Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][C:10]1[N:11]=[C:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:13][C:14]=1[CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][OH:19]>N1C=CC=CC=1>[C:4]([Si:1]([CH3:3])([CH3:2])[O:19][CH2:18][CH2:17][CH2:16][CH:15]([C:14]1[S:13][C:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[N:11][C:10]=1[CH3:9])[OH:20])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 42.2 %

Procedure:
tert-Butyl-dimethylsilyl chloride (115 mg, 0.76 mmol) was added in one portion to a stirred solution of [rac]-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-butane-1,4-diol (212 mg, 0.64 mmol) in pyridine (2 ml) at 0° C. The solution was naturally warmed to ambient temperature and stirred for 14 h. Pyridine was removed under reduced pressure and the residue dissolved in ethyl acetate. The solution was washed with 1 M aqueous HCl solution and two times with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, n-heptane/ethyl acetate) to give 120 mg (0.27 mmol, 42%) of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH:51]([C:52]2[NH:53][C:54]([C:57]3[CH:66]=[CH:65][C:64]4[C:59](=[CH:60][CH:61]=[C:62](Br)[CH:63]=4)[CH:58]=3)=[CH:55][N:56]=2)[CH:50]2[CH2:68][CH:47]1[CH2:48][CH2:49]2)=[O:45])([CH3:42])([CH3:41])[CH3:40].C([O-])([O-])=O.[K+].[K+]>COCCOC.CCOC(C)=O.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:39]([O:43][C:44]([N:46]1[CH:51]([C:52]2[NH:53][C:54]([C:57]3[CH:66]=[CH:65][C:64]4[C:59](=[CH:60][CH:61]=[C:62]([C:26]5[CH:25]=[CH:24][C:23]([C:20]6[NH:19][C:18]([CH:17]7[CH2:16][C:13]8([CH2:14][CH2:15]8)[CH2:12][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=6)=[CH:28][CH:27]=5)[CH:63]=4)[CH:58]=3)=[CH:55][N:56]=2)[CH:50]2[CH2:68][CH:47]1[CH2:48][CH2:49]2)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Yield: 37.1 %

Procedure:
To a solution of [2-Methyl-1-(6-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester (0.95 g, 1.82 mmol) and 3-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.96 g, 1.82 mmol, 1 equiv.) in DME (20 mL) was added K2CO3 (aqueous, 2 M, 3.6 mL, 7.2 mmol, 4 equiv.) and Pd(PPh3)4 (0.11 g, 0.09 mmol, 0.05 equiv.). The slurry was degassed with argon for 5 minutes and heated to 80° C. for 12 hours. The resulting reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was back-extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 50→100% EtOAc in Hexanes) to provide 3-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.53 g, 37%) as a yellow powder. LCMS-ESI+: calc'd for C46H53N7O5: 783.4 (M+). Found: 784.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:30][NH:31][CH3:32].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>C(Cl)Cl>[CH3:30][N:31]([CH3:32])[C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[NH:10]1)=[O:29]
Reactant: CNC
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Yield: 90 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example 1d was reacted with dimethylamine (1.0 M in THF, 2 mL), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid dimethyl amide (57.8 mg, 90.0%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH2:36])(=[O:35])=[O:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:32][C:30]1[CH:29]=[CH:28][C:27]([S:33]([NH2:36])(=[O:35])=[O:34])=[C:26]([CH2:25][CH2:24][NH:23][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[C:3]([CH3:21])([CH3:22])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)[CH:31]=1
Reactant: NCCc1cc(Cl)ccc1S(N)(=O)=O
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)C[C@H](Nc2nc(NCCc3cc(Cl)ccc3S(N)(=O)=O)ncc2C#N)CC[C@@H]1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (100 mg, 0.31 mmol), 2-(2-amino-ethyl)-4-chloro-benzenesulfonamide (150 mg, 0.64 mmol) and DIEA (80 mg, 0.62 mmol) in THF (4 mL) was stirred at 100° C. in a microwave reactor for 1 h. After cooling to room temperature, the reaction mixture was concentrated and the residue purified by standard methods to afford the title compound (53.3 mg, 0.060 mmol, 26% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.18-8.00 (m, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.50-7.34 (m, 2H), 4.41-4.23 (m, 1H), 3.89-3.51 (m, 2H), 3.41-3.33 (m, 2H), 3.29-3.22 (m, 1H), 2.04-1.80 (m, 1H), 1.80-1.68 (m, 2H), 1.67-1.38 (m, 3H), 1.05-0.93 (m, 6H). MS (ESI) m/z 479.1, 481.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[CH:31]>CN(C=O)C.C(N(CC)CC)C.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]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]#[C:30][C:29]([CH3:33])([CH3:32])[CH3:28])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: C#CC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reaction time: 16 h

