([CH:18]1[CH2:19][CH2:20]1)([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11]
Reactant: CC(C)(C)OC(=O)CC(C)(NS(=O)C(C)(C)C)C1CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CC(C)(N)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
tert-butyl 3-(tert-butylsulfinylamino)-3-cyclopropyl-butanoate (example 229a, 1.93 g, 6.36 mmol) was dissolved in a 4M solution of hydrochloric acid in dioxane (4.77 ml, 19.1 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was then diluted with ethyl acetate and poured into a separatory funnel. The organic phase was extracted with a 2M aqueous solution of sodium carbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness to yield the title compound (1.08 g, 85%) as a crude oil which was used without any purification. MS (ESI, m/z): 200.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5](Cl)[CH:4]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:4]=1
Reactant: COc1cc(Cl)nc(N2CCOCC2)n1
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: COc1cc(N2CCNCC2)nc(N2CCOCC2)n1

Procedure:
A solution of 2,4,6-trichloropyrimidine (55 g), methanol (50 ml) and collidine (50 g) is heated in dry tetrahydrofuran (400 ml) for 48 hr. Ether is added and the precipitate is collected. The precipitate is column chromatographed on silica gel to give 6-methoxy-2,4-dichloropyrimidine. This product is mixed with morpholine in THF and stirred at 20°-25° to give 6-methoxy-2-morpholino-4-chloropyrimidine. The 6-methoxy-2-morpholino-4-chloropyrimidine is heated with piperazine in pyridine at 60° for 24 hr to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[CH:3]=1.Cl.[NH2:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:8]([C:5]1[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)=[CH:3][C:2]([NH:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])=[N:7][CH:6]=1)#[N:9]
Reactant: C[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: Cc1cc(C)nc(Nc2cc(Cl)ncc2C#N)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C)nc(Nc2cc(NC[C@H](C)NC(=O)OC(C)(C)C)ncc2C#N)c1
Temperature: 80 °C

