Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH2:25][CH2:26][CH2:27]I)[CH:13]=3)=[CH:11][C:3]=12.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH2:25][CH2:26][CH2:27][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[CH:13]=3)=[CH:11][C:3]=12
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)c(F)cnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCCI
Reactant: C1CCNCC1
Solvent: ClCCl
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)c(F)cnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCCN1CCCCC1
Yield: 62.3 %

Procedure:
a solution of 0.3 g of 3-[4-chloro-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1-(3-iodopropyl)-5,6-dimethoxy-1H-pyrrolo[3,2-b]pyridine and 0.382 g of piperidine in 40 cm3 of dichloromethane is refluxed for about 6 hours. After diluting the reaction mixture with 100 cm3 of dichloromethane, the solution is washed with three times 40 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/methanol (98/2 by volume)], 0.175 g of 3-[4-chloro-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-(3-piperidin-1-ylpropyl)-1H-pyrrolo[3,2-b]pyridine is thus obtained as a resin with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH2:12][CH2:13][N:14]([C:17](OC(C)(C)C)=[O:18])[CH2:15][CH:16]=3)=[CH:10][C:3]=12.[N:34]1[CH:39]=CC=C[CH:35]=1.C1C([N+]([O-])=O)=CC=C([Cl-]C([O-])=O)C=1.Cl.CNC>C(Cl)Cl.FC(F)(F)C(O)=O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([N:34]([CH3:39])[CH3:35])=[O:18])[CH2:15][CH:16]=3)=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Cl)ccnc32)cc1
Reactant: c1ccncc1
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)N(C)C)CC3)cc3c(Cl)ccnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.8 %

