Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Na+].[Cl-].[Ca+2:27].[Cl-]>O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Ca:27]
Reactant: [Ca+2]
Reactant: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Product: [Ca]
Temperature: 27.5 °C
Reaction time: 0.17 h
Yield: 87.3 %

Procedure:
Esomeprazole sodium (20 gm) is dissolved in water (200 ml) and then stirred for 10 minutes at 25-30° C. To the solution added a solution of calcium chloride (6 gm) in water (100 ml) for 15 minutes and stirred for 2 hours at 25-30° C. Filtered the solid, washed with water (40 ml) and then dried at 45-50° C. for 5-6 hours to give 18.2 gm of esomeprazole calcium salt crystalline form 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[C:11]1[C:6]=2[CH:7]=[CH:8][C:9]([NH2:21])=[CH:10]1.[CH:22]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=O.[CH2:29]([N:31]([CH2:34][CH3:35])[CH:32]=O)[CH3:30]>>[CH2:17]([N:16]([CH2:19][CH3:20])[C:12]1[N:13]=[C:14]2[C:5](=[C:6]3[C:11]=1[CH:10]=[C:9]([N:21]=[CH:22][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:8]=[CH:7]3)[CH:4]=[CH:3][C:2]([N:1]=[CH:32][N:31]1[CH2:34][CH2:35][CH2:30][CH2:29]1)=[CH:15]2)[CH3:18]
Reactant: CCN(C=O)CC
Reactant: O=CN1CCCC1
Reactant: CCN(CC)c1nc2cc(N)ccc2c2ccc(N)cc12
Product: CCN(CC)c1nc2cc(N=CN3CCCC3)ccc2c2ccc(N=CN3CCCC3)cc12
Yield: 66 %

Procedure:
As in Example 14, but using 3,8-diamino-6-diethylaminophenanthridine and N-formylpyrrolidine instead of 3,8-diamino-6-dimethylaminophenanthridine and N,N-diethylformamide. Yield 66%, melting point 149°-150° C. (chloroform/petroleum ether (60°-80° C.)).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][C:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:7])[CH3:6].CO[CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[C:35]([S:37]([O-:40])(=[O:39])=[O:38])[CH:34]=[CH:33][C:32]=1[CH3:41]>>[CH3:41][C:32]1[CH:33]=[CH:34][C:35]([S:37]([O-:40])(=[O:39])=[O:38])=[CH:36][CH:31]=1.[CH2:11]([O:10][C:9]([NH:8][C:5]([CH3:7])([CH3:6])[CH2:4][CH2:3][N+:2]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])([CH3:1])[CH3:19])=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)CCC(C)(C)NC(=O)OCc1ccccc1
Reactant: COCCOCCOCCOc1cc(S(=O)(=O)[O-])ccc1C
Product: COCCOCCOCC[N+](C)(C)CCC(C)(C)NC(=O)OCc1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 115 %

Procedure:
A mixture of benzyl 4-(dimethylamino)-2-methylbutan-2-ylcarbamate (0.54 g, 2 mmol) and [2-[2-(2-methoxyethoxy)ethoxy]ethoxy]p-toluenesulfonate (1.3 g, 4 mmol) was stirred overnight at 45° C. The crude reaction mixture was directly purified by reverse phase HPLC eluting from a C18 column with a gradient of 5 to 95% acetonitrile in water (with 0.01% acetic acid) to give a clear oil (0.95 g, 2.3 mmol). 1H NMR (D2O, 400 MHz) δ 1.18 (s, 6H), 2.05 (br m, 2H), 2.29 (s, 3H), 2.86 (s, 6H), 3.17-3.21 (m, 2H), 3.26 (s, 3H), 3.30 (br s, 2H), 3.48-3.56 (m, 8H), 3.71 (br s, 2H), 4.91 (br S, 2H), 7.25-7.27 (d, J=8.1 Hz, 2H), 7.30-7.36 (m, 5H), 7.57-7.59 (d, J=8.1 Hz, 2H); LRMS (ESI/APCI) m/z 411 [M]+
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][C:2]1=[O:8].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH:6]=[CH:5][C:4](=[O:7])[NH:3][C:2]2=[O:8])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)c(=O)[nH]1
Temperature: 80 °C

