Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][C:38]1[C:39]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][O:55][CH3:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH3:37])[C:39]([N:47]4[CH2:48][CH2:49][N:50]([CH2:53][CH2:54][O:55][CH3:56])[CH2:51][CH2:52]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COCCN1CCN(c2cc(OC)c(N)cc2C)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CO
Solvent: OCC(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(C)c(N4CCN(CCOC)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 100 °C
Yield: 55.6 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (200 mg, 0.4 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methyloxy)ethyl]-1-piperazinyl}aniline (99 mg, 0.36 mmol) and p-toluenesulfonicacid (180 mg, 0.95 mmol) were weighed into a 20 mL vial. 2 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (150 mg, 0.2 mmol, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.74 (s, 1H), 9.36 (s, 1H), 8.46 (s, 1H), 8.23 (d, J=5.13 Hz, 1H), 8.04 (d, J=1.83 Hz, 1H), 7.74 (dd, J=8.43, 2.20 Hz, 1H), 7.69 (d, J=9.17 Hz, 1H), 7.49 (s, 1H), 7.41-7.47 (m, 1H), 7.34-7.41 (m, 1H), 7.26 (d, J=8.43 Hz, 1H), 7.19 (t, J=8.07 Hz, 2H), 6.95 (t, J=6.97 Hz, 1H), 6.77 (s, 1H), 6.55 (d, J=5.13 Hz, 1H), 4.26 (q, J=6.84 Hz, 2H), 3.80 (s, 3H), 3.42-3.48 (m, 2H), 3.24 (s, 3H), 2.86 (t, J=4.40 Hz, 4H), 2.50-2.61 (m, 6H), 2.14 (s, 3H), 1.43 (t, J=6.97 Hz, 3H); MS (ESI): 749 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C@@H:6]([OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[C:3]=1[CH:12]=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=[O:17].N1C=CC=CC=1.[Cl:25][CH2:26][C:27](Cl)=[O:28].O>C(OCC)C>[CH3:1][C:2]1[C:7](=[O:8])[C@@H:6]([O:9][C:27](=[O:28])[CH2:26][Cl:25])[CH2:5][C:4]([CH3:10])([CH3:11])[C:3]=1[CH:12]=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=[O:17]
Reactant: CC(C=CC1=C(C)C(=O)[C@@H](O)CC1(C)C)=CC=O
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: CC(C=CC1=C(C)C(=O)[C@@H](OC(=O)CCl)CC1(C)C)=CC=O
Reaction time: 1 h

Procedure:
13 grams of 5-[2,6,6-trimethyl-oxo-4(S)-hydroxy-cyclohex-1-en-1-yl]-3-methyl-penta-2,4-dien-1-al (XIII) are dissolved in 200 ml of diethyl ether. 20 ml of pyridine are added to the solution at 0° C. and 12 g of chloroacetic acid chloride are then added dropwise. The mixture is stirred for 1 hour and then poured into water and extracted with diethyl ether. The 5-[2,6,6-trimethyl-3-oxo-4(S)-(chloroacetoxy)-cyclohex-1-en-1-yl]-3-methyl-penta-2,4-dien-1-al is isolated from the ether extract (IIA).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][C@@H:25]([C:27]([OH:29])=O)[CH3:26])[N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:70]1([NH:74][C:75]([C@@H:77]2[CH2:81][CH2:80][CH2:79][NH:78]2)=[O:76])[CH2:73][CH2:72][CH2:71]1>CN(C=O)C.ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:36])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][C@H:25]([CH3:26])[C:27]([N:78]3[CH2:79][CH2:80][CH2:81][C@H:77]3[C:75](=[O:76])[NH:74][CH:70]3[CH2:71][CH2:72][CH2:73]3)=[O:29])[N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O[C@H](C)C(=O)O)n(-c3ccccc3)n2)CC1
Reactant: O=C(NC1CCC1)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O[C@H](C)C(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 3 h

