Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+].O=[C:24]([CH2:28][CH2:29][CH2:30][CH3:31])[C:25]([O-:27])=[O:26]>C(O)C.C(O)(=O)C.[Pd]>[CH2:8]([C:7]1[C:2]([NH:1][CH:24]([CH2:28][CH2:29][CH2:30][CH3:31])[C:25]([OH:27])=[O:26])=[N:3][CH:4]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[N:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCCC(=O)C(=O)[O-]
Reactant: Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1
Agent: [Pd]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCC(Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1)C(=O)O
Temperature: 65 °C
Reaction time: 4 h
Yield: 46.1 %

Procedure:
4-(5-amino-6-benzylpyrazin-2-yl)phenol (200 mg, 0.72 mmol) was mixed with 2-Ketohexanoic acid sodium salt (220 mg, 1.44 mmol) in ethanol (20 mL). Pd/C (10% Palladium in active carbon, 100 mg) was added with a few drops of acetic acid, and the reaction mixture heated to 65° C. Air was bubbled out by N2 gas, and a hydrogen balloon applied to the reaction flask. The reaction was continuously stirred for 4 hrs. After cooling down, it was filtered and the resulting solution was purified by flash chromatography (eluting solvent: 50% EtOAc in heptanes) to give the product as a yellow powder (130 mg, 46%). MS (ESI): m/z 392.2 (M+1).
Reaction SMILES: O(C)[Na].[CH3:4][O:5][CH:6]([C:12]([O:14]C)=O)[C:7]([O:9]CC)=O.Cl.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](=[NH:26])[NH2:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>CCO>[OH:14][C:12]1[N:25]=[C:24]([C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:28][CH:27]=2)[NH:26][C:7](=[O:9])[C:6]=1[O:5][CH3:4]
Reactant: N=C(N)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(OC)C(=O)OC
Agent: CO[Na]
Agent: Cl
Solvent: CCO
Product: COc1c(O)nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
The NaOCH3 (7.8 g, 3 eq) was added to a stirred solution of 1-ethyl 3-methyl 2-methoxymalonate (11 g, 1.3 eq), 4-nitrobenzimidamide hydrochloride (9.6 g, 1 eq) and EtOH (240 ml) and the mixture was refluxed for 8 hrs. After 8 hrs, the solvent was evaporated and water (10˜15 ml) was added to the mixture then the mixture was cooled to 0° C. and carefully acidified with conc. HCl. After overnight cooling, it led to the formation of brown precipitates. The mixture was filtered and the precipitates was dried in vacuo to give a brown solid (65%) as a product.
Reaction SMILES: [NH2:1][C:2]1[C:16]([F:17])=[CH:15][C:5]([C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]2)=[O:7])=[C:4]([F:18])[CH:3]=1.N1(CCN)CCC[CH2:20]1>>[NH2:1][C:2]1[C:16]([F:17])=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:14][CH2:20][CH2:13][CH2:12]2)=[O:7])=[C:4]([F:18])[CH:3]=1
Reactant: NCCN1CCCC1
Reactant: CN1CC[C@@H](NC(=O)c2cc(F)c(N)cc2F)C1
Product: Nc1cc(F)c(C(=O)NCCN2CCCC2)cc1F

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 229, on a 5.77 mmol scale utilising 2-pyrrolidin-1-ylethanamine (Aldrich; 725 mg, 6.35 mmol), as a beige solid (648 mg, 42%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:41]4[CH2:40][CH2:39][N:38]([CH:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)[CH2:43][CH2:42]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: CN1CCC(N2CCNCC2)CC1
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCN(C2CCN(C)CC2)CC1
Temperature: 105 °C
Yield: 69.6 %

