Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.CI.[C:14](=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH3:14][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2cnccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.6 g (38.6 mmol) of 5-hydroxyisoquinoline was dissolved in 70 ml of DMF. 2.63 ml (38.6 mmol) of methyl iodide and 7.99 g (57.9 mmol) of potassium carbonate were added to the obtained solution, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extracting solvent in an ordinary manner, the crude product was obtained. It was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][CH:13]([F:16])[CH2:14][OH:15]>>[Br:1][C:2]1[C:3]([O:15][CH2:14][CH:13]([F:16])[F:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: OCC(F)F
Product: O=C(O)c1cnc(OCC(F)F)c(Br)c1
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (4.7 g, a pale orange solid) from 5-bromo-6-chloronicotinic acid (3.0 g, 12.7 mmol) and 2,2-difluoroethanol (2.1 g, 25.4 mmol) instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-1.
Reaction SMILES: N12CCCCC1C=NCCC2.Br[C@@H](CO)C(O)=[O:15].[CH:19]1([N:25]=[C:26]=[N:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl-].C([NH2+]CSC(C)(C)C)C1C=CC=CC=1>O1CCCC1>[C:26]([NH:25][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)([NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:15]
Reactant: O=C(O)[C@@H](Br)CO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1=NCCCN2CCCCC12
Agent: CC(C)(C)SC[NH2+]Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 ml of a 2M solution of 1,5-diazabicyclo[5.4.0]-undec-5-ene (DBU) in tetrahydrofuran are added while stirring, at room temperature, to a solution of 845 mg (5 mmol) of 2-(S)-bromo-3-hydroxypropionic acid in 10 ml of absolute tetrahydrofuran and the resulting mixture is stirred for a further 2 hours at room temperature. The solvent is subsequently distilled off in vacuo and 25 ml of methylene chloride are added. To this solution containing the DBU salt of (R)-glycidic acid there are added 1.03 g (5 mmol) of dicyclohexyl carbodiimide and, after stirring for one hour, 1.3 g (5 mmol) of N-benzyl-N-tert.-butylthiomethylammonium chloride. After the addition of the last-mentioned reaction component, crystalline dicyclohexylurea is formed. After a reaction time of 3 hours at room temperature, the latter is filtered off with suction and the filtrate is diluted with methylene chloride and washed with phosphate buffer solution having a pH of 8. After concentration of the organic phase by evaporation, the residue is chromatographed over 50 g of silica gel. After a few first fractions have been removed with toluene, the title compound is eluted with a mixture of toluene/ethyl acetate (9:1) in the form of a colourless, viscous oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[CH3:9][C:10]([CH3:12])=O.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:10]([NH:1][C@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])([CH3:12])[CH3:9]
Reactant: CC[C@@H](N)C(=O)OC
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: CC[C@@H](NC(C)C)C(=O)OC
Reaction time: 3 h
Yield: 54.2 %

Procedure:
Methyl (2R)-2-amino-butanoate 1j (28.78 g, 0.19 mol) was dissolved in 200 mL of dichloromethane followed by the addition of acetone (11.96 g, 0.21 mol) and sodium acetate (30.76 g, 0.38 mol), stirred 3 hours. Sodium triacetoxyborohydride (59.61 g, 0.28 mol) was added. The reaction solution was stirred for 12 hours followed by the addition of 100 mL of 1 M hydrochloric acid and dropwise addition of saturated sodium carbonate solution to adjust pH to 8 to 9, extracted with dichloromethane (100 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl (2R)-2-(isopropylamino)butanoate 22a (16.40 g, yield: 55.0%) as a light yellow oil liquid.
