Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][NH:27][CH3:28])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([O:33][C:34]([CH3:39])([CH3:38])[C:35](Cl)=[O:36])(=O)C.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([CH2:26][N:27]([CH3:28])[C:35](=[O:36])[C:34]([OH:33])([CH3:38])[CH3:39])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CNCc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CN(C)C(=O)C(C)(C)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.2 %

Procedure:
To a cold (5° C.) solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one (0.24 g, 0.52 mmol) in DMF (2.0 ml), was added 2-acetoxyisobutyryl chloride (0.093 g, 0.56 mmol), followed by the addition of triethylamine (0.072 g, 0.71 mmol). The mixture was stirred at room temperature for an additional 2 h and concentrated in vacuo. The residue was partitioned between water (5.0 mL) and EtOAc (15.0 mL). The EtOAc extract was washed with water, dried (Na2SO4), and concentrated to dryness. The resulting material (0.2 g) was stirred with 1M. LiOH (0.5 mL, MeOH/Water 1:1 v/v) at room temperature for 3 h, cooled, acidified with trifluoroacetic acid and the product was purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m/z=551 M+H) were combined and freeze dried to give a white powder. This was partitioned between 5% NaHCO3 (10 mL) and EtoAc (15 mL). The organic layer was washed with water, dried (Na2SO4), and concentrated to dryness to afford the title compound (0.075 g) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.59 (s, 1H), 8.41 (br, 1H), 7.60 (m, 2H), 7.01 (m, 2H), 6.52 (s, 1H), 5.45 (s, 2 h), 5.29 (s, 2H),
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[C:4]([N:18]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38](Cl)=[O:39])=[CH:34][CH:33]=1>O1CCOCC1.CO.O1CCOCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[NH:8]2)=[C:4]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:38](=[O:39])[CH2:37][O:36][C:35]3[CH:41]=[CH:42][C:32]([Cl:31])=[CH:33][CH:34]=3)[CH2:20][CH2:19]2)[N:3]=1
Reactant: Nc1nc(N2CCCNCC2)c2nc(-c3ccc(F)cc3)[nH]c2n1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc(N2CCCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(F)cc3)[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of 2-amino-6-(homopiperazin-1-yl)-8-(4-fluorophenyl)-9H-purine (0.2 mmol) in dioxane/methanol (1:1; 5 ml) was added potassium carbonate (55 mg, 0.4 mmol) and a solution of 4-chlorophenoxyacetyl chloride (60 mg, 0.24 mmol) in dioxane (1 ml). The resulting mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was purified by flash chromatography on silica (methanol/dichloromethane 1:40), yielding the pure title compound (60 mg, 60%).
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([CH3:5])[C:3]#[CH:4]>C1(C)C=CC=CC=1>[CH3:5][C:2]1([CH3:1])[CH:3]=[CH:4][C:16]2[C:7](=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:13]=[CH:14][CH:15]=2)[NH:6]1
Reactant: C#CC(C)(C)Nc1ccccc1C(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1NC(C)(C)C=C2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[(1,1-dimethylprop-2-yn-1-yl)amino]benzoate (1.5 g, 6.90 mmol) in toluene (30 mL) was added cuprous chloride (0.683 g, 6.90 mmol). After stirring at 100° C. overnight the reaction was concentrated under vacuum. Purification by silica gel chromatography (5% EtOAc/hexanes) afforded the desired product.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH2:45][CH3:46])[CH3:44])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH2:45][CH3:46])[CH3:44])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(C)CCOc1ccc(CN(CC)c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1F
Yield: 68.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-ethyl-N-methylacetamide (7.9 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (10 mg) was obtained.
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:3](=[C:4]23)[CH:2]=1.[OH-].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>CS(C)=O>[CH2:42]([N:22]1[C:21](=[O:25])[C:5]2[C:4]3[C:19]4[C:8](=[CH:7][CH:6]=2)[C:9]2[C:20]5[C:13]([CH:12]=[CH:11][CH:10]=2)=[CH:14][CH:15]=[CH:16][C:17]=5[C:18]=4[CH:1]=[CH:2][C:3]=3[C:23]1=[O:24])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH3:29]
Reactant: O=C1NC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Reactant: CCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCN1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Temperature: 25 °C
Reaction time: 90 h