Procedure:
Following the procedure of Example 11, a mixture of 220 mg (0.5 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile, 290 mg (1.6 mmol) of 1-(1-methylpiperidin-4-yl)piperazine in 1.2 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 20 hours to yield the crude product. Purification by silica gel chromatography (gradient 9:1 methylene chloride/methanol to 85:15 methylene chloride/methanol) gives 210 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-methoxy-7-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]quinoline-3-carbonitrile as a beige solid, mp 220-226° C. (shrinks at 205° C.).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:11]2[N:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([NH:21][O:22]C3CCCCO3)=[O:20])=[N:15][CH:16]=2)[CH2:6]1.[ClH:33].C(O)C>C(OCC)(=O)C>[ClH:33].[ClH:33].[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:11]2[N:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([NH:21][OH:22])=[O:20])=[N:15][CH:16]=2)[CH2:6]1
Reactant: O=C(/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3F)C2)cn1)NOC1CCCCO1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3F)C2)cn1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of (2E)-3-(5-{[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (600 mg) and 2N HCl/Ethanol (13.6 ml, 20 eq) was stirred at room temperature for 2 hours. After then, ethyl acetate (10 ml) and IPE (50 ml) was added and stirred. Precipitate was filtered, washed with IPE, and dried under reduced pressure to give 486 mg (83%) of (2E)-3-(5-{[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide dihydrochloride as a powder.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:40][NH:41][C:42](=[O:66])[C:43]1[CH:48]=[C:47]([O:49][C:50]2[CH:65]=[CH:64][C:53]3[N:54]=[C:55]([NH:57][C@H:58]4[CH2:63][CH2:62][CH2:61][NH:60][CH2:59]4)[S:56][C:52]=3[CH:51]=2)[CH:46]=[CH:45][N:44]=1>CC(N(C)C)=O>[C:1]([N:60]1[CH2:61][CH2:62][CH2:63][C@H:58]([NH:57][C:55]2[S:56][C:52]3[CH:51]=[C:50]([O:49][C:47]4[CH:46]=[CH:45][N:44]=[C:43]([C:42]([NH:41][CH3:40])=[O:66])[CH:48]=4)[CH:65]=[CH:64][C:53]=3[N:54]=2)[CH2:59]1)(=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCNC4)sc3c2)ccn1
Reactant: CC(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCN(C(=O)C(C)C)C4)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To the reaction solution of isobutyric acid (4 μl, 40 μmol), HATU (15 mg, 40 μmol) and DIEA (14 μL, 80 μmol) in 400 μL of DMA was added (S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide (13 mg, 30 μmol) and DIPEA (6 μL, 30 μmol). The reaction solution was stirred at room temperature for 16 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give (S)-4-(2-(1-isobutyrylpiperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (6.8 mg, 15 μmol) as white powder. ES/MS m/z 454.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:22](O)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: Cc1ccc(C(=O)O)cc1C
Product: Cc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1C
Yield: 75.4 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 19.6 mg (0.131 mMol) 3,4-dimethylbenzoic acid, 12.0 mg (76%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:31][O:32][C:33](=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41]Br)[CH:36]=1.O>CN(C)C=O>[CH3:31][O:32][C:33](=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:14]([CH:11]2[CH2:12][CH2:13][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:28]=[CH:27][C:5]=4[N:6]=3)[CH2:10]2)[S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])(=[O:16])=[O:17])[CH:36]=1
Reactant: COC(=O)Cc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCN(c2nc3ccc(Cl)cc3s2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(CN(C2CCN(c3nc4ccc(Cl)cc4s3)C2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
N-[1(6-chlorobenzothiazole-2-yl)pyrrolidine-3-yl]-2-nitrobenzenesulfonamide (500 mg) was dissolved in dimethylformamide (5 mL). Sodium hydride (60%, oil, 50 mg) was added thereto and the mixture was stirred at room temperature for 1 hour. (3-bromomethylphenyl)acetic acid methyl ester (305 mg) was added thereto and the mixture was stirred for 16 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (412 mg). Yield: 60%.
Reaction SMILES: [N:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[OH:8].C([O:11][C:12](=O)[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1)[C:14](=O)[CH3:15])C.O>CO.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Zn+2]>[OH:7][C:6]1[N:1]=[C:2]2[O:8][C:12](=[O:11])[C:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[C:14]([CH3:15])[C:3]2=[CH:4][CH:5]=1
Reactant: Oc1cccc(O)n1
Reactant: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1)C(C)=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CO
Solvent: O
Product: Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2nc(O)ccc12
Temperature: 75 °C
Reaction time: 30 h
Yield: 57.4 %

Procedure:
Zn(OTf)2 (669 mg, 1.84 mmol) was added to a suspension of pyridine-2,6-diol (204 mg, 1.84 mmol) and 2-(3-nitrobenzyl)-3-oxobutyric acid ethyl ester (488 mg, 1.84 mmol) in methanol (10 mL), and the mixture was stirred at 75° C. for 30 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. It was then concentrated under reduced pressure to yield a crude product, which was then purified by column chromatography to yield the title compound (330 mg, 57%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([S:36](Cl)(=[O:38])=[O:37])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([S:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)(=[O:37])=[O:38])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(OC)c(OC)c4)cc3)cc2C1=O