Procedure:
To a solution of compounds 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (500 mg, 1.09 mmol) and 3,3-Dimethyl-but-1-yne (385 mg, 4.69 mmol) in DMF (0.5 mL), triethylamine (1.06 mL) and tris(dibenzylideneacetone)dipalladium (0) (70 mg, 0.08 mmol) are added and the reaction mixture is stirred under reflux conditions for 16 h under a N2 atmosphere. DMF and triethylamine are removed under reduced pressure and the residue is partitioned between water and ethyl acetate. The organic layer is separated, dried (Na2SO4), concentrated and the residue is purified by column chromatography using ethyl acetate and hexane (1:2) as eluent to obtain 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as a solid, 330 mg (66%).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[CH:22]([NH:25][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])([CH3:24])[CH3:23]
Reactant: CC(C)N
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC(C)C)[nH]n1
Yield: 89 %

Procedure:
As described for example 26d, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (97 mg, 89%) which was obtained as a colorless oil. MS: m/e=321.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][N:4]=1.C([Li])CCC.[CH2:23]=[O:24]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:23][OH:24])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][N:4]=1
Reactant: C=O
Reactant: COc1ccc(-c2cnc(OC)cc2C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc(OC)cc2CCO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 6.2 %

Procedure:
According to Scheme 30 Step 2: To a stirred solution of 2-methoxy-5-(4-methoxyphenyl)-4-methylpyridine (1 eq, 10.0 mmol, 2.30 g) in anhydrous THF (66 mL) at −78° C. under argon was added dropwise butyl lithium (2.5M, 1.5 eq, 15.1 mmol, 6.0 mL). The reaction mixture was stirred for one hour and then allowed to warm slowly to 0° C. and stirred at 0° C. for a further 30 minutes. The reaction mixture was then cooled to −78° C. and paraformaldehyde (6.07 g) was added. The reaction mixture was then allowed to warm to room temperature and was stirred for 2 hours. The reaction was quenched with saturated aqueous NH4Cl (30 mL), diluted with AcOEt and the aqueous phase was extracted (×3). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure. HCl 3M (15 mL) was added to the solution of the crude residue diluted in acetonitrile (10 mL). The reaction mixture was stirred for 2 hours at 60° C. The aqueous phase was extracted with Et2O, then neutralized with NaHCO3 (40 mL). The aqueous phase was extracted with CH2Cl2. The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 20 g SiO2) using CH2Cl2/AcOEt (99/1) as the eluent to afford 2-(2-methoxy-5-(4-methoxyphenyl)pyridin-4-yl)ethanol (0.62 mmol, 0.16 g, 6%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[F:18])[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([F:18])=[C:11]([Cl:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(F)c(Cl)c1
Product: Fc1ccc(Nc2ncc(F)c(Nc3ccc(F)c(Cl)c3)n2)cc1Cl

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-fluoroaniline were reacted to yield N2,N4-bis(3-chloro-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3+CD3OD)): δ 7.81 (d, 1H), 7.60 (m, 1H), 7.58 (m, 1H), 7.38 (m, 1H), 7.19 (m, 1H), 7.0 (m, 2H); LCMS: ret. time: 28.98 min.; purity: 97%; MS (m/e): 385 (MH+).
Reaction SMILES: [CH:1]([C:3]1[S:20][C:6]2[CH2:7][N:8]([CH3:19])[CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1)=O.[CH3:21][NH2:22]>[Ni].O1CCCC1>[CH3:21][NH:22][CH2:1][C:3]1[S:20][C:6]2[CH2:7][N:8]([CH3:19])[CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1
Reactant: COc1ccc(C2CN(C)Cc3sc(C=O)cc32)cc1
Reactant: CN
Agent: [Ni]
Solvent: C1CCOC1
Product: CNCc1cc2c(s1)CN(C)CC2c1ccc(OC)cc1