Procedure:
Intermediate P-5-I (2 g, 6.94 mmol) was dissolved in CH2Cl2 (20 mL), to which trifluoroacetic acid (10 mL, excess) was added at 0° C. and the reaction mixture was stirred at room temperature for 2 h. Solvents were removed under reduced pressure and saturated NaHCO3 solution (50 mL) was added to it. Extraction was carried out using EtOAc (30 mL×2); the combined organic layers were washed with water (60 mL), brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide corresponding Boc-deprotected intermediate (1.6 g). It (0.5 g, 1.28 mmol) was dissolved in CH2Cl2 (10 mL) and cooled to 0° C. To this was added pyridine (1.0 mL, 12.8 mmol) and 4-nitrophenylchloroformate (1.29 g, 6.44 mmol) sequentially. The reaction mixture was stirred at room temperature for 3 h before solvent was removed under reduced pressure. To the residue obtained was added DMF (10 mL) and cooled to 0° C. To this reaction mixture, TEA (1.6 mL, 12.8 mmol) and dimethylaminehydrochloride (0.525 g, 6.44 mmol) were added and it was stirred at room temperature for 16 h. It was then diluted using water (30 mL) and extraction was carried out using EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (25% acetone in hexane) to provide the title compound P-5-II (0.25 g, 53% yield). LCMS: m/z; 459.2 (M+1)+.
Reaction SMILES: C(O[C:4](=[O:18])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[CH3:19][NH:20][C:21]([NH2:23])=[O:22].C[O-].[Mg+2].C[O-].CO>>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:4]([NH:23][C:21]([NH:20][CH3:19])=[O:22])=[O:18])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccccc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccccc1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
A mixture of 3-cyclopentyl-2-phenyl-propionic acid ethyl ester (1.70 g, 7.06 mmol) and methyl urea (1.04 mg, 14.13 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 130.3 mL, 21.18 mmol) was refluxed at 100° C. for 24 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 1-(3-cyclopentyl-2-phenyl-propionyl)-3-methyl-urea (1.21 mg, 62.4%) as a white solid: mp 145-147° C.; EI-HRMS m/e calcd for C16H22N2O2 (M+) 274.1681, found 274.1682.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:32])([CH3:31])[O:9][C:10](=[O:30])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[CH:14][CH:13]=1)(=O)=O.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:7]2[C:8]([CH3:31])([CH3:32])[O:9][C:10](=[O:30])[C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:17]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC1(C)OC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1OS(=O)(=O)C(F)(F)F
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2(C)C)cc1
Reaction time: 0.5 h
Yield: 0 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (250 mg, 0.5 mol) in 1,4-Dioxane (10 mL) were added 4-methoxyphenylboronic acid (92 mg, 0.6 mol), Na2CO3 (127 mg, 1.5 mol) and water (4 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min followed by addition of Pd(PPh3)4 (58 mg, 0.05 mol) and then refluxed for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl) furan-2(5H)-one- (40 mg, 18%) as a yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.43-8.41 (m, 1H), 8.02-7.98 (m, 2H), 7.78 (t, J=7.8 Hz, 1H), 7.68-7.52 (m, 2H), 7.25-7.21 (m, 4H), 7.02-6.98 (m, 4H), 5.40 (s, 2H), 5.25 (s, 2H), 3.79 (s, 3H). MS: M+H: m/z=452.2; M+Na: m/z=474.3. HPLC: 91%, (Condition-B).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[F:22][C:23]([F:29])([F:28])[S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:22][C:23]([F:29])([F:28])[S:24]([N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:14][CH2:13]1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 150 ml round-bottomed flask equipped with a magnetic stirrer is charged under argon with 2 g of 4-N-boc-aminopiperidine in 35 ml of DCM, 82 mg of 4-dimethylaminopyridine (DMAP) and 1.86 ml of triethylamine. After cooling to 0° C. using an ice bath, 1.6 ml of trifluoromethanesulphonyl chloride are added dropwise. The mixture is stirred at 0° C. for 30 min and then at RT for 1 h. It is poured into 100 ml of saturated aqueous sodium bicarbonate solution. It is extracted with AcOEt, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated to dryness under RP. Chromatography on silica gel (15-40 μm), eluting with a mixture of DCM and methanol (98/02 by vol.), gives 1.5 g of 1,1-dimethylethyl (1-trifluoromethanesulphonylpiperidin-4-yl)carbamate (cream solid). MS (E/I): m/z=232 (M+).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([O:29]CC)=O)[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:29])[CH:15]=[N:14][C:13]=12)(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1ccc(Cl)cc1Cl
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3ccc(Cl)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 41.3 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2,4-dichlorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (2.98 g, 6.13 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (1.5 g, 8.18 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (1.57 g, 41%) was obtained.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.C[Si](C=[N+]=[N-])(C)C.[NH2:20][C:21]1[C:26]([CH:27]=O)=[CH:25][CH:24]=[C:23]([CH2:29][O:30][CH3:31])[N:22]=1>O1CCCC1.C(O)(=O)C>[C:27]([C:26]1[C:21]([NH2:20])=[N:22][C:23]([CH2:29][O:30][CH3:31])=[CH:24][CH:25]=1)#[CH:1]
Reactant: CC(C)NC(C)C
Reactant: COCc1ccc(C=O)c(N)n1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C#Cc1ccc(COC)nc1N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a mixture of diisopropylamine (0.15 mL, 1.1 mmol) and tetrahydrofuran (2 mL) was added dropwise n-butyl lithium (1.6 M n-hexane solution, 0.68 mL, 1.1 mmol) at −78□, which was stirred for 30 minutes at that temperature. Trimethylsilyl diazomethane (2 M n-hexane solution, 0.50 mL, 0.99 mmol) was added to the reaction mixture at −78° C., and stirred for 30 minutes at that temperature. A mixture of 2-amino-6-methoxymethyl-pyridine-3-carbaldehyde (150 mg, 0.90 mmol) described in Manufacturing Example 26-1-6 and tetrahydrofuran (1.5 mL) was added dropwise to the reaction mixture at −78° C., and stirred for 30 minutes at 0° C. The reaction mixture was cooled to −78° C., and a mixture of acetic acid (0.10 mL) and tetrahydrofuran (1 mL) was added dropwise to the reaction mixture. This reaction mixture was gradually warmed to 0° C., and partitioned into water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=2:3) to obtain the title compound (73 mg, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]([C:18]([OH:20])=O)=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=1.[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=1>>[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[N:27]=[CH:28][C:29]([NH:32][C:18]([C:11]2[O:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[N:13][C:12]=2[C:14]([F:15])([F:16])[F:17])=[O:20])=[CH:30][N:31]=1
Reactant: COCCN(C)c1ncc(N)cn1
Reactant: COc1ccccc1-c1nc(C(F)(F)F)c(C(=O)O)o1
Product: COCCN(C)c1ncc(NC(=O)c2oc(-c3ccccc3OC)nc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 1 above, 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was prepared from 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid and N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd for C20H20F3N5O4 (m/e) 451, obsd 452 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Product: COc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3ccc(OC)cc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-methoxy-phenylboronic acid to give [1-(3-methoxy-phenyl)-7-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@@H:18]3[CH2:30][CH3:31])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl.O1CCOCC1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[CH2:30][CH3:31])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@H]1CNCCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.7 %

