Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]1=[O:13]
Reactant: Brc1cnc2ccccc2c1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cnc3ccccc3c2)C1=O
Yield: 73.7 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 3-bromo-quinoline (176.13 mg, 0.847 mmol), 1,4-dioxane (15 mL), copper iodide (16.13 mg, 0.0847 mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium carbonate (233.97 mg, 1.694 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 190 mg of the product (73.76% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:24])[CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C(C2C=CC=CC=2)([C@@H]2CCCN2)O)C=CC=CC=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([OH:24])[CH2:11][CH2:12][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(CCC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Product: O=[N+]([O-])c1ccc([C@@H](O)CC[C@H](O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 66.3 %

Procedure:
The product from Example 1A (30 g, 95 wt %, 91.4 mmol) was subjected to the conditions described in Example 32, substituting (R)-(−)-α,α-diphenyl-2-pyrrolidinemethanol for (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol, to give the title compound (20.14 g, >99.55 ee, 61% yield) which was contaminated with 9.7% of the meso isomer (vs. dl isomer).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[OH-].[K+].[CH2:10]([O:12][P:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[N:32][NH2:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)(=[O:17])[O:14][CH2:15][CH3:16])[CH3:11]>C(O)C.C1COCC1.[Hg]=O>[CH2:10]([O:12][P:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[N+:32]=[N-:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)(=[O:17])[O:14][CH2:15][CH3:16])[CH3:11]
Reactant: CCOP(=O)(Cc1ccc(C(=NN)c2ccccc2)cc1)OCC
Agent: O=S(=O)([O-])[O-]
Agent: O=[Hg]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOP(=O)(Cc1ccc(C(=[N+]=[N-])c2ccccc2)cc1)OCC
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a mixture of mercury (II) oxide (0.21 g, 0.97 mmol), sodium sulphate (0.16 g, 1.1 mmol) and sat potassium hydroxide in ethanol (0.2 ml) was added a solution of 15 (0.28 g, 0.81 mmol) in dry THF (20 ml). The mixture was stirred in the dark for 1 h. the filtered through a celite pad. Concentration of the filtrate in vacuo yielded 16 (0.25 g, 89%) as a dark red oil; δH (CDCl3) 1.28 (6H, d, JH-H=7.1 Hz, 2×CH2CH3), 3.16 (2H, d, JH-P=21.7 Hz, ArCH2P), 3.98-4.13 (4H, m, 2×CH2CH3), 7.15-7.43 (9H, m, Ar—H) ppm; δC (CDCl3) 16.4 (d, JC-P=6.0 Hz, 2×CH2CH3), 33.3 (d, JC-P=138.2 Hz, ArCH2P), 62.1 (d, JC-P=6.8 Hz, 2×CH2CH3), 125.1, 125.2, 125.2, 125.6, 129.1 (Ar—C), 129.4 (4-C), 130.4 and 130.5 (1-, 1′-C) ppm; δP (CDCl3) 26.37 ppm; νmax (thin film) 2982 (C—Hst), 2039 (C═N=Nst), 1248 (P═Ost), 1027 (P—Ost) cm−1; m/z (ES+) 403 ([M+NH4+MeCN]+100%); found (FI+) 344.1778, C18H21N2O3P requires 344.1290.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([NH:27][C:28]1[CH:29]=[C:30](I)[CH:31]=[CH:32][CH:33]=1)(=[O:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:24]([NH:27][C:28]1[CH:33]=[C:32]([C:23]#[C:22][C:15]2([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:8]=3)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]2)[CH:31]=[CH:30][CH:29]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Nc1cccc(I)c1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(NC(C)=O)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 59.6 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.2 g, 0.64 mmol) and 3-acetamido-1-iodobenzene (0.17 g, 0.64 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.3 h, was cooled to room temperature and was concentrated in vacuo. The residue was purified by flash chromatography, eluting with 1:1 hexanes/ethyl acetate, to provide the title compound as tan solid (0.17 g, 60%), m.p. 58°-60° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].C([Li])CCC.[C:16](OCC)(=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].[NH4+].[Cl-]>CCOCC.CCCCCC>[CH3:1][O:2][C:3]1[C:4]([O:9][CH3:10])=[CH:5][CH:6]=[CH:7][C:8]=1[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: COc1ccccc1OC
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1cccc(OC)c1OC
Temperature: -40 °C
Reaction time: 24 h