Procedure:
To a solution of 1.00 g 4-(2-{[5-((R)-1-Carboxy-ethoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-acetyl)-piperazine-1-carboxylic acid butyl ester in 40 ml DMF were added 521 μl DIPEA and 758 mg HATU. After 20 minutes 336 mg (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide were added and the reaction mixture stirred for 3 h. After evaporation of the solvent the crude product was dissolved in dichloromethane and extracted with aqueous LiCl (4% w/w), 0.1 M HCl and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were immediately lyophilized to yield the pure product which was taken up in dichloromethane and washed once with aqueous NaHCO3. The residue obtained after evaporation of the solvent was lyophilized again to give the title compound. Yield: 517 mg MS (ES+): m/e=652.
Reaction SMILES: N.[Li].C([N:10]1[C:23]2[C:18](=[CH:19][C:20]([CH2:24][CH:25]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:21][CH:22]=2)[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:11]1=[O:33])C1C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[CH:25]1([CH2:24][C:20]2[CH:19]=[C:18]3[C:12]4([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]4)[C:11](=[O:33])[NH:10][C:23]3=[CH:22][CH:21]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C1N(Cc2ccccc2)c2ccc(CC3CCCCCCC3)cc2C12CCNCC2
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(CC3CCCCCCC3)cc2C12CCNCC2
Temperature: -78 °C

Procedure:
To a magnetically stirred solution of liquid ammonia (10 mL) was added lithium (20 mg) at −78° C. under nitrogen atmosphere causing the solution to turn dark-blue. To the reaction mixture was then added a solution of 1-benzyl-5-(cyclooctyl-methyl)-spiro[indoline-3,4′-piperidin]-2-one (0.025 g, 0.06 mmol) in dry THF (2 mL). The reaction mixture was stirred −78° C. under nitrogen atmosphere for a few minutes, then ammonium chloride was added and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was partitioned with water and ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield the title compound as a foam.
Reaction SMILES: [Na+].[C:2]1([CH2:8][C:9]([O:11][CH2:12][C:13]([F:19])([F:18])[S:14]([O-:17])(=[O:16])=[O:15])=[S:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].FC(F)(F)S([O-])(=O)=O.[C:29]1([CH:35]([SH+:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:36]1([CH:35]([SH+:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1.[F:19][C:13]([F:18])([S:14]([OH:17])(=[O:16])=[O:15])[CH2:12][O:11][C:9](=[S:10])[CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])C(F)(F)COC(=S)Cc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Agent: [Na]
Product: O=S(=O)(O)C(F)(F)COC(=S)Cc1ccccc1

Procedure:
<2> The reaction described in <3> of Synthesis Example 1 was performed under the same conditions, except that the phenylthioacetyloxymethyl difluoromethanesulfonic acid sodium salt (2.5 g) produced in <1> of Synthesis Example 6 above was used instead of the benzoyloxymethyldifluorosulfonic acid sodium salt in the reaction with diphenylmethylphenylsulfonium trifluoromethanesulfonic acid sodium salt, and thus 3.41 g (yield 98%) of phenylthioacetic acid 2,2-difluoro-2-sulfoethyl ester diphenylmethylphenylsulfonium salt as shown in the following reaction scheme 13 was obtained. The structure of the product was confirmed by 1H-NMR (see FIG. 12).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([CH:11]=[O:12])[C:3]=12.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[CH:9]=[C:10]([CH:11]=[O:12])[C:3]=12
Reactant: O=Cc1c[nH]c2nccc(Cl)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3c(Cl)ccnc32)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of Example 127A (1 g, 5.54 mmol) in toluene (10 mL) was added p-toluenesulfonyl chloride (1.584 g, 8.31 mmol) and tetrabutylammonium hydrogensulfate (0.188 g, 0.554 mmol). The mixture was cooled to 0° C., and a solution of sodium hydroxide (0.554 g, 13.84 mmol) in water (2 mL) was added. The mixture was stirred at room temperature overnight, and partitioned between ethyl acetate and water. The organic phase was washed with water and concentrated. The residue was triturated with 10% ethyl acetate in heptane and filtered to provide the title compound. MS (ESI+) m/z 335 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:27][C:17]1[C:18]2[C:19](=[O:25])[NH:20][CH2:21][CH2:22][C:23]=2[NH:24][C:16]=1[C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[N:15]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([CH3:26])=[N:8]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1nc2cccc(-c3[nH]c4c(c3Br)C(=O)NCC4)c2nc1NC(C)(C)C
Yield: 61.6 %