Procedure:
0.40 g (1.25 mmol) of perylene-3,4-dicarboximide and 0.45 g (8 mmol) of KOH powder are suspended in 30 ml of DMSO, 1.38 g of 1-bromotetradecane are added, and the mixture is stirred at room temperature for 90 h. For precipitation, 300 ml of dist. water are added, the precipitated product is filtered off with suction and washed with dist. water and dilute sodium chloride solution. Chromatographic filtration, followed by column chromatography, in each case on silica gel using chloroform, gives a yellow and a red fraction. According to thin-layer chromatography on silica gel using 3:2 xylene/petroleum ether, the yellow fraction contains 3 products having such similar Rf values that no further purification is undertaken. Yield 30 mg. A colour comparison shows that the red fraction is N-(1-tetradecyl)perylene-3,4-dicarboximide. Yield 30 mg (5%) of a red powder showing a strong solid fluorescence. Rf (CHCl3 /silica gel)=0.81.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH2:24]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH2:27][CH3:28]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:33][C:32]4[CH:34]=[CH:35][C:29]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:30][CH:31]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCCCCc1ccc(N)cc1
Product: CCCCCc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 21.7 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-pentylaniline (55.5 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-pentylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (15.7 mg).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.C([Sn](CCCC)(CCCC)[C:44]1[S:48][C:47]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[N:46][CH:45]=1)CCC>C1(C)C=CC=CC=1.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>[C:34]([O:33][C:32]([NH:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:4]1[N:3]=[C:2]([C:44]2[S:48][C:47]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[N:46][CH:45]=2)[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]=1[F:23])=[O:38])([CH3:35])([CH3:36])[CH3:37]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnc(NC(=O)OC(C)(C)C)s4)c3C2=O)c(OC)c1
Yield: 64.7 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (50 mg, 0.091 mmol), tert-butyl 5-(tributylstannyl)thiazol-2-ylcarbamate (53.5 mg, 0.109 mmol), and tetrakis(triphenylphosphine)palladium(0) (105 mg, 0.091 mmol) in toluene (1 mL) was heated to 102° C. for 24 h. After removal of the solvent, the resulting crude material was reconstituted in MeOH/DMF (6.0 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (70-75% gradient, 0.035% TFA). The collected fractions were stripped to dryness via rotary evaporation to yield the title compound (42 mg, 64%). [M+H] calc'd for C35H45FN6O7S, 713. found, 713.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[C:3]#[CH:4].Br[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2>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.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[C:3]#[C:4][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2
Reactant: C#CC(O)c1cccnc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3cccnc3)c21

Procedure:
Using Method D above, 3-hydroxy-3-(3-pyridinyl)-1-propyne (150 mg, 1.13 mmol) (from Example 24 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (135 mg, 0.42 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (32 mg) (Aldrich) and CuI (17 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 17 h, to yield rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(3-pyridinyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 40 mg, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:21]([NH2:24])([CH3:23])[CH3:22]>>[C:19]([NH:18][C:10]([NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[N:24][CH:21]([CH3:23])[CH3:22])#[N:20]
Reactant: N#CN=C(Nc1cc(Cl)cc(Cl)c1)Oc1ccccc1
Reactant: CC(C)N
Product: CC(C)N=C(NC#N)Nc1cc(Cl)cc(Cl)c1
Yield: 43 %

Procedure:
N-(3,5-Dichlorophenyl)-N'-cyano-O-phenylisourea (0.98 mmol, 300 mg) and isopropylamine (1 ml) was stirred in a sealed flask for 19 h at 75° C. After concentration the residue was dissolved in dichloromethane, washed with 1 N aqueous HCl (2×), water, dried (Na2SO4) and concentrated. The residue was crystallized from ethyl acetate/heptane 1:3 to give the title compound (115 mg, 43%) as white crystals. Mp 156-158.5° C.; 1H-NMR (CDCl3): δ 1.21 (d, 6H), 4.03 (m,1H), 4.70 (br d,1H), 7.16 (m, 2H), 7.29 (m,1H), 7.47 ppm (br,1H); MA calc for C11H12Cl2N4 : C, 48.73%; H, 4.46%; N, 20.66%. Found: C, 48.76%; H, 4.49%; N, 20.38%.
Reaction SMILES: [C:1]12([CH2:11][NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:13]1[CH:18]=[C:17]([C:19]([OH:21])=O)[C:16]([S:22][S:23][C:24]2[C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:15][CH:14]=1>CN(C)C1C=CN=CC=1>[C:1]12([CH2:11][NH:12][C:30](=[O:32])[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:23][S:22][C:16]3[CH:15]=[CH:14][CH:13]=[CH:18][C:17]=3[C:19]([NH:12][CH2:11][C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[O:21])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1ccccc1SSc1ccccc1C(=O)O
Agent: CN(C)c1ccncc1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ccccc1SSc1ccccc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Yield: 30.6 %