Procedure:
A mixture of 3.5 g 1H-Pyrimidine-2,4-dione and 3 g 1-Fluoro-4-nitro-benzene and 13.8 g Cs2CO3 in 60 mL DMF was heated to 80° C. for 12 h. This solution was poured on to 200 mL of water and the resulting precipitate was collected by filtration to yield a bright yellow crystalline product, which was dried under reduced pressure. Yield: 2.6 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[C:14]([CH3:39])=[C:15]([N:19]([CH2:24][C:25]2[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33]CC)=[O:32])=[C:27]([CH3:38])[CH:26]=2)[CH2:20][CH2:21][O:22][CH3:23])[CH:16]=[CH:17][CH:18]=1>>[CH3:23][O:22][CH2:21][CH2:20][N:19]([CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[C:27]([CH3:38])[CH:26]=1)[C:15]1[C:14]([CH3:39])=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)COc1ccc(CN(CCOC)c2cccc(Br)c2C)cc1C
Product: COCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(OC)cc2)c1C

Procedure:
Prepared from 4-methoxyphenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(2-methoxyethyl)amino]methyl}-2-methylphenoxy)acetate using the procedure described for Example 25 (Method A).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([NH2:21])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.[C:22]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+].O1CCCC1>C(O)(=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([NH:21][CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: O=C1CCCC1
Reactant: N#Cc1cc(N)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1cc(NC2CCCC2)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Temperature: 60 °C
Yield: 39 %

Procedure:
A mixture of 3-(5-fluoropyrid-2-yl)-5-(3-amino-5-cyanophenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), cyclopentanone (24 μL, 0.26 mmol), sodium cyanoborohydride, 1.0 M solution in tetrahydrofuran, (128 μl, 0.12 mmol) in acetic acid (4 mL) was heated at 60° C. for 1 hour. After cooling, the reaction mixture was diluted with ethyl acetate and then washed with water (2X) and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography using 20% ethyl acetate/hexanes afforded 15 mg (39%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-cyclopentylaminophenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.69 (d, 1H), 8.25 (m, 1H), 7.79 (s, 1H), 7.61 (m, 2H), 6.99 (s, 1H), 4.17 (d, 1H), 3.88 (m, 1H), 2.10 (m, 1H), 1.74 (s, 2H), 1.50 (m, 1H), 1.27 (m, 2H), 0.87 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH3:23])[CH:14]=1)[CH2:9][C:10](=[O:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Li].CO>C1COCC1>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH3:23])[CH:14]=1)[CH2:9][C:10]([OH:12])([CH3:25])[CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]C
Reactant: CCOc1cc([C@@H](CC(C)=O)NC(=O)OC(C)(C)C)ccc1OC
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(C)(C)O)NC(=O)OC(C)(C)C)ccc1OC
Yield: 14.1 %

Procedure:
To a solution of (1R)-[1-(3-ethoxy-4-methoxy-phenyl)-3-oxo-butyl]-carbamic acid tert-butyl ester (1 g, 3 mmol) in THF (10 mL) was added a solution of methyl lithium (4 mL, 3M, 12 mmol) at 0° C. To the mixture was added methanol (5 mL). The residue was extracted with ethyl acetate (50 mL) and NH4Cl (sat, 25 mL). The organic layer was washed with brine (100 mL) and dried over MgSO4. The solvent was removed in vacuo. The residue was purified with preparative HPLC to give (R)-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-carbamic acid tert-butyl ester (150 mg, 14% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[CH2:10][NH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:19]#[N:20].[C:28](OC(=O)C)(=[O:30])[CH3:29].CC1C=CC=CC=1>CO>[C:28]([N:9]1[CH2:10][C:11](=[O:16])[N:12]([CH3:15])[C:13](=[O:14])[N:8]1[C:6]1[CH:5]=[C:4]([Cl:17])[C:3]([CH:18]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C:19]#[N:20])=[C:2]([Cl:1])[CH:7]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CN1C(=O)CNN(c2cc(Cl)c(C(C#N)c3ccc(Cl)cc3)c(Cl)c2)C1=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(=O)N1CC(=O)N(C)C(=O)N1c1cc(Cl)c(C(C#N)c2ccc(Cl)cc2)c(Cl)c1
Reaction time: 90 h
Yield: 42.9 %