Reaction SMILES: [C:1]([N:4]([C:8]1[N:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[N:18][N:19]3[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)=[N:21][C:20]=23)=[CH:10][N:9]=1)C(=O)C)(=[O:3])[CH3:2].Cl.O>N.C1COCC1>[F:27][C:25]([F:26])([F:28])[C:24]1[N:19]2[N:18]=[CH:17][C:16]([C:15]#[C:14][C:11]3[CH:12]=[N:13][C:8]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][CH:10]=3)=[C:20]2[N:21]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:31][CH:30]=2)[CH:23]=1
Reactant: CC(=O)N(C(C)=O)c1ncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1
Yield: 99.9 %

Procedure:
N-Acetyl-N-{5-[7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-ylethynyl]-pyrimidin-2-yl}-acetamide (example 244) (56 mg, 0.1 mmol) was dissolved in ammonia (200 uL) and THF (5 mL), stirred for 15 minutes at 23° C., then 1N HCl and water added until pH=1. The product was filtered off, washed with water and dried in vacuum to give the title compound as a yellow solid (49 mg, 95%). MS (ISP) 491.2 [(M+H)+]; mp 293° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[C:27]([C:28]([NH2:30])=[O:29])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[CH3:33][N:34]([CH2:36][C:37]([N:39]1[C:47]2[C:42](=[CH:43][C:44]([O:49][CH3:50])=[C:45](N)[CH:46]=2)[CH2:41][CH2:40]1)=[O:38])[CH3:35].Cl.O1CCOCC1.[I-].[K+]>FC(F)(F)CO.ClCCl.C(=O)(O)[O-].[Na+]>[CH3:33][N:34]([CH3:35])[CH2:36][C:37]([N:39]1[C:47]2[C:42](=[CH:43][C:44]([O:49][CH3:50])=[C:45]([NH:3][C:2]3[N:30]4[C:4](=[N:21][C:22]5[C:27]([C:28]4=[O:29])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=5)[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=3)[CH:46]=2)[CH2:41][CH2:40]1)=[O:38]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc(F)c(F)c4C(N)=O)nc(Cl)nc32)cc1
Reactant: COc1cc2c(cc1N)N(C(=O)CN(C)C)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: ClCCl
Solvent: OCC(F)(F)F
Solvent: C1COCCO1
Product: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4ccc(F)c(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Temperature: 90 °C
Reaction time: 24 h
Yield: 108.1 %

Procedure:
To a suspension of 6-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluorobenzamide (350 mg, 0.732 mmol) in 2,2,2-trifluoroethanol (10 ml) was added 1-[(dimethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (228 mg, 0.916 mmol), hydrochloric acid as a 4.0M solution in dioxane (1.47 ml, 5.86 mmol), and catalytic potassium iodide (<10 mg). The resulting slurry was stirred at 90° C. in a pressure vial for 24 hours, at which time all solids had completely dissolved. The resulting solution was cooled to room temperature and diluted with dichloromethane and saturated sodium bicarbonate as to adjust the aqueous layer to pH>10. The organic layer was washed with water and saturated brine solution, dried over sodium sulfate, filtered and solvents were removed under reduced pressure. The resulting green solid was purified via trituration with diethyl ether to afford 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,9-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (533 mg, 0.791 mmol) as a yellow solid. (ESIMS (M+H)+=674)
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[K+].[Br-]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:31]3[CH2:32][CH2:33][N:28]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][N:22]=4)[CH2:29][CH2:30]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(c2cnccn2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(pyrazin-2-yl)-piperazine- White crystals, m.p. 160–161° C.; HPLC-MS: m/z=446 (M+1) at Rt=4.0 min.; 1H NMR (DMSO-d6): δ 8.60–8.57 (m, 1H), 8.39–8.36 (m, 1H), 8.27–8.22 (dd-like, 1H), 8.14–8.11 (m, 1H)7.91–7.87 (d-like, 1H), 7.29–7.21 (m, 5H), 3.80–3.64 (br, 6H), 3.64–3.50 (br, 2H); IR (KBr): ν 1737, 1714 (C═O) cm−1.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][NH:11][CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.Cl[C:18]1[CH:23]=[CH:22][C:21]2=[N:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]([CH3:40])=[C:31]([NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH:32]=3)=[CH:26][N:20]2[N:19]=1>C(O)CCC>[CH3:36][C:35]([CH3:38])([CH3:37])[C:34]([NH:33][C:31]1[CH:32]=[C:27]([C:25]2[N:24]=[C:21]3[N:20]([CH:26]=2)[N:19]=[C:18]([N:14]2[CH2:15][CH2:16][CH:12]([NH:11][CH3:10])[CH2:13]2)[CH:23]=[CH:22]3)[CH:28]=[CH:29][C:30]=1[CH3:40])=[O:39]