Procedure:
A mixture of 27.6 g of 1,2-dimethoxybenzene in 160 ml of ether is cooled to −40° C., 250 ml of 1.6 M solution of n-butyllithium in hexane are added dropwise and the mixture is then stirred for 24 hours while allowing the temperature to return to RT. The reaction mixture is cooled to −20° C., 136 ml of diethyl oxalate are added quickly and the mixture is stirred while allowing the temperature to return to RT. After stirring for 30 minutes at RT, the reaction mixture is poured into saturated NH4Cl solution, the phases are separated by settling, the aqueous phase is extracted with ether, the combined organic phases are washed twice with water and dried over Na2SO4, and the solvents are evaporated off under vacuum. The excess diethyl oxalate is removed by distillation under vacuum (b.p.=90° C. at 2400 Pa). The resulting crude product is chromatographed on silica gel, eluting with a heptane/iso-ether mixture (90/10; v/v). 25 g of the expected product are obtained and are used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]3[CH2:10][NH:9][C:8](=[O:17])[C:7]=3[C:6]=2[CH:5]=1)([O-:3])=[O:2].[Na]>>[N+:1]([CH:4]1[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]3[CH2:10][NH:9][C:8](=[O:17])[C:7]=3[C:6]=2[CH2:5]1)([O-:3])=[O:2]
Reactant: O=C1NCc2ccc3c(c21)C=C([N+](=O)[O-])CO3
Agent: [Na]
Product: O=C1NCc2ccc3c(c21)CC([N+](=O)[O-])CO3
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To 8-nitro-2,3-dihydropyrano[3,2-e]isoindol-1(7H)-one ((70), 1.1 g, 4.74 mmol) in solvent A (CHCl3, 100 ml) and solvent B (i-PrOH 4 ml) was added silica gel (3.3 g), followed by addition of sodium boronhydride (400 mg, 11.5 mmol) in portions. Resulting mixture was stirred for 2 hr. The silica gel was filtered and washed well with CHCl3. The filtrate was washed with H2O, and sat NaCl. The organic solution was separated and dried over Na2SO4 and concentrated in vacuo to give the title compound (790 mg, 71%) as a solid.
Reaction SMILES: [C:1](=[O:14])([O-])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=C(C#CCC)C=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCCCCC>C(OCC)(=O)C>[CH2:3]([O:2][C:1]([N:19]1[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]1)=[O:14])[CH2:8][C:7]#[CH:6]
Reactant: CCC#Cc1cccc(OC(=O)[O-])c1
Reactant: OC1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C#CCCOC(=O)N1CCC(O)CC1
Yield: 101.7 %

Procedure:
10.0 g of 3-butynylphenyl carbonate and 5.8 g of 4-hydroxypiperidine were heated in a solvent-free condition at 100° C. for 30 minutes. After completion of the reaction, silica gel column chromatography (elution solvent: Hexane:ethyl acetate=1:1-1:2) was used for purification to obtain 10.6 g of the intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=3)[CH2:22][CH2:23]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCNCC2)C1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(C(=O)c3ccc(F)cc3)CC2)C1