Procedure:
A mixture of 4 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-4 methyl-3,5-dioxo-1,2,4-triazin-2(1H)-yl)benzeneacetonitrile, 12 parts of acetic acid anhydride and 36 parts of methylbenzene was stirred for 90 hours at reflux temperature. After cooling, 16 parts of methanol were added. The solvent was evaporated in vacuo. The residue was stirred in water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethanol. The precipitated product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 2.0 parts (42.9%) of 1-acetyl-2-[3,5-dichloro-4[(4-chlorophenyl)cyanomethyl]phenyl]-1,6-dihydro-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione; mp. 178.1° C. (compound 78).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]([CH2:38][CH2:39][OH:40])[CH:35]([CH3:37])[CH3:36])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([N:34]([CH2:38][CH2:39][OH:40])[CH:35]([CH3:36])[CH3:37])(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC(C)N(CCO)S(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: CC(C)N(CCO)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-bromo-N-(2-hydroxyethyl)-N-isopropylbenzene-sulfonamide. MS (ESI): mass calcd. for C21H23FN4O3S, 430.15; m/z found, 431.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=1.4, 2H), 8.10 (dd, J=8.0, 1.4, 1H), 7.65-7.57 (m, 1H), 7.58-7.49 (m, 1H), 7.49-7.38 (m, 1H), 7.37-7.28 (m, 3H), 5.22 (s, 2H), 3.72 (p, J=6.7, 1H), 3.65-3.50 (m, 2H), 2.99 (t, J=6.0, 2H), 2.19 (d, J=7.0, 1H), 1.04 (d, J=6.7, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:63])[NH:21][C:22]3[C:27]([Cl:28])=[CH:26][C:25]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[N:36]=[C:37]([C@@H:40]6[CH2:44][C@H:43]([C:45]#[N:46])[CH2:42][N:41]6[C:47](=[O:57])[C@@H:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])[NH:38][CH:39]=5)=[CH:31][CH:30]=4)=[C:24]([O:58][C:59]([F:62])([F:61])[F:60])[CH:23]=3)=[CH:16][N:15]=2)[C@H:10]([CH3:64])[CH2:9]1)=O)(C)(C)C.[O:65]1CCOCC1>Cl>[CH3:56][O:55][C:53](=[O:54])[NH:52][C@H:48]([C:47]([N:41]1[CH2:42][C@@H:43]([C:45](=[O:65])[NH2:46])[CH2:44][C@H:40]1[C:37]1[NH:38][CH:39]=[C:35]([C:32]2[CH:33]=[CH:34][C:29]([C:25]3[CH:26]=[C:27]([Cl:28])[C:22]([NH:21][C:20]([C:17]4[CH:16]=[N:15][C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]5[CH3:64])=[CH:19][CH:18]=4)=[O:63])=[CH:23][C:24]=3[O:58][C:59]([F:60])([F:61])[F:62])=[CH:30][CH:31]=2)[N:36]=1)=[O:57])[CH:49]([CH3:50])[CH3:51]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C#N)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Reactant: C1COCCO1
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C(N)=O)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCNC[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C

Procedure:
A solution of (R)-4-[5-(5-chloro-4′-{2-[(2S,4S)-4-cyano-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester 2 TFA (6.3 mg, 0.0055 mmol; Example 17) in 4.0 M HCl in 1,4-dioxane (0.14 mL) was stirred at RT for 1 h and concentrated under vacuum to provide the title intermediate as a yellow powder. (m/z): [M+H]+ calcd for C39H43ClF3N9O6 826.30. found 826.5.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[NH2:17])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[NH:17][C:30]([NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[Br:22])=[O:31])(=[O:12])=[O:13])[CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccccc1NS(=O)(=O)c1cccc2cccnc12
Product: O=C(Nc1ccccc1Br)Nc1ccccc1NS(=O)(=O)c1cccc2cccnc12
Yield: 46.2 %

