Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[CH:18]=[C:17]([C:19]([OH:21])=O)[S:16][C:15]=3[CH:22]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.[F:24][C:25]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:24][C:25]1([F:31])[CH2:30][CH2:29][N:28]([C:19]([C:17]2[S:16][C:15]3[CH:22]=[C:11]([O:10][CH:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]4)[CH:12]=[CH:13][C:14]=3[CH:18]=2)=[O:21])[CH2:27][CH2:26]1
Reactant: FC1(F)CCNCC1
Reactant: CC(C)N1CCC(Oc2ccc3cc(C(=O)O)sc3c2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2ccc3cc(C(=O)N4CCC(F)(F)CC4)sc3c2)CC1
Yield: 76.2 %

Procedure:
In a flask were mixed together the above prepared 6-(1-isopropyl-piperidin-4-yloxy)-benzo[b]thiophene-2-carboxylic acid (0.147 g, 0.320 mmol, corrected for purity), 4,4-difluoropiperidine hydrochloride (0.060 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (0.170 g, 1.2 eq.) and 2.5 eq. of N-ethyldiisopropylamine (0.760 mL) in 2 mL of abs. THF and allowed to react during one night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, CH2Cl2/MeOH=9/1) produced 0.103 g of the title compound as white foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[N:11]1([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][CH:18]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>O=P(Cl)(Cl)Cl>[Cl:10][C:5]1[C:6]([Cl:9])=[C:7]2[NH:8][C:21]([C:20]3[CH:19]=[CH:18][C:17]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:25][CH:24]=3)=[N:1][C:2]2=[N:3][CH:4]=1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: Nc1ncc(Cl)c(Cl)c1N
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cnc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1Cl
Temperature: 105 °C
Yield: 20.5 %

Procedure:
2,3-Diamino-4,5-dichloropyridine (Example 206a) (0.10 g, 0.56 mmol) and 4-morpholin-4-ylbenzoic acid (0.12 g, 0.56 mmol) were dissolved in POCl3 (5 ml) and heated to 105° C. for 5 h. The excess of POCl3 was evaporated off and the residue was dissolved in EtOAc and aqueous K2CO3. The aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), evaporated in vacuo and the residue was purified by HPLC-C18. The product crystallized from the chromatography fraction and was filtered off and dried to yield a white powder (0.040 g, 20%).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH2:3].N#N.[H][H]>[Pd].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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].CN([C@H]([C]1[C](P(C2C=CC=CC=2)C2C=CC=CC=2)[CH][CH][CH]1)C1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=CC=1)C.[CH]1[CH][CH][CH][CH]1.[Fe]>[CH3:3][CH:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:1]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: [Fe]
Agent: [Pd]
Agent: [Rh]
Product: COC(=O)CC(C)C(=O)OC
Reaction time: 0.17 h
Yield: 98 %

Procedure:
The catalyst [(10% Pd/C, 5.0 mg, 0.12 mol %), (Tris(triphenylphosphine)rhodium(I) chloride, 0.05 g, 1.35 mol %) (bis(norbornadiene)rhodium(I) BF4, Taniaphos, 0.003 mmol, 0.75 mol %)] was weighed into a dry 2-neck round bottom flask. The predried CIL (2.0 mL) was then added to the flask, followed by dimethyl itaconate 5 (0.63 g, 4.00 mmol) and 3 N2/vacuum cycles were performed. The reaction mixture was stirred for 10 minutes or until reaching 55° C. Hydrogen was then introduced to the reaction via a balloon, and the progress of the reaction was monitored by 1H NMR. Upon termination of the reaction, the products were extracted using hexane (10×3 mL). The mass recovery after extraction from the CIL was 100% (0.63 g). Dimethyl 2-methylsuccinate 9 was obtained in 98% yield (0.63 g, 3.94 mmol) as a racemic mixture using either Pd—C (KG 813) or Wilkinson's catalyst (KG 834) and in 68% conversion using the Taniaphos catalyst (KG 813).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1>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>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:2]([F:1])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: Brc1ccc(I)cc1
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1F