Procedure:
A mixture of 161c (502 mg, 1.02 mmol), dichloromethane (2 mL), and 4.0 M HCl/dioxane (4 mL) was stirred at room temperature for 5 h. It was then concentrated under reduced pressure to afford crude 161d as a yellow solid (263 mg, 66%), which was used in the next step without further purification. MS: [M+H]+ 392.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:22]([NH:24][CH3:25])=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:33][CH2:34]1)[C:22]([NH:24][CH3:25])=[O:23]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(Cl)c1
Temperature: 105 °C
Yield: 25.7 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-chloro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (132 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)-3-chloro-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (53.1 mg, 0.117 mmol, 25.6% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-2.02 (m, 3H) 2.10-2.24 (m, 1H) 2.51 (br. s., 4H) 2.75 (d, J=4.55 Hz, 3H) 3.03 (br. s., 4H) 3.36-3.45 (m, 3H) 3.52-3.65 (m, 1H) 3.93-4.03 (m, 1H) 6.98 (d, J=1.77 Hz, 1H) 7.17 (d, J=8.34 Hz, 1H) 7.63 (d, J=1.77 Hz, 1H) 7.75 (dd, J=8.34, 2.02 Hz, 1H) 7.86 (d, J=2.02 Hz, 1H) 8.41 (q, J=4.13 Hz, 1H) 10.45 (s, 1H). [M+H] calc'd for C23H27ClN6O2, 455; found, 455.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:13]#[N:14])[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=1.Cl[C:16]1[C:21]([CH:22]([CH3:24])[CH3:23])=[C:20]([O:25][CH3:26])[N:19]=[C:18]([O:27][CH3:28])[N:17]=1>CN(C=O)C.CCOC(C)=O>[CH:22]([C:21]1[C:16]([N:10]2[C:11]3[CH:12]=[C:4]([CH3:3])[CH:5]=[C:6]([C:13]#[N:14])[C:7]=3[CH:8]=[CH:9]2)=[N:17][C:18]([O:27][CH3:28])=[N:19][C:20]=1[O:25][CH3:26])([CH3:24])[CH3:23]
Reactant: Cc1cc(C#N)c2cc[nH]c2c1
Reactant: COc1nc(Cl)c(C(C)C)c(OC)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nc(OC)c(C(C)C)c(-n2ccc3c(C#N)cc(C)cc32)n1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 42 %

Procedure:
NaH (148 mg, 1.1 eq.) was added to 6-methyl-1H-indole-4-carbonitrile (526 mg, 3.37 mmol) in 20 mL of DMF. After 5 minutes, 4-chloro-5-isopropyl-2,6-dimethoxy-pyrimidine was added to the reaction mixture. The reaction mixture was heated at 50° C. for 5 hours. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was concentrated and purified (silica gel, 0-80% EtOAC/hexane) to give a white solid (470 mg, 42%). LC-MS shows 337.2 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1B(O)O>>[CH2:21]([CH:18]([N:13]1[C:12]([C:32]2[S:31][CH:35]=[CH:34][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH2:19][CH3:20])[CH3:22]
Reactant: OB(O)c1cccs1
Reactant: CCC(CC)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCC(CC)n1nc2c(c1-c1cccs1)CCNCC2
Yield: 37.2 %