Procedure:
Compound 760 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and 4-fluoro-benzoyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 30% acetonitrile/water/0.5% TFA) and isolated as a white powder (0.0098 g, 2% yield). HRMS (M−H) calcd for C26H26N4Cl2O4F: 547.13151. found: 547.1310.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][C:8]2[N:9]([N:21]=[C:22]([CH3:24])[CH:23]=2)[C:10]=1[NH:11][C:12](=[O:20])[CH2:13]C1C=CC=CC=1)=[O:4].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(Cl)Cl>O>[CH3:24][C:22]1[CH:23]=[C:8]2[N:7]=[CH:6][C:5]3[C:3]([OH:4])=[CH:13][C:12]([OH:20])=[N:11][C:10]=3[N:9]2[N:21]=1
Reactant: COC(=O)c1cnc2cc(C)nn2c1NC(=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2ncc3c(O)cc(O)nc3n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 250 mL round bottom flask containing Compound (20-1) (1.62 g, 5.0 mmol, 1 eq.), THF (30 mL), and NaHMDS (7.5 mL, 7.5 mmol, 1.5 eq.) was stirred at room temperature for 2 h. The reaction was treated with CH2Cl2 (30 mL) and water (40 mL). The aqueous phase was extracted with CH2Cl2 (2×15 mL). The water layer was acidified with concentrated HCl (˜10 mL). The precipitated solid was filtered and washed with CH2Cl2 (4 mL) to furnish Compound (20-2) as a yellowish solid. The acidified water layer was extracted with 5% MeOH in CH2Cl2 (3×25 mL). The combined organic phases were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography using MeOH and CH2Cl2 as the mobile phases to furnish Compound (20-2) as a yellowish solid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:19]([CH3:20])[C:13]2=[N:14][CH:15]=[C:16](I)[CH:17]=[C:12]2[N:11]=1)[CH3:2].[F:21][C:22]([F:33])([F:32])[C:23]([F:31])([F:30])[C:24]([F:29])([F:28])C([O-])=O.[Na+].C(=O)([O-])O.[Na+].N>[Cu](I)I.C1(C)C(C)=CC=CC=1.CN1C(=O)CCC1>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:19]([CH3:20])[C:13]2=[N:14][CH:15]=[C:16]([C:24]([F:29])([F:28])[C:23]([F:31])([F:30])[C:22]([F:33])([F:32])[F:21])[CH:17]=[C:12]2[N:11]=1)[CH3:2]
Reactant: O=C([O-])C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCSc1ccccc1-c1nc2cc(I)cnc2n1C
Agent: I[Cu]I
Agent: N
Agent: O=C([O-])O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1C
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)C(F)(F)C(F)(F)F)cnc2n1C
Temperature: 150 °C
Yield: 34.3 %

Procedure:
A mixture of 2-(2-ethylsulfanyl-phenyl)-6-iodo-3-methyl-3H-imidazo[4,5-b]pyridine (311 mg), copper iodide (1.5 g), sodium heptafluorobutyrate (1.8 g), NMP (5 ml), and xylene (25 ml) was stirred with heating at 150° C. for 12 hours. Into the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution and 28% aqueous ammonia were poured, and extracted with tert-butyl methyl ether. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 118 mg of 2-(2-ethylsulfanyl-phenyl)-6-heptafluoropropyl-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 128).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[CH:6][N:7]=1)[C:14]#[N:15]
Reactant: N#Cc1ccc(O)c(Br)c1
Reactant: O=Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(C=O)cn2)c(Br)c1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
Combine 6-chloro-pyridine-3-carbaldehyde (1.00 g, 7.09 mmol), 3-bromo-4-hydroxy-benzonitrile (1.48 g, 7.80 mmol) in dimethylacetamide (40 mL). Add potassium carbonate (1.47 g, 10.64 mmol) and stir and heat the reaction at 130° C. for 2 h. Let cool down the reaction to room temperature and poured into water. Filter the precipitate formed, washing with water, to give the title compound (1.55 g, 72%)
Reaction SMILES: CS/[C:3](/[NH2:6])=[N:4]/[NH2:5].[IH:7].[NH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>O>[IH:7].[NH2:5][NH:4][C:3]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])=[NH:6]
Reactant: CS/C(N)=N/N
Reactant: CCCCN
Agent: I
Solvent: O
Product: CCCCNC(=N)NN