Procedure:
Prepared according to the method of Example 14 from 1-adamantanemethylamine (0.23 g), 4-dimethylaminopyridine (0.006 g) and 2,2′dithiosalicylic acid (0.2 g) to give the sub-title compound as an off-white solid (0.12 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:33][CH2:32]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:4]=1[C:5]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:32][CH2:33]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(NC(C)=O)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(NC(C)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-acetamidobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound:Rf=0.18 (silica gel, 1/1 ethyl acetate/methanol).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=2)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:9]=[C:8]([C:26]([F:29])([F:28])[F:27])[CH:7]=1.[H-].[Na+].O.[CH2:33]1COCC1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=2)[CH2:14][N:15]([CH3:33])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])[N:9]=[C:8]([C:26]([F:29])([F:27])[F:28])[CH:7]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(Cc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1)C(=O)OC(C)(C)C
Temperature: 21 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a stirred solution of 55 (3.51 g, 8.62 mmol) in THF (43 ml) was added NaH (0.689 g, 17.23 mmol). After 15 minutes Mel (2.69 ml, 43.1 mmol) was added and the resulting suspension was allowed to stir at 0° C. for 1 h and at 21° C. for 16 h. Water was added the product was extracted with EtOAc. After the usual work-up the residue was purified via Biotage (5% to 45% EtOAc/Hexane; 40+M column) to afford 138 (3.2 g, 7.59 mmol, 88% yield) as colorless oil. LRMS (ESI): (calc.) 421.4; (found) 444.2 (MNa)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[N:8]([CH2:20][CH2:21][C@H:22]3[CH2:24][O:23]3)[CH2:7][C:6]=2[CH:25]=1.C(O)C.[CH3:29][NH2:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:18])(=[O:19])[N:8]([CH2:20][CH2:21][C@H:22]([OH:23])[CH2:24][NH:30][CH3:29])[CH2:7][C:6]=2[CH:25]=1
Reactant: CN
Reactant: O=S1(=O)N(CC[C@H]2CO2)Cc2cc(F)ccc2N1c1ccccc1F
Solvent: CCO
Product: CNC[C@@H](O)CCN1Cc2cc(F)ccc2N(c2ccccc2F)S1(=O)=O
Temperature: 100 °C
Yield: 83 %

Procedure:
6-fluoro-1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.12 g, 0.29 mmol) was dissolved in an 8 M solution of methylamine in ethanol (3 mL, 24 mmol) and was heated to 100° C. for 192 sec. in the microwave. The reaction mixture was evaporated and the residue purified by flash chromatography (SiO2, 0-5% 7 M NH3-methanol/dichloromethane). The purified free-base was dissolved in dichloromethane (3 mL) and treated with hydrogen chloride (1.0 mL of a 2 M solution in ethyl ether), resulting in a white precipitate that was evaporated and dried under vacuum to provide (2S)-4-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-1-(methylamino)butan-2-ol (0.10 g. 83%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16](F)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])=[C:4]([F:22])[CH:3]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O-:27].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([O:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])=[C:4]([F:22])[CH:3]=1
Reactant: CN(C)CC[O-]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cl)cc1F
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2cn1
Yield: 64 %

Procedure:
To 250 mg of 4-(4-chloro-2-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile under an inert atmosphere was added 8 mL of 1 M sodium (2dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 2 hours, the reaction was stripped of tetrahydrofuran and water was added. The product was filtered, washed with water, dried, and recrystallized from chloroform/ether/hexanes to give 204 mg (64%) of 4-(4-chloro-2-fluoro-phenylamino)-6-(2-dimethylamino-ethoxy)-[1,7]naphthyridine-3-carbonitrile as a yellow solid: melting point 150-152° C.; mass spectrum (m/e): M+H 385.9.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@@H:11]([CH3:15])[NH:10]1>C1(C)C=CC=CC=1>[CH3:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@@H:11]([CH3:15])[N:10]1[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccn1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: Cc1ccccc1
Product: C[C@@H]1CNC[C@H](C)N1c1ncccn1