Procedure:
A mixture of 2.87 gm (0.01 mol) of 2-formyl-4-(p-methoxy-phenyl)-6-methyl-4,5,6,7-tetrahydro-thieno-[2,3-c]pyridine (prepared analogous to Example 5; light yellow oil), 70 ml of tetrahydrofuran, an excess of methylamine, and Raney nickel was kept at a temperature of 60° C. for several hours under a hydrogen pressure of 5 bar. After the catalyst had been removed by suction filtration, the title compound was precipitated in the form of the dimaleate by the addition of ethanolic maleic acid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1>>[F:14][C:15]1[CH:16]=[C:17]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:18][N:19]1[CH2:20][CH2:21][CH:22]([NH:25][C:2]2[C:3]3[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:23][CH2:24]1
Reactant: CC(C)c1cc2c(Cl)ncnc2s1
Reactant: NC1CCN(Cc2cc(F)cc(F)c2)CC1
Product: CC(C)c1cc2c(NC3CCN(Cc4cc(F)cc(F)c4)CC3)ncnc2s1

Procedure:
The title compound was prepared (264 mg, 56%) from 4-chloro-6-isopropylthieno[2,3-d]pyrimidine (0.25 g, 1.18 mmol) and 1-(3,5-difluorobenzyl)piperidin-4-amine (0.4 g, 1.77 mmol) by following the general procedure described for Preparation 6. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 6.90 (m, 2H), 6.80 (s, 1H), 6.70 (m, 1H), 4.95 (d, 1H), 4.20 (m, 1H), 3.50 (s, 2H), 3.20 (m, 1H), 2.85 (m, 2H), 2.25 (m, 2H), 2.10 (m, 2H), 1.60 (m, 2H), 1.40 (d, 6H). MS (ESI) m/z: Calculated: 402.5; Observed: 403.1 (M++1).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].Br[C:36]([CH3:43])([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:6]2[C:5](=[O:27])[N:4]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:36]([CH3:43])([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:30][CH:29]=3)[C:3]([CH2:1][CH3:2])=[N:8][C:7]=2[CH2:9][CH2:10][CH3:11])=[CH:14][CH:15]=1)#[N:26]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)C(=O)OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.5 g) in N,N-dimethylacetamide (20 mL) were added ethyl 2-bromo-2-methylpropionate (0.98 g) and cesium carbonate (1.6 g), and the mixture was stirred at 120° C. for 24 hr. The mixture was allowed to cool to room temperature, and the insoluble material was filtered off. The filtrate was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as a colorless solid (1.6 g, 83%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[C:9]([N:14]2[CH2:17][CH:16]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=4[N:19]=3)[CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1.CN1C(=O)CCC1.[O:35]1[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]1>CCOC(C)=O>[CH3:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:18]([CH:16]3[CH2:17][N:14]([C:9]4[C:8]([O:41][CH:38]5[CH2:39][CH2:40][O:35][CH2:36][CH2:37]5)=[N:13][CH:12]=[CH:11][N:10]=4)[CH2:15]3)=[N:19][C:20]=2[CH:26]=1
Reactant: OC1CCOCC1
Reactant: Cc1ccc2[nH]c(C3CN(c4nccnc4Cl)C3)nc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc2[nH]c(C3CN(c4nccnc4OC4CCOCC4)C3)nc2c1
Temperature: 100 °C
Yield: 49.4 %

Procedure:
To a mixture of cesium carbonate (0.223 g, 0.684 mmol) and 2-(1-(3-chloropyrazin-2-yl)azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole (0.103 g, 0.344 mmol) was added NMP (1 mL) and tetrahydro-2H-pyran-4-ol (0.20 mL, 2.1 mmol). The reaction mixture was heated to 100° C. for 1 h, heated to 130° C. for 2 h, and heated to 150° C. for 21 h. The reaction was diluted with EtOAc, and the organic phase was washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (60% to 100% EtOAc in hexanes) gave 5-methyl-2-(1-(3-(tetrahydro-2H-pyran-4-yloxy)pyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole (0.061 g, 0.17 mmol, 49% yield) as a pale yellow foam. [M+1] 366. IC50 (uM) 0.2388.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl[C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([C:36]3[N:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: Clc1ncccn1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(c1ncccn1)CN2c1ccccc1Cl

Procedure:
The title compound, MS: m/e=584.0 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH3:39])[C@@H:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH2:13][C@H:12]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)=[O:9])=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([C@@H:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:13][C@H:12]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)[CH3:39])=[O:9])=[CH:6][CH:7]=1
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(CC2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(CC2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 168 %