Procedure:
S-Methylisothiosemicarbazide hydroiodide (46.6 g) and 1-aminobutane (48 ml) and water (100 ml) were heated under reflux for 1 hour. The resulting solution was evaporated to an oil which was crystallised from amyl alcohol/80-100 PE, to give the title compound (a).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]3[C:19]4[CH:31]=[CH:30][C:29](=[O:32])[N:28]([C:33]5[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=5[F:40])[C:20]=4[N:21]=[C:22](S(C)(=O)=O)[N:23]=3)[CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[NH:41]1[CH2:46][CH2:45][CH:44]([NH:47]C(=O)OC(C)(C)C)[CH2:43][CH2:42]1>>[NH2:47][CH:44]1[CH2:45][CH2:46][N:41]([C:22]2[N:23]=[C:18]([C:13]3[CH:12]=[C:11]([NH:10][C:8]([C:5]4[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:9])[CH:16]=[CH:15][C:14]=3[CH3:17])[C:19]3[CH:31]=[CH:30][C:29](=[O:32])[N:28]([C:33]4[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=4[F:40])[C:20]=3[N:21]=2)[CH2:42][CH2:43]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1-c1nc(N2CCC(N)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 2 from 6-chloro-N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-3-pyridinecarboxamide and 1,1-dimethylethyl 4-piperidinylcarbamate: LC-MS m/z 602 (M+H)+, 1.75 min (ret time).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.Cl.[CH2:13]([O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.O>CS(C)=O>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=2)=[CH:26][CH:27]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccnc(Cl)c1[N+](=O)[O-]
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccnc(Nc2ccc(OCc3ccccc3)cc2)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
A suspension of 2-chloro-4-methyl-3-nitropyridine (8.63 g), 4-benzyloxyaniline hydrochloride (13.0 g) and triethylamine (20.9 ml) in DMSO (150 ml) was stirred at 120° C. overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (10.7 g).
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=O)[C:7]([CH3:11])([CH3:10])[CH2:6][CH2:5][C:4]1=[O:12])C.CC1C(=O)C(C)(C)CCC1=O>>[CH3:1][CH:3]1[CH2:8][C:7]([CH3:11])([CH3:10])[CH2:6][CH2:5][C:4]1=[O:12]
Reactant: CCC1C(=O)CCC(C)(C)C1=O
Agent: CC1C(=O)CCC(C)(C)C1=O
Product: CC1CC(C)(C)CCC1=O

Procedure:
When working like indicated above, but replacing 2-ethyl-4,4-dimethyl-cyclohexane-1,3-dione by the appropriate compound of formula (II), namely 2,4,4-trimethyl-cyclohexane-1,3-dione (prepared as described in DE 3,112,056), 2,4,4-trimethyl-1-cyclohexanone was obtained and showed the following analytical data:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])=[CH:20][CH:21]=2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(CCN(C)C)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(CCN(C)C)cc1
Yield: 31.4 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{4-[2-(dimethylamino)ethyl]phenylamino}-1,5-naphthyridin-3-yl)ethanone (40 mg, 0.11 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) followed by formation of the dihydrochloride salt to afford the desired product (13 mg, 22%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.29 (s, 1H), 8.42 (d, J=9.1 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 7.44 (d, J=8.5 Hz, 2 H), 7.41-7.35 (m, 3H), 7.11 (br s, 1H), 3.43-3.36 (m, 2H), 3.23-3.13 (m, 2H), 2.98 (s, 6H), 2.80 (s, 3H); ESI MS m/z 479 [M+H]+; HPLC>99% (AUC), tR=9.67 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14]3=[N:15][C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:17]=4[N:13]3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([O:28][C:29]([F:32])([F:31])[F:30])[CH:3]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[CH3:60][NH:61][CH3:62]>C1(C)C=CC=CC=1.O.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]>[Cl:22][C:21]1[C:16]2[N:15]=[C:14]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([N:61]([CH3:62])[CH3:60])=[CH:3][C:4]=4[O:28][C:29]([F:32])([F:30])[F:31])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[C:17]=2[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][CH:20]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(Br)cc1OC(F)(F)F
Reactant: CNC
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(N(C)C)cc1OC(F)(F)F
Temperature: 70 °C
Reaction time: 3 h
Yield: 47.3 %