Procedure:
A solution of 820 mg 2-chloropyrimidine and 1.6 g cis-2,6-dimethylpiperazine in 25 mL toluene was heated at reflux temperature for 12 hours. The solvent was evaporated, the residue was basified with 5% sodium hydroxide and extracted with 2×100mL of dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give cis-2,6-dimethyl-1-(2-pyrimidyl)-piperazine. This amine was then used to prepare 2-phenyl-4(5)-[(4-(2-pyrimidinyl)-cis-2,6-dimethylpiperazin-1-yl)-methyl]-imidazole (Compound 140), m.p. 130°-135° C., according to the procedures described in Example VIII.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[N:10]=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18].O>ClCCl>[CH3:3][CH:2]([CH3:4])[CH2:1][NH:5][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[N:10]=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18]
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)CNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
Isobutylamine (15.6 mL, 157 mmol) was added dropwise to a 5° C. solution of 4-chloro-3-nitro[1,5]naphthyridine (15.0 g, 71.6 mmol) in dichloromethane (300 mL). The reaction was allowed to stir at room temperature for 4 hours, then was concentrated under reduced pressure to afford a residue that was treated with water (300 mL). The mixture was stirred for 30 minutes, then a solid was isolated by filtration, rinsed with water (100 mL), and dried in a vacuum oven at 50° C. overnight to afford 17.25 g of N-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[C:9](Cl)(=[O:11])[CH3:10].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: Nc1ccccc1Br
Agent: Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1Br
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of 2-bromophenylamine (1.0 equiv.) in DCM (0.2 M) was added acetyl chloride (1.5 M) at 0° C. The resulting mixture was stirred at this temperature overnight. 1 N hydrochloric acid (0.4 equiv.) was added to quench the reaction. The mixture was extracted with DCM and sodium bicarbonate and the combined organic layers were washed with brine, dried over sodium sulfate, concentrated and triturated from 16% ethyl acetate in petroleum ether to give the desired product (73% yield) as a white power. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 8.33-8.31 (m, 1H), 7.61 (br, 1H), 7.54-7.52 (m, 1H), 7.33-7.26 (m, 1H), 6.99-6.95 (m, 1H), 2.24 (s, 3H); MS (ESI) m/z 203.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Referring to FIG. 37, to a solution of 3,5-dimethylphenol (10 g, 82 mmol) in CH3CN (150 mL) were added ethyl 2-bromoacetate (14.9 g, 90 mmol) and K2CO3 (16.9 g, 123 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was poured into water (200 mL) and the resulting mixture was extracted with ethyl acetate (150 mL×2). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give product as a yellow oil, which was used in the next step without further purification (19 g); 1H NMR (CDCl3, 300 MHz): δ 6.13 (s, 1H), 6.11 (s, 2H), 4.59 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 3.77 (s, 6H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O:13][C:14]([C:16]1[S:26][C:19]2[N:20]=[C:21]([NH2:25])[N:22]=[C:23](Cl)[C:18]=2[CH:17]=1)=[O:15])C>C1COCC1>[NH2:25][C:21]1[N:22]=[C:23]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:18]2[CH:17]=[C:16]([C:14]([OH:15])=[O:13])[S:26][C:19]=2[N:20]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)c1cc2c(Cl)nc(N)nc2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(OCc2ccccc2)c2cc(C(=O)O)sc2n1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a nitrogen filled flask containing sodium hydride (0.5 mmol, 60% in mineral oil) in anhydrous THF (5 ml) was added benzyl alcohol (0.5 mmol). The suspension was stirred vigorously for 10 minutes until no more gas was evolved before being transferred to a microwave reaction tube containing 2-amino-4-chloro-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.129 g, 0.5 mmol). The sealed tube was heated to 90° C. for 5 mins using 300 W in a CEM microwave apparatus (CARE!). The reaction mixture was partitioned between DCM and water, the water layer neutralised and evaporated to dryness in vacuo to leave the pure product.