Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([OH:14])[CH2:13][CH2:12][N:11]([C:16]3[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C:25]([F:26])([F:28])[F:27])=[N:23][N:24]=4)[N:21]=3)[CH2:10][CH2:9]2)[CH:3]=1
Reactant: Cc1ccnc(C2(O)CCNCC2)c1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: Cc1ccnc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Yield: 81 %

Procedure:
A mixture of 4-(4-methylpyridin-2-yl)piperidin-4-ol and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by the method of Example 306 to give 4-(4-methylpyridin-2-yl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol in 81% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[Cl:11]NC(=O)CCC(N)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11]
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: NC(=O)CCC(=O)NCl
Solvent: CC#N
Product: Clc1n[nH]c2ccc(Br)cc12
Temperature: 60 °C
Yield: 95 %

Procedure:
To a solution of 5-bromoindazole 162 (0.234 g, 1.19 mmol.) in anhydrous acetonitrile (8 mL) was added N-chlorosuccinamide (0.174 g, 1.31 mmol.). The reaction mixture was heated at 60° C. for 2 hours. The organic solvent was evaporated under reduced pressure. Ethyl acetate (100 mL) was added. The organic layer was washed was 1N sodium hydroxide solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to yield 5-bromo-3-chloroindazole 163 (0.26 g, 1.13 mmol.). The crude product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:14]([O:16][CH3:17])=[O:15])[C:7]2=[O:12].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Cl:65][C:66]1[CH:71]=[CH:70][C:69]([CH:72]([CH3:76])[C:73](O)=[O:74])=[CH:68][CH:67]=1>>[Si:20]([O:19][CH2:18][C@@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:73](=[O:74])[CH:72]([C:69]2[CH:70]=[CH:71][C:66]([Cl:65])=[CH:67][CH:68]=2)[CH3:76])[C:7]1=[O:12])[C:14]([O:16][CH3:17])=[O:15])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(N)cccc2c1=O
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(NC(=O)C(C)c3ccc(Cl)cc3)cccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (R)-methyl 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-3-(tert-butyldimethylsilyloxy)propanoate (500 mg, 0.001 mol), N,N-dimethylformamide (2 mL, 0.03 mol), N,N-diisopropylethylamine (0.5 mL, 0.003 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1 g, 0.003 mol) and 2-(4-chlorophenyl)propanoic acid (340 mg, 0.0018 mol) and the reaction stirred at room temperature overnight then for another 12 h. The solvent was removed and the residue purified by flash chromatography to yield the product as a white solid. MS m/z=545.4 (M+H).
Reaction SMILES: C(OC([N:8]([C:24]1[N:25]([CH2:38][CH2:39][CH3:40])[N:26]=[C:27]2[C:36]=1[C:35]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:29]=[C:28]2[Cl:37])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=O)(C)(C)C.[ClH:41].[NH3:42]>CO.C(O)C>[ClH:37].[ClH:41].[NH:14]1[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][NH:8][C:24]2[N:25]([CH2:38][CH2:39][CH3:40])[N:26]=[C:27]3[C:36]=2[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:29]=[C:28]3[NH2:42])[CH2:16][CH2:15]1
Reactant: CCCn1nc2c(Cl)nc3ccccc3c2c1N(CCC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C
Reactant: N
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CCCn1nc2c(N)nc3ccccc3c2c1NCCC1CCNCC1
Temperature: 150 °C