Procedure:
The compound of example 85 was prepared analogous to compound of example 77 by reaction of compound of example 6 with 3,4-dimethoxybenzene sulfonyl chloride. The compound of example 85 was used directly without isolation for the preparation of compound of example 86.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[N:26]=[N:27][NH:28][N:29]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[N:26]=[N:27][NH:28][N:29]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(-c3nn[nH]n3)ccc21
Product: CC1c2ccc(-c3nn[nH]n3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:9][NH:8][CH2:7][CH2:6]2.I[CH2:17][CH2:18][F:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:19][CH2:18][CH2:17][N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CNCC2
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(cc1[N+](=O)[O-])CN(CCF)CC2
Temperature: 65 °C

Procedure:
6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (222 mg, 1.07 mmol) was taken in acetonitrile (5 mL), treated with 1-iodo-2-fluoroethane (0.40 g, 2.3 mmol) and potassium carbonate (500 mg, 3.62 mmol, Aldrich). The mixture was heated at 65° C. for 16 h, cooled, and partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to provide 2-(2-fluoroethyl)-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline which was taken directly to the next step without determination of yield. 1H NMR (400 MHz, CDCl3) δ ppm 2.89-3.04 (m, 6 H), 3.77 (s, 2 H), 3.94 (s, 3 H), 4.62-4.80 (dt, JHF=47.6, J=4.6 Hz, 2 H), 6.82 (s, 1 H), 7.63 (s, 1 H); ESIMS (M+H)+=255.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][N:30]=4)[N:25]=[CH:24][C:23]=3[NH2:32])[O:17][N:16]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][CH2:4][C:5]([NH:32][C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:22]=1[NH:21][CH2:20][C:18]1[O:17][N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=3)[CH:19]=1)=[N:30][CH:29]=[CH:28][CH:27]=2)=[O:6])[CH3:2]
Reactant: Nc1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, ethoxyacetyl chloride (1.6 g, 13 mmol) was added over a period of ten minutes to a cooled (6° C.) solution of N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}[1,5]naphthyridine-3,4-diamine (4.1 g, 12 mmol) and anhydrous triethylamine (2.6 mL, 18 mmol) in anhydrous dichloromethane (150 mL). After the reaction was stirred for 30 minutes, an analysis by HPLC indicated the presence of starting material, and additional ethoxyacetyl chloride (1.1 g) was added. The reaction was stirred for an additional 30 minutes and then was diluted with dichloromethane and washed with saturated aqueous potassium carbonate. The aqueous layer was separated and extracted with dichloromethane, and the combined organic fractions were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-ethoxy-N-[4-({[3-(4-fluorophenyl)isoxazol-5-yl]methyl}amino)[1,5]naphthyridin-3-yl]acetamide as a black oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH:23]=[C:24]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:25]=[CH:26][CH:27]=2)O1>>[CH:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:26]3[CH:25]=[C:24]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:23]=[CH:22][CH:27]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Product: CC(C)c1ccn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromo-7-isopropylimidazo[1,2-a]pyrimidine was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-(7-isopropylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile as a white powder: Found C, 76.71; H, 5.17; N 16.24. C22H18N4.0.3(H2O) requires C, 76.59; H, 5.43; N, 16.24; δH (400 MHz, CDCl3) 1.38 (6H, d, J 7), 3.16 (1H, septet, J 7), 6.88 (1H, d, J 7), 7.48-7.76 (7H, m), 7.82 (1H, dd, J 8 and 1), 7.85 (1H, s), 8.85 (1H, d, J 7); m/z (ES+) 339 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16].[CH3:20][Mg]Br>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:17]1[CH2:18][CH2:19]1)([OH:16])[CH3:20]
Reactant: C[Mg]Br
Reactant: Nc1ccc(-c2cccc(Cl)c2)cc1C(=O)C1CC1
Solvent: C1CCOC1
Product: CC(O)(c1cc(-c2cccc(Cl)c2)ccc1N)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (4-amino-3′-chloro-biphenyl-3-yl)-cyclopropyl-methanone (0.67 g, 2.5 mmol) in anhydrous THF (10 mL) at −78° C. was added a solution of methylmagnesium bromide (3.0 M in diethyl ether, 2.5 mL, 7.5 mmol) under nitrogen. The reaction mixture was slowly warmed to rt, stirred under nitrogen for 12 hours, and quenched with a saturated aqueous ammonium chloride solution (40 mL). Ethyl acetate (50 mL) was added, the organic layer was separated, and dried (MgSO4). After removal of the solvent, the residue was purified via silica gel chromatography (hexane:ethyl acetate/7: 1) to afford 1-(4-amino-3′-chloro-biphenyl-3-yl)-1-cyclopropyl-ethanol as yellow oil: MS (EI) m/z 287/289 (M+).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][C@@H:15]2[O:20][C:19]3[C:21]([NH2:26])=[C:22]([NH2:25])[CH:23]=[CH:24][C:18]=3[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[F:27][C:28]([F:33])([F:32])[C:29](O)=O>C(Cl)Cl>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][CH:15]2[O:20][C:19]3[C:18](=[CH:24][CH:23]=[C:22]4[NH:25][C:29]([C:28]([F:33])([F:32])[F:27])=[N:26][C:21]4=3)[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1