Procedure:
This was prepared using a similar method to that described for compound 8. Quantities: 3-fluoro-4-octoxyphenyl boronic acid (7.0 g, 0.026 mol), 4-bromoiodobenzene (5.88 g, 0.021 mol), tetrakis(triphenylphosphine)palladium (0) (0.8 g, 0.7 mol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][C:8]1([CH3:11])[CH2:10][S:9]1.O>C1C=CC=CC=1>[CH3:7][C:8]([SH:9])([CH3:11])[CH2:10][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CC1(C)CS1
Reactant: C1CNCCN1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(S)CN1CCNCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
Piperazine (7.72 g, 89.8 mmol) was dissolved in benzene (10 mL) and 2,2-dimethylthiirane (3.16 g, 35.9 mmol) was added. The reaction mixture was stirred at 80° C. for 1 hour, poured into the water and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. Volatiles were evaporated and the residue was dried on vacuum pump overnight to afford 3.9 g of the title compound. 1H NMR (CDCl3, 300 MHz): δ1.29 (s, 6H), 2.34 (s, 2H), 2.58 (t, 4H), 2.63 (s, 1H), 2.85 (t, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:3]=1
Reactant: Cc1cc(Cl)cc(Cl)n1
Reactant: C1COCCN1
Solvent: ClCCl
Product: Cc1cc(Cl)cc(N2CCOCC2)n1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
2-Methyl-4,6-dichloropyridine (256 mmol) is dissolved in dichloromethane (200 mL) and chilled to −78° C. in an inert atmosphere. Morpholine (550 mol) dissolved in dichloromethane (100 mL) is added slowly. The reaction is allowed to warm to room temperature while stirring overnight. The organic layer is washed with saturated ammonium chloride (2×100 mL), dried with sodium sulfate, and evaporated to give 2-methyl-4-chloro-6-morpholino-pyridine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:8]1[N:13]=[C:12]2[N:14]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[CH:21]4)[N:15]=[N:16][C:11]2=[N:10][CH:9]=1)\[CH3:7].C[Si]([N:32]=[C:33]=[O:34])(C)C>C(Cl)Cl>[N:24]1[C:25]2[C:20](=[CH:19][C:18]([CH2:17][N:14]3[C:12]4=[N:13][C:8](/[C:6](=[N:5]/[O:4][CH2:3][CH2:2][NH:1][C:33]([NH2:32])=[O:34])/[CH3:7])=[CH:9][N:10]=[C:11]4[N:16]=[N:15]3)=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: C/C(=N\OCCN)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: C/C(=N\OCCNC(N)=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reaction time: 24 h
Yield: 69.8 %

Procedure:
To a solution of (E)-1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-2-aminoethyl oxime (example 34) (15 mg, 0.041 mmol) in DCM (5 mL) was added trimethylsilyl isocyanate (19.07 mg, 0.166 mmol). The mixture was stirred for 24 h. After concentration, the crude product was purified by chromatography on silica gel to afford 11.6 mg (69%) of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.32 (s, 1H), 8.89 (dd, 1H), 8.35 (d, 1H), 8.01 (m, 2H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.21 (s, 2H), 6.05 (t, 1H), 5.50 (s, 2H), 4.27 (t, 2H), 3.35 (m, 2H), 2.32 (s, 3H). LCMS (method B): [MH]+=406, tR=1.91 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[CH3:2].S(Cl)([Cl:18])(=O)=O>C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][C:12]=1[Cl:18])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CCc1cccc(O)c1
Solvent: CCOCC
Product: CCOC(=O)CCc1cc(O)ccc1Cl
Reaction time: 2.5 h

Procedure:
To a 0° C. solution of 3-(3-hydroxy-phenyl)-propionic acid ethyl ester (1.0 g, 5.15 mmol) in diethyl ether (50 ml) was added sulfuryl chloride (0.493 mL, 6.18 mmol). After 2.5 h at 0° C., the reaction was quenched with sat. sodium carbonate (50 ml). The aqueous layer was extracted with ethyl acetate. The organic portions were combined and dried with magnesium sulfate. The solvent was removed in vacuo to afford crude product, which was purified by column chromatography (10% ethyl acetate/hexanes). The title compound was obtained as colorless oil (0.73 g, yield 62%): 1H NMR (CDCl3) δ 6.96 (d, J=10.1 Hz, 1H); 6.54 (d, J=2.97 Hz, 1H); 6.46 (dd, J=8.6, 3.0 Hz, 1H); 3.96 (dd, J=12.5 5.3 Hz, 2H); 2.82-2.78 (m, 2H); 1.08-1.00 (m, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:19])[C:12]([C:16]([OH:18])=[O:17])=[CH:13][NH:14][CH:15]=2)=[CH:6][CH:5]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:20]([N:14]1[CH:15]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[C:11](=[O:19])[C:12]([C:16]([OH:18])=[O:17])=[CH:13]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: BrCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(Cc2ccccc2)cc(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Fifty-five percent sodium hydride (131 mg) dispersed in oil was added to a solution of 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (233 mg) in DMF (5 ml) under ice cooling, and the mixture was stirred at room temperature for one hour. Benzyl bromide (356 μl) was then added and the mixture was stirred for two days. A 1 N aqueous sodium hydroxide solution was then added, followed by stirring overnight. A 10% aqueous citric acid solution was added to the reaction solution, and the precipitate was collected by filtration to give the title compound (253 mg) as a solid.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[NH:24]([CH3:49])[C@H:25]([C:29]([N:31]([CH3:48])[C@H:32]([C:45]([NH2:47])=[O:46])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:35]=1)=[O:30])[CH:26]([CH3:28])[CH3:27].O>C1COCC1>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([N:24]([CH3:49])[C@H:25]([C:29]([N:31]([CH3:48])[C@H:32]([C:45]([NH2:47])=[O:46])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([C:41]([CH3:44])([CH3:42])[CH3:43])[CH:35]=1)=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of Z-Phe(4-F)—OH (1.09 g, 3.44 mmol), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (1.04 g, 2.87 mmol) and CMPI (878 mg, 3.44 mmol) in THF (30 ml), TEA (0.96 ml, 6.88 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=1:3) to give Z-Phe(4-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (1.73 g, 91%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=[CH:7][C:6]=1[NH:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=O)[CH3:2].OS(O)(=O)=O.[OH-].[Na+]>CCO>[CH2:12]([O:11][C:10]1[C:5]2[N:4]=[C:1]([CH3:2])[N:19]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]=2[CH:7]=[CH:8][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CNc1cccc(OCc2ccccc2)c1NC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)Cn1c(C)nc2c(OCc3ccccc3)cccc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a suspension of ethyl N-[2-acetamido-3-(benzyloxy)phenyl]glycinate (2.82 g) in EtOH (28.2 mL) was added H2SO4 (1.62 g) at ambient temperature. The mixture was stirred at 70° C. for 1 hour. After cooling, the reaction mixture was added ice and alkalized with 2M NaOH aqueous solution (pH=8) under ice cooling. The formed precipitate was collected by filtration and washed with water to give ethyl [4-(benzyloxy)-2-methyl-1H-benzimidazol-1-yl]acetate (2.65 g) as a white solid.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH2:12]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Yield: 75.5 %