Procedure:
To a solution of 6-chloro-4-[(4,6-dimethylpyridin-2-yl)amino]pyridine-3-carbonitrile (PrepEx 1.2) (50 mg, 0.19 mmol) in 1,4-dioxane (0.8 mL) was added tert-butyl [(2S)-1-aminopropan-2-yl]carbamate hydrochloride (61 mg, 0.29 mmol) and cesium carbonate (126 mg, 0.387 mmol). The mixture was purged with argon, and then Pd2(dba)3 (4 mg, 0.004 mmol) and Xantphos (7 mg, 0.012 mmol) were added. The reaction mixture was heated to 80° C. After complete consumption of starting material (as determined by LCMS analysis), the reaction mixture was cooled to ambient temperature, filtered through CELITE (washed with chloroform), and diluted with water. The organics were separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-40% acetone/hexanes, linear gradient) to afford tert-butyl [(2S)-1-({5-cyano-4-[(4,6-dimethylpyridin-2-yl)amino]pyridin-2-yl}amino)propan-2-yl]carbamate. The isolated material was diluted with hydrochloric acid (2.0 M in dioxanes, 1 mL, 2 mmol) and stirred at ambient temperature. After 1 hour, the reaction mixture was concentrated under reduced pressure (azeotroping with toluene). The residue was diluted with DMSO (0.5 mL). To this mixture was added hydrogen peroxide (35% solution in water, 0.020 mL, 0.23 mmol) and sodium hydroxide (4.0 N in water, 0.050 mL, 0.20 mmol). After 1 hour, the reaction mixture was filtered and purified directly by reverse phase HPLC (5-60% acetonitrile/water with 0.1% TFA, linear gradient) to afford 6-{[(2S)-2-aminopropyl]amino}-4-[(4,6-dimethylpyridin-2-yl)amino]pyridine-3-carboxamide TFA salt. MS ESI calc'd. for C16H23N6O [M+H]+ 315. found 315. 1H NMR (500 MHz, CD3OD) δ 8.37 (s, 1H), 8.28 (s, 1H), 6.90 (s, 1H), 6.80 (s, 1H), 3.74-3.50 (m, 3H), 2.51 (s, 3H), 2.34 (s, 3H), 1.41 (br s, 3H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([CH:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:45])[CH2:25][CH2:26]/[C:27](/[CH3:44])=[CH:28]/[CH2:29][C:30]1[C:31]([OH:43])=[C:32]2[C:36](=[C:37]([CH3:41])[C:38]=1[O:39][CH3:40])[CH2:35][O:34][C:33]2=[O:42])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.I[CH3:47].Cl>O1CCCC1>[CH2:11]([CH:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:45])[CH2:25][CH2:26]/[C:27](/[CH3:44])=[CH:28]/[CH2:29][C:30]1[C:31]([OH:43])=[C:32]2[C:36](=[C:37]([CH3:41])[C:38]=1[O:39][CH3:40])[CH2:35][O:34][C:33]2=[O:42])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1.[CH2:11]([CH:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:45])[CH:25]([CH3:47])[CH2:26]/[C:27](/[CH3:44])=[CH:28]/[CH2:29][C:30]1[C:31]([OH:43])=[C:32]2[C:36](=[C:37]([CH3:41])[C:38]=1[O:39][CH3:40])[CH2:35][O:34][C:33]2=[O:42])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CI
Agent: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)N1C(=O)OCC1Cc1ccccc1)C(=O)OC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)CC(C)C(=O)N1C(=O)OCC1Cc1ccccc1)C(=O)OC2
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
A 1M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.43L, 0.43 mol) was cooled to -78° C. and treated dropwise with a precooled solution of (S) 4-benzyl-3-[(E) 6-(1,3-dihydro-4-hydroxy -6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoyl]-2-oxazolidinone (86 g, 0.179 mol) in tetrahydrofuran (250 mL), maintaining a temperature below -65° C. After 15 minutes stirring, iodomethane (56 mL, 0.9 mol) was added and the solution was warmed to -30° C. After 1 hour, the solution was warmed to 0° C. and 2N hydrochloric acid (0.4L) was added. The organic layer was washed with 2% sodium sulfite (0.2L) and brine (0.2L) and dried over sodium sulfate. After filtration, the volatiles were distilled at reduced pressure and the residue was applied to a bed of silica gel (0.45 kg). Elution with 40% ethyl acetate/hexane (4L) and concentration of the eluent gave the alkylation product (S) 4-benzyl-3-[(E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2,4-dimethyl-4-hexenoyl]-2-oxazolidinone as a white foam. The product consisted of an 85:13 mixture of diastereomers at the 2-hexenoyl position.
Reaction SMILES: C(OC(=O)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(NC[C@H]3CC[C@H](C(O)=O)CC3)=O)C3C=CC(F)=CC=3N=2)=CC=1.[CH2:77]([O:79][C:80](=[O:90])[CH2:81][CH2:82]C1C=CC(N)=CC=1)[CH3:78].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>>[CH2:77]([O:79][C:80](=[O:90])[CH2:81][CH2:82][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:9][CH:10]=1)[CH3:78]
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: CCOC(=O)CCc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)ccc21
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was synthesized in analogy to example 20, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 20, intermediate c), 3-(4-amino-phenyl)-propionic acid ethyl ester, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and N-ethyldiisopropylamine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]3[NH:14][CH2:15][CH2:16][CH:10]3[CH2:9]2)=[CH:6][C:5]([C:17]#[N:18])=[CH:4][C:3]=1[NH:19][C:20]1[N:25]=[C:24]([N:26]([CH:36]2[CH2:38][CH2:37]2)CC2C=CC(OC)=CC=2)[C:23]2=[N:39][CH:40]=[C:41]([C:42]#[N:43])[N:22]2[N:21]=1.[CH3:44][CH:45]1[CH2:47][O:46]1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.ClC(Cl)C>C(O)C.C1COCC1>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]3[N:14]([CH2:44][CH:45]([OH:46])[CH3:47])[CH2:15][CH2:16][CH:10]3[CH2:9]2)=[CH:6][C:5]([C:17]#[N:18])=[CH:4][C:3]=1[NH:19][C:20]1[N:25]=[C:24]([NH:26][CH:36]2[CH2:37][CH2:38]2)[C:23]2=[N:39][CH:40]=[C:41]([C:42]#[N:43])[N:22]2[N:21]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5NCCC5C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC1CO1
Solvent: COc1ccccc1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)CN1CCC2CN(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)CCC21
Temperature: 35 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
A mixture of 2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 443F, 29 mg, 0.049 mmol) and 2-(=/−)-methyloxirane (14.15 mg, 0.244 mmol) in ethanol (0.8 mL)/THF (0.2 mL) in a sealed 1-dram vial was heated at 80° C. overnight. A clear solution was observed and LCMS showed completion of reaction. Solvent was evaporated and to the crude intermediate were added anisole (0.027 ml, 0.244 mmol) and 25% TFA in dichloroethane (2 ml, 6.49 mmol) and the resulting solution was stirred at 35° C. overnight. Solvent was evaporated and the crude was purified by prep-HPLC to give the title compound (9.8 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:26]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:33])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cccnc1
Yield: 14.3 %

Procedure:
A mixture of 0.628 g (2 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.551 g (3 mmol) of nicotinoyl chloride, hydrochloride, 0.606 g (6 mmol) of triethylamine and 15 mg of 4-(dimethylamino)pyridine in 17 ml of dichloromethane is refluxed for 7 hours. The mixture is washed with H2O, 2N citric acid, H2O, 1N NaHCO3, brine and dried (Na2SO4). The solvent is removed and the solid recrystallized from hexane-dichloromethane to give 0.12 g of crystals, m.p. 217°-220° C. Anal Calc'd for C27H21N3O2H2O: C,74.1; H,5.3; N,9.6. Found: 73.6; H,4.7; N,9.8.