Procedure:
A solution of tert-butyl 4-{2-[(tert-butoxycarbonyl)(4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)amino]ethyl}piperidine-1-carboxylate (1.41 g) in 7N ammonia in methanol (25 mL) was placed in a stainless steel pressure vessel and heated at 150° C. for 18 hours. The reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure to provide a brown residue. The residue was suspended in anhydrous ethanol (20 mL). Hydrochloric acid (4 mL of 3M) was added and the reaction mixture was heated at reflux for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether and the resulting solid was isolated by filtration to provide 0.7 g of N1-(2-piperidin-4-ylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine dihydrochloride as a brown solid. MS (APCI) m/z 353.30 (M+H)+. The experiment was repeated using 5.75 g of tert-butyl 4-{2-[(tert-butoxycarbonyl)(4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)amino]ethyl}piperidine-1-carboxylate in 70 mL of 7N ammonia in methanol followed by treatment with 16.75 mL of 3M hydrochloric acid to provide 4.1 g of product as a brown solid. MS (APCI) m/z 353.26 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]([NH2:18])(=[O:17])[CH:14]([CH3:16])[CH3:15]>>[C:13]([NH:18][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C(N)=O
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Product: COC(=O)c1cc(C)nc(NC(=O)C(C)C)c1

Procedure:
The title compound is prepared in quantitative yield (1.27 g, yellow syrup) from methyl 2-chloro-6-methylisonicotinate (1.00 g, 5.39 mmol) and isobutyramide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].Cl.[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH2:14]([O:21][NH:22][C:6]1[N:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NOCc1ccccc1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccnc1NOCc1ccccc1
Yield: 52.3 %

Procedure:
2-Chloro-nicotinic acid ethyl ester (4.55 g, 24.6 mmol), O-benzylhydroxyamine hydrochloride (7.85 g, 49.2 mmol) and N,N-diisopropylethylamine (6.36 g, 49.2 mmol) in 10 mL 1,4-dioxane were reacted in a sealed tube at 120° C. for 48 hours. The reaction mixture was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The aqueous layer was re-extracted with ethyl acetate (2×50 mL). The organic layers were combined and dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (9:1) to provide the title compound (3.5 g, 53%). MS (DCI) m/z 273 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:7]2[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[Br:19]N1C(=O)CCC1=O>>[C:1]([C:4]1[C:5]([Br:19])=[C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:7]2[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cc(-c2cccnc2)n2c1CCCC2
Product: CC(=O)c1c(Br)c(-c2cccnc2)n2c1CCCC2
Yield: 37.6 %