Reactant: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Reactant: CNC1CCNC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CNC1CCN(c2ccc3nc(-c4ccc(C)c(NC(=O)C(C)(C)C)c4)cn3n2)C1
Temperature: 180 °C
Yield: 14.8 %

Procedure:
An small microwave vial is charged butanol (0.183 mL), diisopropylethylamine (0.122 mL, 0.7 mmol), N-methylpyrrolidin-3-amine (0.050 g, 0.5 mmol), and N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-methyl-phenyl]-2,2-dimethyl-propanamide (0.0397 g, 0.1 mmol). The vial is sealed and heated at 180° C. for 30 min in microwave. The mixture is concentrated, taken up in DMSO and purified on reverse phase preparative HPLC with gradient (15% B:85% A to 100% B, where solvent A=95% water, 5% acetonitrile and 0.1% TFA; solvent B=90% acetonitrile, 10% water and 0.1% TFA) to give the title compound (0.006 g, 15% yield). LCMS m/z=407.6 [M+H]+, tR=1.32 min. (compound same as Example 360)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.CCCCCC.[Cl:18][C:19]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][N:23]2[C@H:29]1[CH2:33][CH2:32][O:31][C:30]1=[O:34]>C(Cl)Cl>[Cl:18][C:19]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][N:23]2[C@@H:29]([CH2:33][CH2:32][OH:31])[C:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:34]
Reactant: O=C1OCC[C@@H]1N1CCc2c1ccc(F)c2Cl
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(Nc1ccccc1)[C@H](CCO)N1CCc2c1ccc(F)c2Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
Prepared using general procedure 60: To a solution of aniline (1.4 mL, 15.6 mmol) in CH2Cl2 (37 mL) under nitrogen at RT was added a solution of trimethylaluminum in hexane (2.0 M, 7.8 mL, 15.6 mmol) over 5 min. After stirring at RT for 20 min, a solution of (S)-3-(4-chloro-5-fluoroindolin-1-yl)-dihydrofuran-2(3H)-one (4.0 g, 15.6 mmol) in CH2Cl2 (37 mL) was added over 10 min. Heated to reflux for 12 h, then the reaction mixture was cooled to 0° C. and quenched by careful addition of aqueous 1M HCl (70 mL). Phases were separated, and the aqueous phase was extracted with CH2Cl2 (2×75 L). The combined organic extracts were dried over MgSO4 and concentrated. Purification via silica gel chromatography using 2-7.5% MeOH in CH2Cl2 gave (S)-2-(4-chloro-5-fluoroindolin-1-yl)-4-hydroxy-N-phenylbutanamide as a white solid (5.44 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.59 (d, J=7.6 Hz, 2H), 7.31-7.27 (m, 2H), 7.07-6.99 (m, 2H), 6.53 (dd, J=3.6, 8.6 Hz, 1H), 4.70 (t, J=4.9 Hz, 1H), 4.35 (t, J=7.4 Hz, 1H), 3.92-3.80 (m, 1H), 3.68-3.62 (m, 1H), 3.55-3.47 (m, 2H), 3.05-2.89 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.88 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=349.1; tR=1.69 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].Cl.Cl.[CH:26]1([NH:29][CH:30]2[CH2:33][NH:32][CH2:31]2)[CH2:28][CH2:27]1>>[CH:26]1([NH:29][CH:30]2[CH2:33][N:32]([C:18]3[C:19]([F:21])=[CH:20][C:10]4[C:11]([CH:17]=3)=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7](=[O:23])[C:8]=3[CH:9]=4)[CH2:31]2)[CH2:28][CH2:27]1
Reactant: C1CC1NC1CNC1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: Cl
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CC(NC5CC5)C4)c(F)cc3cc2c1=O
Yield: 72.2 %

Procedure:
