Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=1.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>CS(C)=O.C(NCC)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[C:21]1([C@@H:19]2[CH2:20][C@H:18]2[C:16]([N:13]2[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][C:5]3[N:4]=[CH:3][C:2]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:7][N:6]=3)[CH2:11][CH2:12]2)=[O:17])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCC(CNc2ncc(Br)cn2)CC1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1cnc(NCC2CCN(C(=O)[C@@H]3C[C@H]3c3ccccc3)CC2)nc1
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-N-[(1-{[(1R,2R)-2-phenylcyclopropyl]carbonyl}piperidin-4-yl)methyl]pyrimidin-2-amine (EXAMPLE 153) (0.300 g, 0.722 mmol), trimethylsilylacetylene (0.177 g, 1.81 mmol), Pd(PPh3)4 (0.083 g, 0.072 mmol), and copper iodide (0.007 g, 0.036 mmol) in DMSO (1 mL) and diethylamine (1 mL) was heated in a sealed tube at 100° C. for 3 h. The reaction mixture was cooled to RT, diluted with ethyl acetate (50 mL), washed with water (10 mL), and brine (10 mL), then dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60 (35 g), eluting with 10:1–10:89–80 CH2Cl2:2-propanol:hexane to give the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4Cl)[C:11]3=[O:22])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:23][O-:24].[Na+].CO>O1CCOCC1.C(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[O:24][CH3:23])[C:11]3=[O:22])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C[O-]
Reactant: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Yield: 32.4 %

Procedure:
1-Benzothiazol-6-yl-3-(4-chloro-pyridin-3-yl)-imidazolidin-2-one (84A: 50 mg, 0.1515 mmol) was added dropwise to a solution of sodium methoxide (0.122 g, 2.259 mmol) in 1,4-dioxane (15 mL) over a period of 5 minutes. The resulting mixture was refluxed for 10 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ice water and ethylacetate. The organic layer was dried over Na2SO4 and concentrated. Purification by preparative HPLC afforded 16 mg of the product (31.66% yield).
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[NH:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[CH:31]=[C:32]([C:34](Cl)=[O:35])[N:33]=1>C(Cl)Cl>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]([C:37]2[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=2)[CH:31]=[C:32]([C:34]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[O:35])[N:33]=1
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)c2cn(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)n2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 77 %

Procedure:
Triethylamine (1.46 mL, 10.45 mmol) was added to a suspension of 4-piperidinone trifluoroacetate (0.76 g, 3.58 mmol) in CH2Cl2 (10 mL) and a solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carbonyl chloride in CH2Cl2 (5 mL) was added. The mixture was stirred at rt under argon for 17 h, diluted with CH2Cl2 (50 mL), washed with water (2×50 mL), dried over MgSO4, and concentrated to give 1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol4-yl]carbonyl}-4-piperidinone as a yellow solid (0.96 g, 77%). MS (Electrospray) 414 (MH+), 1H NMR (300 MHz, CD2Cl2) δ 7.80 (s, 1H), 7.37-7.20 (m, 6H), 7.06-7.00 (m, 6H), 4.47 (br, 2H), 3.92 (br, 2H), 2.46 (t, 4H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:26])[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1.[Si:27]([O:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:47]=[CH:46][C:41]([O:42][CH2:43][C:44]#[CH:45])=[CH:40][CH:39]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].[Si](OCCCCCCCC#CC1C2C(=CC(OC)=CC=2)SCC1(C1C=CC(OC)=CC=1)C)(C(C)(C)C)(C)C>>[Si:27]([O:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]#[C:45][C:9]2([OH:26])[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=3)[O:12][CH2:11][C:10]2([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:21]=2)[CH3:15])=[CH:46][CH:47]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2=O)cc1
Reactant: C#CCOc1ccc(CCCO[Si](C)(C)C(C)(C)C)cc1
Agent: COc1ccc(C2(C)CSc3cc(OC)ccc3C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)C#CCOc2ccc(CCCO[Si](C)(C)C(C)(C)C)cc2)cc1