Procedure:
The urea was synthesized from 2-((8-quinolinyl) sulfonyl amino) aniline(11 mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.23 g, 46%).EI-MS m/z 495(M-H)-
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].[CH2:25]([C:27]1[CH:28]=[N:29][C:30](Cl)=[N:31][CH:32]=1)[CH3:26].CCN(C(C)C)C(C)C>C(O)(C)C>[CH2:25]([C:27]1[CH:28]=[N:29][C:30]([NH:1][CH2:2][C@H:3]2[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])=[N:31][CH:32]=1)[CH3:26]
Reactant: CCc1cnc(Cl)nc1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1cnc(NC[C@H]2[C@@H](C)CCCN2C(=O)c2nc(C)sc2-c2ccc(F)cc2)nc1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 5-ethyl-2-chloropyrimidine, and DIPEA in isopropanol was stirred at 110° C. for 18 h. The reaction was cooled and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 454.02 (M+H).
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]23[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[N+:13]([CH3:20])([CH3:19])[CH2:12][CH2:11]3)[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+]>O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2([CH2:11][CH2:12][N:13]([CH3:20])[CH3:19])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C23CCCCC2[N+](C)(C)CC3)c1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(C2(CCN(C)C)C=CCCC2)c1
Temperature: 170 °C

Procedure:
1 g of hexahydro-3a-(m-methoxyphenyl)-1,1-dimethyl-indolinium iodide is dissolved in 40 ml of water. The solution is applied to a column containing 50 g of Amberlite IRA 400 (pre-treated with sodium hydroxide; washed with distilled water until neutral). Thereafter, the column is eluted with 500 ml of distilled water. After distillation of the water, the hexahydro-3a-(m-methoxyphenyl)-1,1-dimethyl-indolinium hydroxide remaining as the residue is heated at 170° C. in a distillation apparatus in a high vacuum, an oil distilling over. This oil still contains, besides rac. 1-(m-methoxyphenyl)-N,N-dimethyl-2-cyclohexene-1-ethylamine, a relatively small amount of hexahydro-3a-(m-methoxyphenyl)-1-methylindoline.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[C@H:10]([CH3:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)CCN1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of (R)-1-benzyl-3-methylpiperazine (10 g, 52.6 mmol) in dichloromethane (30 mL) at room temperature was added triethylamine (10.6 g, 106 mmol) and the reaction mixture was stirred for 1 h. To the reaction mixture was added (BOC)2O (13.7 g, 62.8 mmol) and the contents were stirred for further 4 h. The reaction mixture was quenched in water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography eluting with 10% ethyl acetate in n-hexanes to afford 13.0 g of (R)-tert-butyl 4-benzyl-2-methylpiperazine-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)[CH:5]=O.[CH:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23]>>[CH:22]([N:25]1[CH2:30][CH2:29][N:28]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([N:10]3[CH2:15][CH2:14][CH:13]([CH2:16][N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:12][CH2:11]3)=[C:2]([CH3:1])[CH:3]=2)[CH2:27][CH2:26]1)([CH3:24])[CH3:23]
Reactant: Cc1cc(C=O)ccc1N1CCC(CN2CCCC2)CC1
Reactant: CC(C)N1CCNCC1
Product: Cc1cc(CN2CCN(C(C)C)CC2)ccc1N1CCC(CN2CCCC2)CC1

Procedure:
Prepared from the product of Example 66 and 1-isopropylpiperazine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](=O)([O-])[O-].[K+].[K+].C(=O)(OC)OC>CN(C)C=O>[CH3:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Product: Cn1ccc2ccccc21
Temperature: 130 °C
Yield: 227.6 %

Procedure:
Indole (10 g, 85.4 mmole), potassium carbonate (5 g), N,N-dimethylformamide (70 mL) and dimethyl carbonate (11 mL, 0.13 mol) were mixed together and refluxed (˜130° C.) for 2 h. At this point TLC analysis of the reaction showed two compounds, the N-methylated indole along with a significant amount of starting material. The reaction mixture was cooled down to ˜50° C. and a second portion of dimethyl carbonate (5.5 mL, 0.065 mol) was added. The mixture was heated at reflux for another 7 h until TLC analysis indicated total consumption of starting indole. The reaction mixture was cooled down to room temperature and it was slowly diluted with water (150 mL). The resulting mixture was extracted with tert-butyl methyl ether (150 mL) and the separated organic layer was washed with water (2×100 mL). The solvent was evaporated in vacuao to furnish 10.8 g of 1-methylindole as light yellow oil (96.5% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.ClCl.CS(C)=O.[OH:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CCCCCC.CCOC(C)=O>[CH:14]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: ClCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 84 %