8-(3-Cyclopropylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 15, but starting with 1.45 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine and 1.7 g of 3-(cyclopropylamino)azetidine dihydrochloride. 1.35 g of 8-(3-cyclopropylamino-1-azetidinyl)3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 221° C. and then 245° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:34][N:35]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:38]4[CH2:39][CH2:40][CH2:41][N:35]([CH3:34])[CH2:36][CH2:37]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CN1CCCNCC1
Product: CN1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-[1,4]diazepan-1-yl)-thiazol-4-one was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-methyl-[1,4]diazepane following General Procedure C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[CH:3]=1.C(N(CC)CC)C.CN([C:38]([O:42][N:43]1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.CNO>CN(C=O)C>[CH3:38][O:42][NH:43][C:19]([C:16]1[S:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:22][C@@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)[C:10]=2[C:17]=1[CH3:18])=[O:21]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCOC3)c12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNO
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CONC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCOC3)c2c1C
Reaction time: 0.17 h

Procedure:
4-{4-Fluoro-2-[(R)-(tetrahydro-furan-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (100 mg) was dissolved in DMF (3 ml) and triethylamine (79 μl) was added. To this mixture TBTU (90 mg) was added and the reaction was stirred for 10 mins. After this time methylhydroxylamine hydrochloride (27 mg) was added and the reaction was stirred at 40° C. overnight. The mixture was purified by RP-chromatography (method A).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[C:14]1([S:24](Cl)(=[O:26])=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.O.Cl>[OH-].[Na+].O1CCOCC1>[C:14]1([S:24]([NH:1][C@H:2]([C:4]([N:6]2[CH2:13][CH2:12][CH2:11][C@H:7]2[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])(=[O:26])=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
L-alanyl-L-proline (1.86 g, 10 mmole) was dissolved in 1N aqueous sodium hydroxide (10 ml)-dioxane (5 ml), and dioxane (5 ml) solution of α-naphthalenesulfonylchloride (2.26 g, 10 mmole) was added dropwise to the solution while cooling with ice and stirring while keeping pH value thereof to between 10 and 11 with 1N aqueous sodium hydroxide. After the addition, the mixture was stirred further for 2 hours at room temperature. Water (20 ml) was added thereto and the mixture thus obtained was washed with diethyl ether (40 ml). The water layer was filtered and the filtrate thus obtained was adjusted to pH 2.0 with 1N aqueous hydrochloric acid while cooling with ice and stirring and extracted with ethyl acetate (100 ml). The ethyl acetate was washed with 1N aqueous hydrochloric acid (50 ml) and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure and crystallized by cooling with ice to give N-α-naphthalenesulfonyl-L-alanyl-L-proline[yield: 1.77 g, 47.0%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[N:17]([CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24])=[N+:18]=[N-:19]>C(Cl)Cl>[N:17]([CH2:20][CH2:21][CH2:22][C:23]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])=[O:24])=[N+:18]=[N-:19]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: [N-]=[N+]=NCCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(C(=O)CCCN=[N+]=[N-])C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (3.82 g, 26.5 mmol) and pyridine (4.20 g, 53.0 mmol) in 150 ml of CH2Cl2 was added dropwise a solution of crude 4-azidobutyric chloride (3.90 g, 26.5 mmol) in 30 ml of CH2Cl2 at 0° C. The mixture was stirred at 0° C. for 1 hr then at room temperature