Procedure:
The title compound was prepared from 7-methoxymethyloxy-3-(4-methoxymethyloxyphenyl)-3-methylchroman-4-one and 3-[4-(3-t-butyldimethylsilyloxypropyl)phenoxy]-1-propyn according to the same method for the synthesis of 4-[9-(t-butyldimethylsilyloxy)1-nonynyl]-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:7]=[C:6]([N:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)[CH:5]=1)[CH3:2].S(=O)(=O)(O)[OH:23].[N+:27]([O-])([OH:29])=[O:28]>>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:7]=[C:6]([N:16]2[CH2:17][CH2:18][S:19](=[O:23])[CH2:20][CH2:21]2)[C:5]=1[N+:27]([O-:29])=[O:28])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])O
Reactant: CCOc1cc(N2CCSCC2)nc(N2CCNCC2)n1
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
1 gm of 6-ethoxy- 2-piperazino-4-thiomorpholino-pyrimidine was added to 3 ml of concentrated sulfuric acid, whereby the temperature of the resulting suspension rose to 50°C. After cooling to 0°C, 2 ml of concentrated nitric acid were added dropwise while stirring. After stirring it for another hour at room temperature, the reaction mixture was filtered through glass wool, and the filtrate was stirred into ice water. By careful addition of aqueous 40% sodium hydroxide, the mixture was adjusted to pH 9 and extracted with chloroform. The chloroform phase was washed with water, dried with sodium sulfate, and the solvent was distilled off in vacuo. The residue was recrystallized from ethanol. Yield: 0.8 gm (66.9% of theory); m.p. 223°-224°C.
Reaction SMILES: C(OC([CH2:8][NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[CH:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:8][NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: CCOC(=O)CCc1ccc(-c2cc(NCC(=O)OC(C)(C)C)ccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCc1ccc(-c2cc(NC)ccn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.9 %

Procedure:
415 mg (1.08 mmol, 1 eq) of ethyl 3-{4-[4-(tert-butoxycarbonylmethylamino)pyrid-2-yl]phenyl}propanoate are dissolved in 10 mL of dichloromethane. 3 mL of trifluoroacetic acid are added and the reaction mixture is stirred for 4 hours at room temperature. The reaction is stopped by adding 100 mL of saturated sodium hydrogen carbonate solution and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off. 270 mg of ethyl 3-[4-(4-methylaminopyrid-2-yl)phenyl]propanoate are obtained. Yield=88%.
Reaction SMILES: CC(O[CH2:6][C:7]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH:16]([CH3:18])[CH3:17])[O:9][N:8]=1)(C)C.FC(F)(F)C(O)=O.OCC1C(C(OC)=O)=C(C(C)C)ON=1.C(Br)(Br)(Br)[Br:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CCCCCC>[Br:41][CH2:6][C:7]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH:16]([CH3:18])[CH3:17])[O:9][N:8]=1
Reactant: COC(=O)c1c(COC(C)(C)C)noc1C(C)C
Reactant: BrC(Br)(Br)Br
Agent: COC(=O)c1c(CO)noc1C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(CBr)noc1C(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 56.1 %

Procedure:
A solution of methyl 3-{[(1,1-dimethylethyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolecarboxylate (2.00 g, 7.83 mmol) in dichloromethane (32.5 mL) was stirred at 0° C. as trifluoroacetic acid (32.5 mL, 0.42 mol) was added dropwise. The resulting solution was allowed to stir at 0° C. for 5 minutes then at room temperature for 30 minutes. The solution was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, hexane to 2:3 ethyl acetate:hexanes). Fractions containing methyl 3-(hydroxymethyl) -5-(1-methylethyl)-4-isoxazolecarboxylate were combined and concentrated. A solution of methyl 3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (1.042 g, 5.23 mmol) in dichloromethane (24.3 mL) was stirred as carbon tetrabromide (1.85 g, 5.5 mmol) was added. The solution was cooled in ice bath before the addition of triphenyl phosphine (1.44 g, 5.5 mmol) in three portions. The solution was allowed to stir at 0° C. for 30 minutes then at room temperature for 1.5 hours. Hexane (67 mL) was added before the mixture was filtered through Celite® and concentrated. The residue was purified by chromatography (silica gel, hexane to 1:4 ethyl acetate:hexanes). Fractions containing the product were combined and concentrated to yield methyl 3-(bromomethyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (0.809 g, 57% as 0.10 ethyl acetate). 1H NMR (400 MHz, DMSO-d6): δ 4.70 (s, 2H), 3.82 (s, 3H), 3.69 (septet, J=7 Hz, 1H), 1.26 (d, J=7 Hz, 6H). ESI-LCMS m/z 262 (M+H)+.
Reaction SMILES: [N:1]1([C@H:8]2[CH2:11][C@H:10]([C:12]3[S:13][C:14]4[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.BrC1C=CC2N=C([C@H]3[CH2:33][C@H:32]([N:34]4[CH2:38][CH2:37][CH2:36][C@H:35]4[CH3:39])C3)SC=2C=1.CC1C(B2OC(C)(C)C(C)(C)O2)=CC=C(C)N=1.N1C=C(B(O)O)C=NC=1>>[N:1]1([C@H:8]2[CH2:11][C@H:10]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([C:38]5[C:32]([CH3:33])=[N:34][C:35]([CH3:39])=[CH:36][CH:37]=5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1ccc2nc([C@H]3C[C@H](N4CCCCCC4)C3)sc2c1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Agent: OB(O)c1cncnc1
Product: Cc1ccc(-c2ccc3nc([C@H]4C[C@H](N5CCCCCC5)C4)sc3c2)c(C)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the product of Example 71A for the product of Example 1E, and substituting Example 2A (2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine) for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.02 (d, J=8.54 Hz, 1H) 7.76 (d, J=1.53 Hz, 1H) 7.46 (d, J=7.63 Hz, 1H) 7.39 (dd, J=8.24, 1.83 Hz, 1H) 7.07 (d, J=7.63 Hz, 1H) 3.78-3.86 (m, 1H) 3.32-3.43 (m, 1H) 2.59 (s, 6H) 2.45-2.56 (m, 8H) 1.58-1.73 (m, 8H). MS: (M+H)+=392.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.Cl.Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH3:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:27]2[CH2:28][CH2:29][N:24]([C:19]3[N:18]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:25][CH2:26]2)=[CH:4][CH:5]=1)[CH3:11]
Reactant: CC(=O)NC(C)(C)c1ccc(CCl)cc1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Product: CC(=O)NC(C)(C)c1ccc(CN2CCN(c3ncccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(2-pyrimidyl)piperazine dihydrochloride instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=137-138° C.
Reaction SMILES: Br.[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][N:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[S:11][C:10]1=[NH:16].[C:17]12([C:27](O)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][N:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[S:11]/[C:10]/1=[N:16]\[C:27]([C:17]12[CH2:26][CH:21]3[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]3)[CH2:24]1)[CH2:18]2)=[O:28]
Reactant: COCCOCCn1c(C)c(C)sc1=N
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCn1c(C)c(C)s/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 100 °C