Procedure:
1-Acetyl-2-bromo-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine is prepared as described in Example 23, from 1.2 g of 1-acetyl-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine and 1.1 g of N-bromosuccinimide. 0.6 g of 1-acetyl-2-bromo-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine are thus obtained in the form of white crystals melting at 163° C.
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[S:35][CH:34]=[N:33][CH:32]=1)CCC.O1CCOCC1>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>[Cl:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:31]1[S:35][CH:34]=[N:33][CH:32]=1)[C:11]([C@@H:12]([N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH3:13])=[CH:10]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C[C@@H](c1cc2cccc(Cl)c2nc1-c1cncs1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (0.2000 g, 0.5388 mmol), 5-(tributylstannyl)thiazole (0.4032 g, 1.078 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.06226 g, 0.05388 mmol) in 1,4-dioxane (4.490 mL, 0.5388 mmol) was stirred at 100° C. After 94 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 7 min as eluent to give 2-((S)-1-(8-chloro-2-(thiazol-5-yl)-quinolin-3-yl)ethyl)isoindoline-1,3-dione as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (1H, s), 8.83 (1H, s), 8.30 (1H, d, J=0.8 Hz), 8.13 (1H, dd, J=8.2, 1.2 Hz), 7.99 (1H, dd, J=7.6, 1.4 Hz), 7.71-7.82 (4H, m), 7.60-7.69 (1H, m), 6.03 (1H, q, J=7.2 Hz), 1.88 (3H, d, J=7.0 Hz); LC-MS (ESI) m/z 420.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH2:20]([N:22]([CH2:29][CH3:30])[CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21]>C(#N)C>[CH2:20]([N:22]([CH2:23][CH:24]1[CH2:28][CH2:27][N:26]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:15])[CH2:25]1)[CH2:29][CH3:30])[CH3:21]
Reactant: CCN(CC)CC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC#N
Product: CCN(CC)CC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A mixture of 0.5 g (1.8 mmole) 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5 ml acetonitrile, 0.27 g (1.8 mole) of 1,8-diazobicyclo[5.4.0]undec-7-ene, and 0.3 g (1.9 mmole) of N,N-diethyl-3-pyrrolidinemethanamine was stirred at room temperature overnight. The formed precipitate was filtered, washed with acetonitrile then ethyl ether until dry to yield 0.45 g (60%) of the title compound, mp 210°-211° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([CH2:11][OH:12])=[CH:6][CH:5]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1.O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:12][CH2:11][C:7]1[C:8]([CH3:10])=[N:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[CH3:19]
Reactant: Cc1nc(Cl)ccc1CO
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)COCc1ccc(Cl)nc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (266 mg of 60%, 6.66 mol) was suspended in tetrahydrofuran (14.8 mL) and cooled to 0° C. (6-Chloro-2-methylpyridin-3-yl)methanol (Example 421 Step 1) (350 mg, 2.22 mmol) was added and the mixture was stirred for 30 minutes at 0° C. Ethyl bromoacetate (0.25 mL, 2.22 mmol) was added and the solution was heated to 50° C. for 4 hours. The reaction mixture was then cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The aqueous layer was acidified with 1N HCl and extracted with ethyl acetate three times. All the organic layers were combined, dried over magnesium sulfate, filtered, concentrated, and purified via silica gel chromatography (0-100% ethyl acetate in hexane) to afford the title compound.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])=[C:14]2[N:13]=[C:12]([CH3:28])[CH:11]=1>C1COCC1>[CH2:2]([CH:3]([O:6][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[C:14]2[N:13]=[C:12]([CH3:28])[CH:11]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(O)CC
Reactant: Cc1cc(C)c(-c2cnn3c(Cl)cc(C)nc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc2c(-c3c(C)cc(C)cc3C)cnn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
A solution of 3-pentanol (140 mg, 1.5 mmol) in 1 ml of dry THF was treated with 60% sodium hydride in oil (28 mg, 0.7 mmol) and stirred at room temperature for 10 min. A solution of 7-chloro-5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (75 mg, 0.262 mmol) in 1 ml of dry THF was added and the resulting mixture was heated at reflux for 5 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give the crude material. The residue was purified through silica gel column chromatography using 3:7 chcloroform:hexane as eluent to give 75 mg (88%) of the title compound. 1H NMR (CDCl3) ä 7.97(s, 1H), 6.97(s, 2H), 6.03(s, 1H), 4.56(m, 1H), 2.53(s, 3H), 2.32(s, 3H), 2.13(s, 6H), 2.10(m, 4H), 1.09(t, 6H) ppm.
Reaction SMILES: CI.[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[NH:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][N:12]1[C:11]([CH:13]=[O:14])=[CH:10][N:9]=[C:8]1[C:4]1[S:3][CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c[nH]c(-c2cccs2)n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(C=O)cnc1-c1cccs1
Temperature: 70 °C