Procedure:
Ethyl isonipecotate (212 g, 1 35 mole), benzyl chloride (170 g, 1.35 mole), and potassium carbonate (322 g, 233 mole) were stirred at room temperature in absolute EtOH (1.8 L) for 72 hours. The crude mixture was filtered through Celite, rinsed with Et2O, and concentrated in vacuo. The resulting mixture was diluted with Et2O, and extracted with H2O (3×), then brine, dried (MgSO4), and concentrated in vacuo. The product was distilled under high vacuum, bp 128°-130° C. at 0.8 mm Hg, to yield 252 g of a colorless liquid (76%). Analysis: Calculated for C15H21NO2 : C,72.84; H,8.56; N,5.66; found: C,72.91; H,8.38; N,5.88
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1.[Na+].[I-]>CN(C)C=O>[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)=[CH:34][CH:33]=1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(F)cc2)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccc(F)cc3)c(=O)c2-c2ccc(F)cc2)cc1

Procedure:
A solution of the nitrogen-unsubstituted pyridazinone product from Example 19 (160 mg, 0.465 mmol), K2CO3 (193 mg, 1.4 mmol), 4-fluorobenzylbromide (0.09 mL, 0.7 mmol) and NaI (catalytic) in 10 mL of anhydrous N,N-dimethylformamide (DMF) was stirred at room temperature for 18 hours. The reaction mixture was quenched with 2N HCl, extracted with ethyl acetate (2×20 mL), washed with brine and water, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (2:2:6 ethyl acetate/dichloromethane/pentanes). Crystallization from ether/pentanes provided white crystals (yield: 110 mg, 52%). mp 153-154° C. 1H NMR (CDCl3, 300 MHz) δ 3.06 (s, 3H), 5.36 (s, 2H), 6.96 (t, J=8.4 Hz, 2H), 7.04 (t, J=8.7 Hz, 2H), 7.16 (dd, J=9.1 Hz, J=5.4 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.54 (dd, J=8.8 Hz, 5.5 Hz, 2H), 7.84 (s, 1H), 7.87 (d, J=8.8 Hz, 2H). MS (DCI/NH3) m/z 453 (M+H)+.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[CH3:5][N:6]([C:8]([N:11]([CH3:13])[CH3:12])(Cl)[Cl:9])[CH3:7]>C(#N)C>[S-:1][C:2]#[N:3].[CH3:5][N:6]([C+:8]([N:11]([CH3:13])[CH3:12])[Cl:9])[CH3:7]
Reactant: CN(C)C(Cl)(Cl)N(C)C
Agent: N#C[S-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)[C+](Cl)N(C)C
Reaction time: 24 h
Yield: 88.2 %