Procedure:
A mixture of 4,5-Dimethylthiazol-2-ylamine (20 mg, 0.16 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (0.20 mmol) was heated at 80° C. overnight to afford 3-[2-(2-methoxyethoxy)-ethyl]-4,5-dimethyl-1,3-thiazol-2(3H)-ylideneamine hydrobromide, which was used without purification. The alkylated thiazolylidine hydrobromide (1.25 equiv), 1-adamantane carboxylic acid (1.0 equiv), polymer-bound dicyclohexylcarbodiimide (PS-DCC, 3 equiv), 1-hydroxybenzotriazole hydrate (HOBT, 1 equiv), N,N-diisopropylethylamine (3 equiv), were combined in dimethylacetamide (DMA, 2.8 mL) and heated in a microwave to 100° C. for 420 seconds. The mixture was filtered through Si-Carbonate (6 mL-1 g cartridge from Silicycle Chemical Division, MeOH wash) and then concentrated to dryness. Purification by reverse phase HPLC afforded the title compound. 1H NMR (DMSO-d6, 500 MHz) δ ppm 11.68 (q, J=12.27 Hz, 6 H) 1.84 (d, J=2.50 Hz, 6 H) 1.94-2.02 (m, 3 H) 2.16 (s, 3 H) 2.22 (s, 3 H) 3.19 (s, 3 H) 3.39 (dd, J=5.62, 3.74 Hz, 2 H) 3.51 (dd, J=5.62, 3.74 Hz, 2 H) 3.73-3.77 (m, 2 H) 4.25 (t, J=5.46 Hz, 2 H); MS (ESI) m/z 393 (M=H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19]([NH:21][C@@H:22]4[CH2:26][CH2:25][NH:24][C:23]4=[O:27])=[O:20])=[C:16]4[CH2:28][CH2:29][CH2:30][CH2:31][C:15]=34)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)=O.CO>>[Cl:8][C:6]1[CH:5]=[C:4]([C@:9]2([C:32]([F:34])([F:33])[F:35])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19]([NH:21][C@@H:22]4[CH2:26][CH2:25][NH:24][C:23]4=[O:27])=[O:20])=[C:16]4[CH2:28][CH2:29][CH2:30][CH2:31][C:15]=34)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1.[Cl:8][C:6]1[CH:5]=[C:4]([C@@:9]2([C:32]([F:34])([F:33])[F:35])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19]([NH:21][C@@H:22]4[CH2:26][CH2:25][NH:24][C:23]4=[O:27])=[O:20])=[C:16]4[CH2:28][CH2:29][CH2:30][CH2:31][C:15]=34)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(N[C@@H]1CCNC1=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Agent: O=C=O
Solvent: CO
Product: O=C(N[C@@H]1CCNC1=O)c1sc(C2=NO[C@@](c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Product: O=C(N[C@@H]1CCNC1=O)c1sc(C2=NO[C@](c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2