for 1 hr. The solution was washed with 0.5N aqueous HCl (60 ml), water (60 ml) followed by brine (60 ml) and dried. After evaporation of solvent, 5-(4-azidobutanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was obtained as a light pink oil (6.20 g, 92%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[C:26]([Si:28]([CH3:31])([CH3:30])[CH3:29])#[CH:27].O.COC(C)(C)C>N1CCCCC1>[CH3:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][C@@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[C:5]2[CH:6]=[CH:7][C:2]([C:27]#[C:26][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:3][CH:4]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: C#C[Si](C)(C)C
Solvent: C1CCNCC1
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1cc(C(=O)C[C@H](c2ccc(C#C[Si](C)(C)C)cc2)c2ccccc2C)ccn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of (R)-3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 142, step 2, 150 mg) in piperidine (3 mL) were added under argon copper(I) iodide (3.6 mg) and tetrakis-triphenylphosphine palladium(0) (22 mg). The reaction mixture was heated at 50° C. and ethynyltrimethylsilane (480 μL) was added. The reaction mixture was stirred at 50° C. overnight. water and tert-butyl methyl ether were added, the phases were separated and the inorganic one was extracted with tert-butyl methyl ether (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (15% to 50% ethyl acetate in n-heptane) to yield the title compound as a light yellow oil (105 mg, 61%), MS (ESI+): m/z=412.4 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])=[CH:28][CH:29]=4)[CH:24]=[CH:23]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)C(=O)Nc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)C(=O)Nc1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate 06) and N-(1H-indol-5-yl)isobutyramide (intermediate 10).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH3:6])=[O:4].C(C1(C2C=CC(OC)=C(C=2)[CH:25]=[O:26])CC1)#N>>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH3:6])=[CH:12][C:11]=1[CH:25]=[O:26]
Reactant: COC(=O)C(C)c1ccc(OC)cc1
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Product: COC(=O)C(C)c1ccc(OC)c(C=O)c1

Procedure:
This compound was prepared from Compound 32 in the same manner of Compound 2.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C1COCC1.CCN(C(C)C)C(C)C.[C:41]([C:45]1[N:49]([CH2:50][CH:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)[C:48]2[CH:57]=[CH:58][C:59]([S:61]([N:64]3[CH:68]=[C:67]([C:69]([OH:71])=O)[CH:66]=[N:65]3)(=[O:63])=[O:62])=[CH:60][C:47]=2[N:46]=1)([CH3:44])([CH3:43])[CH3:42]>CN(C=O)C>[C:41]([C:45]1[N:49]([CH2:50][CH:51]2[CH2:52][CH2:53][O:54][CH2:55][CH2:56]2)[C:48]2[CH:57]=[CH:58][C:59]([S:61]([N:64]3[CH:68]=[C:67]([C:69]([NH:2][CH3:1])=[O:71])[CH:66]=[N:65]3)(=[O:62])=[O:63])=[CH:60][C:47]=2[N:46]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1

Procedure:
Following the same procedure in Example 24, Step A, using HATU (37 mg, 0.09 mmol), methylamine in THF (0.07 mL, 2M, 0.14 mmol), DIPEA (0.02 mL, 0.10 mmol) and 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (40 mg, 0.09 mmol) (see following step B for preparation) in DMF (5 mL). The crude product was purified by MPLC on silica gel using EtOAc/DCM (1:1) to provide the title compound as a white solid. The product was converted to its TFA salt. Yield: 15 mg (29%); 1H NMR (400 MHz, CD3OD) δ 1.38-1.46 (m, 2 H), 1.46-1.54 (m, 2 H), 1.54-1.59 (s, 9 H), 2.22-2.36 (m, 1 H), 2.83 (s, 3 H), 3.25-3.35 (m, 2 H), 3.89 (dd, J=11.43, 3.61 Hz, 2 H), 4.36 (d, J=7.42 Hz, 2 H), 7.79 (d, J=8.59 Hz, 1 H), 7.90 (dd, J=8.69, 1.86 Hz, 1 H), 8.01 (s, 1 H), 8.29 (d, J=1.95 Hz, 1 H), 8.72 (s, 1 H); MS (ESI) (M+H)+=459.8; Anal. Calcd for C22H29N5O4S+0.1H2O: C, 57.27; H, 6.38; N, 15.18. Found: C, 57.49; H, 6.55; N, 14.34.