Procedure:
To a solution of tert-butyl 4-{[(3R,4R)-4-{[(4-chlorophenyl)carbonyl] (methyl)amino}-3-(3,4-dichlorophenyl)piperidin-1-yl]methyl}piperidine-1-carboxylate (200 mg) obtained in Example 461 in ethyl acetate (4 mL) was added 4N hydrogen chloride/ethyl acetate (4 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (150 mg, 85%) as a white powder.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[ClH:9].Cl.[NH2:11][CH2:12][C:13]1[O:17][C:16]([C:18]([O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31](=[NH:33])[NH2:32])[CH:27]=3)[CH:22]=2)=[O:19])=[CH:15][CH:14]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[ClH:9].[C:4]([CH2:3][CH2:2][C:1]([NH:11][CH2:12][C:13]1[O:17][C:16]([C:18]([O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31](=[NH:32])[NH2:33])[CH:27]=3)[CH:22]=2)=[O:19])=[CH:15][CH:14]=1)=[O:8])([OH:6])=[O:5]
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)o3)ccc2c1
Reactant: O=C(O)CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)CCC(=O)O)o3)ccc2c1
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
To 22.3 g of succinic acid, 24.0 g of 6-amidino-2-naphthyl 5-aminomethylfuran-2-carboxylate dihydrochloride and 790 mg of DMAP was added 240 ml of pyridine, and the mixture was stirred while cooling with ice. After 10 minutes, 25.9 g of DCC was added and the mixture was stirred for 3 hours while cooling with ice and then for 16 hours at room temperature. The precipitate was filtered off, and the filtrate was added in small portions into 2 l of ether and stirred at room temperature for 3 hours. After removing the supernatant by decantation, 1 l of acetone was added to the residue and stirred for 3 hours. The precipitate was collected by filtration to obtain 24.0 g of the intended product.
Reaction SMILES: [CH:1]([CH:4]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[N:9]=[C:8](Br)[C:7]3[N:16]=[CH:17][CH:18]=[CH:19][C:6]=3[C:5]1=2)([CH3:3])[CH3:2].[C:20]([Cu])#[N:21].N>>[CH:1]([CH:4]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[N:9]=[C:8]([C:20]#[N:21])[C:7]3[N:16]=[CH:17][CH:18]=[CH:19][C:6]=3[C:5]1=2)([CH3:3])[CH3:2]
Reactant: CC(C)C1CC(=O)Nc2nc(Br)c3ncccc3c21
Reactant: N#C[Cu]
Agent: N
Product: CC(C)C1CC(=O)Nc2nc(C#N)c3ncccc3c21
Reaction time: 1 h
Yield: 21 %

Procedure:
1.6 g (0.005 mol) of 1-isopropyl-6-bromo-1,2-dihydropyrido[2,3-c][1,8]naphthyridin-3(4H)-one are melted at 220° C. in a heavy-oil bath with 0.45 g (0.05 mol) of CuCN. After 1 hour, the melt is cooled, and the residue is ground in a mortar and stirred with concentrated ammonia solution. The precipitate is filtered off under suction, washed with water, dried and purified on a silica gel column with chloroform. 0.28 g (21% of theory) of 1-isopropyl-6-cyano-1,2-dihydropyrido[2,3-c][1,8]naphthyridin-3(4H)-one is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][N:14]([CH3:33])[CH2:15][CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][N:27]([CH3:32])[C:28](=[O:31])[CH:29]=[CH2:30])=[CH:18]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:33][N:14]([CH3:13])[CH2:15][CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][N:27]([CH3:32])[C:28](=[O:31])/[CH:29]=[CH:30]/[C:2]2[CH:11]=[N:10][C:9]3[NH:8][C:7](=[O:12])[CH2:6][CH2:5][C:4]=3[CH:3]=2)=[CH:18]1
Reactant: C=CC(=O)N(C)Cc1cn(CCN(C)C)c2ccccc12
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN(C)CCn1cc(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)c2ccccc21
Yield: 17.2 %

Procedure:
A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (0.61 g, 2.70 mmole), N-[1-(2-dimethylaminoethyl)-1H-indol-3-ylmethyl]-N-methyl-acrylamide (1.00 g, 3.50 mmole), Pd(OAc)2 (0.08 g, 0.35 mmole), tri-ortho-tolylphosphine (0.21 g, 0.70 mmole), and diisopropylethylamine (0.91 mL, 5.25 mmole) in propionitrile (70 mL) was deoxygenated, then was and heated to reflux under a N2 overnight. The dark mixture was filtered through a pad of celite®, and the filter pad was rinsed with acetonitrile (250 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (10% MeOH/CHCl3 containing 5% NH4OH in the MeOH). The title compound (0.20 g. 13%) was obtained as a light yellow solid after drying in vacuo: MS (ES) m/e 432 (M+H)+.