Procedure:
A mixture of 1-[4-bromo-2-(trifluoromethoxy)phenyl]-10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (500 mg, 0.942 mmol), sodium tert-butoxide (226 mg, 2.35 mmol), 2-(di-tert-butylphosphino)biphenyl (22.4 mg, 0.0754 mmol), tris(dibenzylideneacetone)dipalladium (86.2 mg, 0.0942 mmol), and dimethylamine (2.0 M solution of tetrahydrofuran, 1.4 mL, 2.8 mmol) in toluene (1.4 ml) was stirred at 70° C. under nitrogen for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (221 mg, 0.446 mmol, 47%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[N:5]([CH2:17][C:16]1[CH:19]=[CH:20][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=1)[CH2:17][C:16]1[CH:19]=[CH:20][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Nc1ccc(F)c(F)c1
Product: O=[N+]([O-])c1ccc(CN(Cc2ccc([N+](=O)[O-])cc2)c2ccc(F)c(F)c2)cc1

Procedure:
3,4-Difluoroaniline and 4-nitrobenzyl bromide were processed using the method described in Example 32A to afford the title compound. LC/MS Rt 2.15 m/z 400 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH:19]=2)=[CH:16][C:15]([C@H:44]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]2)[CH3:45])=[CH:14][N:13]=1.[F:56][C:57]1[CH:58]=[C:59]([NH2:65])[CH:60]=[N:61][C:62]=1[O:63][CH3:64].[NH4+].[Cl-]>C1COCC1>[F:56][C:57]1[CH:58]=[C:59]([NH:65][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)[CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH:19]=3)=[CH:16][C:15]([C@H:44]([N:46]3[CH2:47][CH2:48][N:49]([S:52]([CH3:55])(=[O:53])=[O:54])[CH2:50][CH2:51]3)[CH3:45])=[CH:14][N:13]=2)[CH:60]=[N:61][C:62]=1[O:63][CH3:64]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3F)nc(C)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)c(F)c3)nc(C)n2)cc1
Yield: 56.2 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M solution in THF) (1.42 mL, 1.42 mmol) was added to a solution of 6-(2-fluoro-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.300 g, 0.47 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, Inc. North Brunswick, N.J.) (0.101 g, 0.71 mmol) in THF (1.5 mL) at −10° C. More lithium bis(trimethylsilyl)amide (1.0 M solution in THF) (1.42 mL, 1.42 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.101 g, 0.71 mmol) were added and the reaction mixture was stirred for another hour. Saturated NH4Cl (aq.) was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.200 g, 0.264 mmol, 55.9% yield) as a brown foam. m/z (ESI, +ve) 757.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.92 (br. s., 1H) 8.24 (dd, J=12.52, 2.15 Hz, 1H) 8.13 (d, J=1.57 Hz, 1H) 8.03 (d, J=2.15 Hz, 1H) 7.50 (br. s., 1H) 7.19 (d, J=6.46 Hz, 4H) 6.87 (d, J=8.61 Hz, 5H) 6.52 (br. s., 1H) 4.79 (br. s., 4H) 4.01 (s, 3H) 3.79 (s, 6H) 3.44 (br. s., 1H) 3.17 (br. s., 4H) 2.75 (s, 3H) 2.66 (s, 3H) 2.40-2.59 (m, 4H) 1.34 (br. s., 3H)