Procedure:
Methyl iodide (477 mg, 3.36 mmol) dissolved in DMF (0.5 ml) was added dropwise to a stirred solution of 2-Thiophen-2-yl-1H-imidazole-4-carbaldehyde (0.57 g, 3.2 mmol) and Potassium carbonate (0.486 g, 3.52 mmol) in dry N,N-Dimethylformamide (6 mL) at rt. The solution was stirred at 70° C. 3 h. Most of the DMF was evaporated off and the residue was partioned between EtOAc (50 ml) and brine (25 ml). The phases were separated and the organic phase was dried (Na2SO4) and the solvent was evaporated off. The crude product was purified by silica gel chromatography (Eluent: 50%-100% EtOAc in n-heptane). Yield: 211 mg of the title compound as an oil. H-NMR (DMSO-d6): δ 9.71 (s, 1H), 7.80 (s, 1H) 7.54 (m, 2H), 7.17 (m, 1H), 4.14 (s, 3H). LC-MS: m/z=192.9 (MH+), tR=0.34 min, method C. (211 mg of a fast eluting isomer (3-Methyl-2-thiophen-2-yl-3H-imidazole-4-carbaldehyde) was also isolated and discarded).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[N:35][C:34]2=[CH:38][C:31]3=[N:32][N:33]2[C:13]=1[N:14]1[CH2:40][CH2:39][C:17]([CH3:41])([O:18][CH2:19][CH:20]=[CH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:28][CH:29]=[CH:30]3)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+]>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[N:35][C:34]2=[CH:38][C:31]3=[N:32][N:33]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:41])([O:18][CH2:19][CH:20]=[CH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:28][CH:29]=[CH:30]3)[CH2:39][CH2:40]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=Cc1ccccc1CC=C3
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=Cc1ccccc1CC=C3
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of the ethyl (2S)-2-(tert-butoxy)-2-[4,23-dimethyl-22-oxa-1,5,7,8-tetraazapentacyclo[21.2.2.16,9.02,7.013,18]octacosa-2,4,6(28),8,10,13(18),14,16,19-nonaen-3-yl]acetate (0.0366 g, 0.066 mmol)) in dioxane (1 mL)/MeOH (1 mL) was added 10N sodium hydroxide (0.066 mL, 0.655 mmol) and the mixture was stirred at 70° C. for 1 h. The reaction was cooled and concentrated. The crude material was purified via preparative HPLC to give the title compound as diastereomers. LCMS (M+H) calcd for C31H38N4O4: 531.29. found: 531.4.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[NH2:30][CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][N:34]([CH3:36])[C:32]([CH2:31][NH:30][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([O:25][C:26]([F:28])([F:27])[F:29])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14])=[O:33]
Reactant: CN(C)C(=O)CN
Reactant: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N(C)C)ccc21
Yield: 37.5 %

Procedure:
1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (45.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-amino-N,N-dimethyl-acetamide (25.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 508; and 1H NMR (DMSO-d6, 400 MHz): δ 8.19 (1H, br. s), 7.88 (1H, br. s), 7.68 (1H, br. s), 7.55 (1H, br. s), 7.34-7.24 (2H, m), 7.13 (1H, m), 4.19-4.16 (2H, m), 4.12-4.10 (2H, d), 3.03 (3H, s), 2.88 (3H, s), 1.31-1.27 (3H, t), —NH proton signal was not observed.
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].I[C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CN(C)C=O>[CH2:20]([O:19][C:17]([C:16]1[CH:22]=[CH:23][C:13]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:14][CH:15]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#CC2(O)CN3CCC2CC3)cc1
Temperature: 65 °C
Yield: 46.4 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (604 mg), ethyl 4-iodobenzoate (1.1 g), bis(triphenylphosphine)-palladium (II) chloride (140 mg), copper (I) iodide (70 mg) and anhydrous triethylamine (4 ml) and anhydrous dimethylformamide (8 ml) was stirred under an atmosphere of argon. The reaction mixture was heated at 65° C. for 18 hours. The reaction mixture was cooled and the triethylamine and dimethylformamide removed by evaporation. To the residue was added 2M sodium hydroxide (25 ml) and the mixture extracted with dichloromethane. The organic phase was washed with water, saturated brine and dried (MgSO4). Evaporation gave a solid which was crystallised from acetonitrile to give 3-[2-(4-ethoxycarbonylphenyl)ethynyl]-3-hydroxyquinuclidine (553 mg) as a colourless solid, m.p. 176°-177° C.; microanalysis, found: C, 72.2; H, 7.3; N, 4.8%; C18H21NO3 requires: C, 72.2; H, 7.07; N, 4.68%; NMR (DMSO-d6): 1.32(3H, t), 1.49-2.01(5H, m), 2.68(4H, t), 2.78-3.14(2H, d of d), 4.32(2H, q), 5.66(1H, br.s), 7.49-7.58(2H, d) and 7.90-7.98(2H, d); m/Z 300 (M+H).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6](=[O:12])[C:7]([NH:9][CH2:10][CH3:11])=[O:8].Cl>C(O)(=O)C>[CH2:4]([N:5]1[CH:11]=[CH:10][N:9]=[C:7]([OH:8])[C:6]1=[O:12])[CH3:3]
Reactant: CCNC(=O)C(=O)NCC(OC)OC
Agent: Cl
Solvent: CC(=O)O
Product: CCn1ccnc(O)c1=O
Reaction time: 1 h
Yield: 79.9 %