Procedure:
A solution of 3.1 g (7.3 mmole) of [(2R)-7,8-diamino-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate dihydrochloride in 50 mL of trifluoroacetic acid was refluxed under nitrogen for 6 hours. The mixture was diluted to 400 mL with methylene chloride, washed with 400 mL of water and with 400 mL of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to a crude foam in vacuum. The crude product was column chromatographed on silica gel with 1% methanol in chloroform and the product fractions combined and concentrated in vacuum to give 3.3 g of the (R)-enantiomer of the title compound as a white solid, m.p. 114-116° C., which retains one equivalent of chloroform.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:13][C:14]1([CH3:17])[CH2:16][O:15]1>>[I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:13][C:14]([CH3:17])([OH:15])[CH3:16])[CH:6]=1
Reactant: Ic1c[nH]cn1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(O)Cn1cnc(I)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
A mixture of 4-iodo-1H-imidazole, Cs2CO3 in 2,2-dimethyl oxirane was stirred at 120° C. for 20 min under irradiation with microwave. The reaction mixture was concentrated, and purified to give 1-(4-iodo-1H-imidazol-1-yl)-2-methylpropan-2-ol (Yield=71%). LC-MS: m/z=266 [M+H+] 1H NMR (CDCl3, 400 MHz): δ7.36 (s, 1 H), 7.06 (s, 1 H), 3.84 (s, 2 H), 1.22 (s, 6 H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:16]1=O>C(COC)OC>[CH3:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:16]=1[CH2:11][C:12]#[N:13]
Reactant: CC1C(=O)CCc2ccccc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1=C(CC#N)CCc2ccccc21
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 7.2 g (0.15 mole) of sodium hydride (50% in oil dispersion) in 200 ml of dimethoxyethane was added dropwise 28.1 g (0.15 mole) of diethylcyanomethylphosphonate [(C2H5O)2P(O)CH2CN]. The addition was complete in ten minutes while the reaction temperature rose to 44° C. The reaction mixture was stirred for 45 minutes and then 25.0 g (0.14 mole) of 1-methyl-2-tetralone was added dropwise over a 30 minute period. The reaction mixture was then warmed at 40° C. for two hours and poured into ice-water. The product was extracted with ether, and the ether extracts were dried over anhydrous magnesium sulfate and concentrated to a yellow oil (31.3 g). The latter was crystallized from ether-hexane to give 3,4-dihydro-1-methyl-2-naphthaleneacetonitrile as a light yellow solid, m.p. 48°-49° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:39]=[CH:38][C:34]([CH:35]=[N:36][OH:37])=[CH:33][CH:32]=1>>[F:26][C:23]([F:24])([F:25])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:5]1[CH:6]=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:37]/[N:36]=[CH:35]/[C:34]2[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:41])[F:40])=[CH:39][CH:38]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:28])=[O:27]
Reactant: ON=Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1ccccc1C(F)(F)F
Product: O=C(O)c1ccc(OCCCO/N=C/c2ccc(C(F)(F)F)cc2)cc1NC(=O)c1ccccc1C(F)(F)F
Yield: 70 %

Procedure:
The title compound (0.404 g, 70%) was prepared as a white solid from 4-(3-bromo-propoxy)-2-(2-trifluoromethyl-benzoylamino)-benzoic acid methyl ester and 4-trifluoromethyl-benzaldehyde oxime using a procedure similar to step 1 of example 6. mp=147.2-147.9° C.; mass spectrum −ES, (M−H) m/z 553. 1H NMR (400 MHz, DMSO-d6); δ 13.40 (bs, 1H), 11.90 (bs, 1H), 8.38 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H), 7.86 (d, 1H), 7.77 (m, 7H), 6.81 (dd, 1H), 4.33 (t, 2H), 4.18 (t, 2H), 2.18 (m, 2H). Elemental analysis: Calcd. for C26H20F6N2O5: C, 56.32; H, 3.64; N, 5.05, Found: C, 55.83; H, 3.27; N, 4.88.