Procedure:
Separate 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide (6.2 g 11.29 mmol) by SFC (Column: Chiralcel OD 250×30 mm I.D., 5 um. Mobile phase: Supercritical CO2/MeOH=60/40, Flow rate: 200 ml/min) to afford two diastereoisomers 3-((R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxo pyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide (2.7 g, 4.92 mmol) and 3-((S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide (2.6 g, 4.74 mmol) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[NH:5][C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:2].C(=O)([O-])[O-].[K+].[K+].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.O>CN(C)C=O>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[N:5]([S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C=O)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 18 h

Procedure:
Combine 3-formyl-2-carboethoxy-4,6-dichloroindole (46.3 g. 162 mmol) and anhydrous potassium carbonate (44.9 g, 325 mmol) in dimethylformamide (600 mL). Add p-toluenesulfonyl chloride (42.9 g, 225 mmol). After 18 hours, pour the reaction mixture into water (3 L) and stir to give a solid. Filter, rinse with water and diethyl ether, and recrystallize from acetonitrile/dichloroethane to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH2:24].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH:24][C:18]([C@@H:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[O:20]
Reactant: Nc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (200 mg, 721 μmol, Eq: 1.00) and 2,6-difluoroaniline (121 mg, 101 μL, 938 μmol, Eq: 1.3) in pyridine (2 mL) at 0° C. was added dropwise phosphorus oxychloride (166 mg, 101 μL, 1.08 mmol, Eq: 1.5). The cooling bath was removed and the reaction stirred at RT overnight. The reaction mixture was concentrated in vacuo and water was added to the residue. The resulting mixture was extracted with EtOAc and the combined organic layers were washed with 0.1 M HCl, 0.1 M NaOH, and brine and concentrated in vacuo. The crude material was purified by flash chromatography to give (S)-tert-butyl 3-(2,6-difluorophenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a colorless oil (90 mg), m/z=411 (M+Na).
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][CH2:2]1.[CH2:11](Br)[C:12]#[CH:13].O=CC1C=CC(O)=C(OC)C=1>ClCCl>[CH3:8][O:7][C:5]([CH:4]1[CH2:9][CH2:10][N:1]([CH2:13][C:12]#[CH:11])[CH2:2][CH2:3]1)=[O:6]
Reactant: C#CCBr
Reactant: COC(=O)C1CCNCC1
Agent: COc1cc(C=O)ccc1O
Solvent: ClCCl
Product: C#CCN1CCC(C(=O)OC)CC1
Reaction time: 36 h

Procedure:
To a solution of methyl isonipecotate 3.5 g (24.4 mmol, 3.30 mL) in 100 mL dichloromethane was added TEA (1.5 eq, 36.6 mmol, 5.1 mL), propargyl bromide (3.0 eq, 73.2 mmol, 6.5 ml), at room temperature for 36 hrs. The reaction was quenched with 35 mL water to yield to provide a clear solution. The solution was extracted with dichloromethane 2×25 mL, dried with Na2SO4, and the solvent evaporated to provide a yellow oil. r.f. (40% EtOAc/Hexanes) 0.26 stains faint white with Vanillin, starting material r.f. 0.05 stains yellow with Vanillin. The product appeared pure after extraction.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25][CH3:26])[C:15]2[C:20]([NH:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:25]([N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]1[C:20]([NH:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:26]
Reactant: CCCNc1cccnc1N(CC)C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCNc1cccnc1N(CC)C1CCNCC1

Procedure:
1-Benzyl-4-[N-ethyl-N-(3-propylamino-2-pyridinyl)amino]piperidine (EXAMPLE 191, 4.34 g, 12.3 mmol) and palladium hydroxide on carbon (2.0 g) in 50 ml ethanol is hydrogenated at 40 p.s.i. hydrogen for 40 hr. Filtration and removal of the solvent gives the title compound, NMR (400 MHz, CDCl3) 7.72, 6.95, 6.83, 3.72, 3.42, 3.09, 2.87, 2.00, 1.66, 1.24, 1.00 and 0.87δ.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].FC(F)(F)C(O)=O.[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.[CH3:61][C:62]1[O:66][N:65]=[C:64]([C:67](Cl)=[O:68])[CH:63]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:55][CH2:56][N:57]([C:67]([C:64]2[CH:63]=[C:62]([CH3:61])[O:66][N:65]=2)=[O:68])[CH2:58][CH2:59]1
Reactant: Clc1cnc2nc1Nc1ccc(NCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(CCNc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 55 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-N-(2-piperidin-4-ylethyl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 55% yield. LCMS for C29H32ClN8O2 (M+H)+: m/z=559.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Reactant: OC1CCCCC1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OC2CCCCC2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, cyclohexanol and DBU in DME. EI-MS m/e (%): 294 (M+, 12), 213 ([M—C6H9]+, 100), 212 ([M—C6H10]+, 48), 170 (60).