Procedure:
67.5 g (330 mM) of N-(2,2-dimethoxyethyl)-N′-ethylethanediamide and 2 ml of concentrated hydrochloric acid, in 390 ml of acetic acid, were refluxed under stirring for 1 h. The solvent was removed under vacuum to give an oil, which was further purified by silica gel column chromatography, using dichloromethane/methanol (95/5) as eluant to give 37 g of 1-ethyl-3-hydroxy pyrazine-2(1H)-one as an oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][NH:5][CH2:4]1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:14]1([S:20]([N:5]2[CH2:6][CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:3]([CH2:2][O:1][S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH2:4]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: OCC1CNCC1c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(OCC1CN(S(=O)(=O)c2ccccc2)CC1c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A solution of 196 mg (1.1 mmol) of 3-(SR)-hydroxymethyl-4-(SR)-phenylpyrrolidine (from Example 1, Step C) and 27 mg (0.2 mmol) of 4-(N,N-dimethylamino)pyridine in 5 mL of pyridine at 0 ° C. was treated with 488 mg (2.8 mmol) of benzenesulfonyl chloride. The cooling bath was removed and the resulting mixture was stirred at rt for 1 h. The reaction mixture was treated with an additional 290 mg of benzenesulfonyl chloride and the resulting mixture was stirred at rt for 1 h. The reaction mixture was partitioned between 50 mL of ether and 20 mL of sat'd CuSO4 and the layers were separated. The organic layer was washed with 30 mL of H2O, 30 mL of sat'd NaCl, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 30 g of silica gel using3:2 v/v hexanes/ether afforded 340 mg (67%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3): δ2.65-2.72 (m, 1H), 3.21 (dd, J=7.8, 10.3, 1H), 3.44-3.67 (6H), 6.94-7.90 (15H). Mass Spectrum (NH3-CI): m/z 458 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:22]([C:23]([O:25]C)=[O:24])=[CH:21][N:20]=1>C1COCC1.CCOC(C)=O>[F:32][C:29]([F:30])([F:31])[C:27]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=[C:19]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])[CH:28]=1
Reactant: CC(O)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(Oc1cc(C(F)(F)F)c(C(=O)O)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To a solution of 180 mg (1.56 mmol) of 1,1,1-trifluoro-2-propanol in 10 mL of THF at −78° C. was added 1.56 mL (1.56 mmol) of sodium bis(trimethylsilyl)amide (1.0M in THF). After 30 min at −78° C., 250 mg (1.04 mmol) of methyl 6-chloro-4-(trifluoromethyl)nicotinate was added. The reaction mixture was gradually warmed up to rt and stirred over night. The mixture was diluted with 10 mL of EtOAc and washed with brine. The organic layer was dried over MgSO4 and concentrated. Purification using HPLC B gave 160 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.57 (d, J=6.6, 3H), 5.91 (m, 1H), 7.26 (s, 1H), 8.98 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:20])[C:16]#[C:17][CH2:18][OH:19].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:19][CH2:18][C:17]#[C:16][CH2:15][OH:20])[N:3]=[CH:4][N:5]=1
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Reactant: OCC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCC#CCOc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 9 h
Yield: 61.8 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 608 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 527 mg of 2-butyn-1,4-diol, to which 245 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 465 mg of 4-(2-fluorophenyl)-6-(4-hydroxy-2-butynyloxy)pyrimidine.