Procedure:
To a solution of oxalyl chloride (28 mL, 56.2 mmol) in 14 mL dry CH2 Cl2 cooled at -78° C. (a dry ice acetone bath) was added 12 mL dry DMSO over 40 minutes. The reaction was stirred at -74° C. for additional 40 minutes and (S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester, (5.40 g, 26.86 mmol) in 14 mL CH2 Cl2 was added dropwise at -65° C. over 30 minutes. The reaction stirred additional 20 minutes at room temperature and partitioned between Et2O and H2O. The Et2O layer was washed with more H2O (50 mL×4) and the H2O layers was extracted with Et2O (40 mL×3). All the Et2O layers was combined, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The crude product was isolated by a silica-gel column using EtOAc and hexane (1:5 ratio) as an eluting solvent to give title compound (84% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]#[C:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33])=[CH:27][CH:26]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1.[ClH:75]>>[ClH:75].[ClH:75].[F:1][C:2]1[CH:3]=[C:4]([NH:23][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]#[C:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(Oc2ccncc2C#Cc2cccnc2)c(F)c1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: Cl
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccncc2C#Cc2cccnc2)c(F)c1
Yield: 38 %

Procedure:
The title compound was prepared from 3-fluoro-4-(3-(2-(pyridin-3-yl)ethynyl)pyridin-4-yloxy)benzenamine (22 mg, 0.072 mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.50 mL, 0.15 mmol) in a manner similar to Step D of Example 33. Purification of the reaction mixture by flash column chromatography on SiO2 eluting with 0-100% EtOAc/CH2Cl2 gave a white solid which was converted to the hydrochloride in a manner similar to Step D of Example 33 to give the title compound (15 mg, 38%) as a white solid. 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 10.59 (s, 1H), 8.76 (s, 1H), 8.74 (d, 1H, J=1.1 Hz), 8.60 (dd, 1H, J=5.6, 1.1 Hz), 8.45 (d, 1H, J=6.1 Hz), 7.98 (d, 1H, J=7.7 Hz), 7.80 (d, 1H, J=12.1 Hz), 7.47-7.45 (m, 1H), 7.41 (s, 2H), 7.36-7.34 (m, 2H), 7.16 (dd, 2H, J=8.8, 8.9 Hz), 6.78 (d, 1H, J=5.5 Hz), 3.74 (s, 2H); MS (ESI+): 485.13 m/z.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1COCC1.ClCCl.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C(N(CC)CC)C>[NH:17]1[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]=[C:13]1[C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:34]([C:33]3[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=3[C:31]([F:30])([F:41])[F:42])=[O:35])[CH2:3][CH2:2]2)=[N:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: c1ccc2[nH]c(-c3ccc(N4CCNCC4)nc3)nc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(-c3nc4ccccc4[nH]3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
To the suspension of 2-(6-piperazin-1-ylpyridin-3-yl)-1H-benzoimidazole (0.403 g, 1.440 mmol) in 25 mL of mixture of THF:dichloromethane (1:1) was added 2-trifluoromethylbenzoyl chloride (0.300 g, 1.440 mmol) in the presence of triethylamine (1 mL). The mixture was stirred at room temperature for 1 hour. The solvent was then evaporated and ethyl acetate was added. The suspension was ultrasonicated and filtered. The filtrate was concentrated in vacuo and the residue was subjected to column chromatography. The title compound was obtained as a white solid in 15% yield (0.097 g). 1H NMR (300 MHz, CDCl3) δ 8.71 (s, 1H), 8.24 (dd, J=2.4 and 9.0 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.74 (t, J=7.5 Hz, 1H), 7.63 (t, J=7.5 Hz, 1H), 7.52-7.48 (m, 2H), 7.51 (d, J=7.5 Hz, 1H), 7.14-7.11 (m, 2H), 6.97 (d, J=9.0 Hz, 1H), 3.78-3.71 (m, 4H), 3.60-3.46 (m, 2H), 3.29-3.11 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 166.8, 159.2, 150.4, 146.8, 136.1, 135.1, 135.1, 133.4, 130.1, 128.0, 127.1, 127.0, 126.1, 126.0, 125.6, 122.4, 116.2, 107.4, 46.6, 44.6, 44.4, 41.4. MS (ES+) m/z 452.3 (M+1).