Procedure:
2.84 g (35.0 mmol) of sodium thiocyanate are added at room temperature to a solution of 3.0 g (17.5 mmol) of bis(dimethylamino)dichloromethane in 50 ml of acetonitrile. The reaction mixture is stirred for 24 hours, and the precipitate NaCl is subsequently filtered off. The solvent is subsequently distilled off, and the residue is extracted a number of times with 50 ml of dichloromethane. After distillation of the dichloromethane, the residue is dried at 60° C. and 7 Pa, giving 2.99 g of the liquid bis(dimethylamino)chlorocarbenium thiocyanate, corresponding to a yield of 88.2%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>N1C=CC=CC=1.C(OCC)(=O)C>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:34](=[O:35])[CH2:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([F:37])([F:25])[F:38])=[CH:32][CH:31]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Cc1ccc(C(F)(F)F)cc1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 53.3 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.29 mmol) produced in Example 16(vi) was dissolved in pyridine (2.0 mL), [4-(trifluoromethyl)phenyl]acetic acid (120 mg, 0.58 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (220 mg, 0.58 mmol) were added, and the mixture was stirred at 80° C. for 12 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed successively with 5% aqueous ammonium chloride solution (10 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate/heptane to give the title compound (82 mg, 53%) as a colorless powder.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[CH:32]=O)[CH:25]=[CH:24]1>ClCCCl.ClCCl>[CH2:1]([NH:4][CH2:32][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:31]=1[NH:23][CH:24]=[CH:25]2)[CH:2]=[CH2:3]
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: C=CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: C=CCNCc1cccc2cc[nH]c12
Temperature: 22 °C
Reaction time: 5 h
Yield: 81.9 %

Procedure:
Add allylamine (2.50 mL, 33.1 mmol), acetic acid (3.4 mL), and sodium triacetoxyborohydride (5.85 g, 27.6 mmol) to a solution of indole-7-carboxaldehyde (4.00 g, 27.6 mmol) in 1,2-dichloroethane (120 mL) at 20-24° C. and stir the resulting mixture at 20-24° C. for 5 hours. Add an additional 1.5 g (7.1 mmol) of sodium triacetoxyborohydride and stir the resulting mixture overnight. Dilute the mixture with dichloromethane (300 mL), wash carefully with aqueous sodium bicarbonate (100 mL), and separate the layers. Wash the organic layer sequentially with water (100 mL) and saturated aqueous sodium chloride (100 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 10-30% ethyl acetate in hexanes. Combine fractions containing product and concentrate them under reduced pressure to provide the desired compound as a light yellow oil (4.21 g, 82%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[C:38]1([CH2:44][CH2:45][CH2:46][N:47]2[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1CCN2C(=NCCC2)CC1.C(N(CC)CC)C>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:50]1[CH2:51][CH2:52][CH2:53][N:47]([CH2:46][CH2:45][CH2:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:48][CH2:49]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: c1ccc(CCCN2CCCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC(=O)N1CCCN(CCCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a suspension of 2.8 g (15.98 mmol.) of N-tert-butoxycarbonyl glycine and 3.67 g (23.96 mmol.) of 1-hydroxybenzotriazole monohydrate was added, at room temperature, 4.6 g (24.0 mmol.) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride. The mixture was stirred for one hour. To the reaction system, was added an acetonitrile solution (20 ml) of 5.65 (16.99 mmol.) of 1-(3-phenylpropan-1-yl)-2,3,5,6-tetrahydro-7H-1,4-diazepine dihydrochloride, 5.17 g (33.96 mmol.) of 1,8-diazabicyclo[5.4.0]unde-7-cene (DBU) and 2.3 ml (16.5 mmol.) of triethylamine. The mixture was stirred for 2 hours. The solvent was distilled off under reduced pressure. To the residue was added water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The crude product thus-obtained was purified by means of a column chromatography (methanol/ethyl acetate 10-20%). The solvent was distilled off under reduced pressure to afford the object compound as a pale yellow oily product. The yield was 5.64 g (94%).
Reaction SMILES: [C:1]1([C:7]2[C:8](O[C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.C([O-])(=O)C.[Na+].O.[NH2:23][NH2:24]>C(O)(=O)C>[C:1]1([C:7]2[C:8](=[O:9])[NH:23][NH:24][C:11](=[O:13])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(-c2ccccc2)c(=O)[nH][nH]1
Temperature: 7 °C
Yield: 34.4 %

Procedure:
Phenylmaleic anhydride (30 g, 0.17 mol), sodium acetate trihydrate (28 g, 0.21 mol) and hydrazine monohydrate (10 ml, 0.21 mol) were heated together at reflux in 40% acetic acid (600 ml) for 18 h. The mixture was cooled at 7° C. for 2 h, then filtered. The solid was washed with diethyl ether and dried in vacuo to give 11 g (34%) of the title compound: 1H NMR (250 MHz, DMSO-d6) δ 7.16 (1H, br s), 7.44 (5H, m), 7.80 (2H, br s); MS (ES+) m/e 189 [MH+].