Procedure:
The title compound (35 mg) was prepared as in Example 177, Steps C and D, using 148 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 122 mg of 2-thiopheneboronic acid. MS (ESI): exact mass calculated for C16H23N3S, 289.16. found, m/z 290.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.72-7.67 (m, 1H), 7.25-7.21 (m, 1H), 7.13-7.09 (m, 1H), 4.01-3.94 (m, 1H), 3.43-3.38 (m, 2H), 3.34-3.28 (m, 2H), 3.20-3.14 (m, 2H), 2.86-2.80 (m, 2H), 1.95-1.85 (m, 2H), 1.79-1.69 (m, 2H), 0.71 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([CH:4]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH2:8][CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5]1)#[C:2][CH3:3].C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+].C(N(CC)CC)C.[NH2:63][C:64]1[N:69]=[CH:68][C:67]([S:70](Cl)(=[O:72])=[O:71])=[CH:66][CH:65]=1>C(Cl)Cl>[NH2:63][C:64]1[N:69]=[CH:68][C:67]([S:70]([N:6]2[CH2:7][CH2:8][N:9]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:25])([C:17]([F:20])([F:18])[F:19])[C:21]([F:22])([F:23])[F:24])=[CH:14][CH:15]=3)[CH:4]([C:1]#[C:2][CH3:3])[CH2:5]2)(=[O:72])=[O:71])=[CH:66][CH:65]=1
Reactant: CC#CC1CN(C(=O)OCc2ccccc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: Nc1ccc(S(=O)(=O)Cl)cn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CC1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 2-L round-bottomed flask was charged with benzyl 3-(1-propyn-1-yl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (21.8 g, 43.5 mmol, step 5) and TFA (130 mL). Trifluoromethanesulfonic acid (11.6 mL, 131 mmol, Acros/Fisher Scientific, Waltham, Mass.) was added slowly at rt resulting orange cloudy mixture. After stirring at rt for 10 min, the volume of the reaction mixture was reduced to half in vacuo. Solid NaHCO3 was added in potions until the mixture became sludge. Saturated aqueous NaHCO3 (800 mL) was added slowly until the pH was about 8. The aqueous phase was extracted with EtOAc (3×250 mL). The combined organic phases were washed with water (500 mL) and saturated aqueous NaCl (500 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. This material was dissolved into DCM (200 mL) and triethylamine (31.0 mL, 222 mmol) was added. Then 6-aminopyridine-3-sulfonyl chloride (9.40 g, 48.8 mmol, published PCT patent application no. WO 2009/140309) was added in potions over 10 min period. The brown mixture was stirred at room temperature for 10 min. The reaction mixture was washed with water (300 mL) and saturated aqueous NaCl (300 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (780 g of total silica, 30 to 90% EtOAc in hexanes) to afford 2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (19.4 g) as a mixture of two enantiomers.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].[CH:6]([CH:8]([CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1)[C:9](OCC)=O)=[O:7]>C(O)C>[N:17]1[CH:16]=[C:15]([CH2:14][C:8]2[C:6](=[O:7])[NH:2][C:3](=[S:4])[NH:5][CH:9]=2)[CH:20]=[N:19][CH:18]=1
Reactant: CCOC(=O)C(C=O)Cc1cncnc1
Reactant: NC(N)=S
Agent: [Na]
Solvent: CCO
Product: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Reaction time: 18 h
Yield: 33.7 %

Procedure:
Sodium (0.25 g) was dissolved in ethanol (5 ml), thiourea (0.77 g) added, and the mixture stirred under reflux for 1 hour. A solution of ethyl 2-formyl-3-(5-pyrimidyl)propionate (1.99 g) in ethanol (5 ml) was added slowly, and reflux continued for 18 hours. The solvent was evaporated, and the residue taken up in water and washed with dichloromethane. The aqueous solution was acidified to pH 5, and the precipitate filtered off, washed with water and dried to obtain 5-(pyrimid-5-ylmethyl)-2-thiouracil (0.71 g). 1H-NMR (d6-DMSO) δ 3.58 (2H, s), 7.54 (1H, s), 8.70 (2H, s) and 9.02 (1H, s). MPt 265-6° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[C:37]#[N:38].CCCCCC.C(OCC)(=O)C>C1COCC1.CCCCCC>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:34][C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[C:37]#[N:38])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Reactant: N#Cc1ccccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccccc2C#N)C(=O)O1

Procedure:
Analogously to Example 21 D) 1)c), 2.0 g (6.55 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Example 21 D) 1)b)] dissolved in 40 ml of THF are deprotonated with 13.1 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated (75 min) with 1.4 g (7.2 mmol) of 2-bromomethylbenzonitrile (Fluka; Buchs/Switzerland). Column chromatography (SiO2, hexane/ethyl acetate 2:1) and stirring in hexane yields the pure title compound: TLC Rf (D)=0.45; tRet (I)=16.2 min.