Procedure:
A solution of 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (193) (0.30 g, 0.86 mmol) and 1-bromopyrrolidine-2,5-dione (0.23 g, 1.28 mmol) in CHCl3 (8.6 mL) was stirred at RT for 3 h. The reaction mixture was diluted with DCM (150 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (3×150 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was directly injected onto the column and was purified via automated flash chromatography (silica gel) with 1-4% of 2 M NH3 in MeOH/DCM to give 3-bromo-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (349) (228 mg, 0.53 mmol, 62% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.60 (s, 9H) 2.55 (s, 3H) 2.97 (t, J=6.85 Hz, 2H) 3.61 (td, J=6.85, 2.74 Hz, 2H) 4.85 (s, 1H) 5.51 (br. s., 1H) 7.44 (t, J=7.92 Hz, 1H) 7.74 (dd, J=8.02, 1.37 Hz, 1H) 8.71 (dd, J=7.63, 1.37 Hz, 1H) 12.28 (br. s., 1H). MS (ESI, pos. ion) m/z: 428.0/430.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH2:18][OH:19])([CH:8]([CH3:10])[CH3:9])[O:5][C:4](=[O:20])[CH:3]=1.[NH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([S:29]S(C2C=CC(C)=CC=2)(=O)=O)=[C:24]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:23]=1.CCN(CC)CC>C(#N)C>[NH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([S:29][C:3]2[C:4](=[O:20])[O:5][C:6]([CH2:11][CH2:12][C:13]3[CH:17]=[CH:16][S:15][C:14]=3[CH2:18][OH:19])([CH:8]([CH3:9])[CH3:10])[CH2:7][C:2]=2[OH:1])=[C:24]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:23]=1
Reactant: CC(C)C1(CCc2ccsc2CO)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(N)cc2C(C)(C)C)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(SC2=C(O)CC(CCc3ccsc3CO)(C(C)C)OC2=O)c(C(C)(C)C)cc1N

Procedure:
The title compound was prepared as described in General Method 16b using 4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one (Example E-24; 1 mmol), toluene-4-thiosulfonic acid S-(4-amino-2-tert-butyl-5-methyl-phenyl)ester (Example BB-11; 1.05 mmol), NEt3 (2.2 mmol) in acetonitrile (5 mL). The product was triturated from Et2O, mp 107-115° C. MS (APCI): 488 (M−H).
Reaction SMILES: Cl[C:2]1[C:7]([S:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[N:3]=1.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])=[O:34].C(N(CC)CC)C>CN(C=O)C>[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][N:39]([C:2]2[C:7]([S:8][CH3:9])=[C:6]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[N:5]=[C:4]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[O:24])=[CH:20][CH:21]=3)[N:3]=2)[CH2:38][CH2:37]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CSc1c(Cl)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc1N1CCOCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1c(N2CCOCC2)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc1N1CCN(S(C)(=O)=O)CC1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 1-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea (120 mg, 0.26 mmol.), 1-methanesulfonyl-piperazine (65 mg, 0.39 mmol, 1.5 eq.), triethylamine (40 mg, 0.39 mmol, 1.5 eq.), and DMF (4.0 ml) was added to the reaction vessel and flushed with argon. The reaction mixture was stirred at 80° C. for 5 hrs and then dried, and the solvent was evaporated. The reaction mixture was partitioned between EA and NH4Cl(aq), the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified with flash chromatography on silica gel (Hexane/EtOAc 1:1) to give a pale yellow solid of 77.2 mg (50.3%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])/[CH:5]=[CH:6]/[CH:7]=[O:8])[CH3:2].[N+](C1C=CC=CC=1C(O)=O)([O-])=O.N1CCCC1.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[C:29]=1[CH:30]=O>CS(C)=O>[CH2:1]([O:3][C:4]([CH:5]1[C:6]([CH:7]=[O:8])=[CH:30][C:29]2[C:32](=[CH:33][CH:34]=[CH:35][C:28]=2[Cl:27])[O:36]1)=[O:9])[CH3:2]
Reactant: O=Cc1c(O)cccc1Cl
Reactant: CCOC(=O)/C=C/C=O
Agent: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: C1CCNC1
Solvent: CS(C)=O
Product: CCOC(=O)C1Oc2cccc(Cl)c2C=C1C=O
Temperature: 25 °C
Reaction time: 78 h
Yield: 24.4 %

Procedure:
(E)-4-Oxo-but-2-enoic acid ethyl ester (4.60 mL, 38.32 mmol), 2-nitrobenzoic acid (1.08 g, 6.39 mmol), and pyrrolidine (0.53 mL, 6.39 mmol) were added simultaneously to a solution of commercially available 2-chloro-6-hydroxy-benzaldehyde (5.0 g, 31.93 mmol) in dimethysulfoxide (30 mL) at 25° C. and the solution was stirred for 78 hours at 25° C. The reaction was quenched by the addition of water. The reaction mixture was then partitioned between water and ethyl acetate. The combined organics were washed with a saturated brine solution, dried over anhydrous sodium sulfate, filtered, rinsed and concentrated in vacuo. The residue obtained was purified on a silica gel Flash column chromatography using ethyl acetate-hexanes (1:1.2) as eluents, yielding 5-chloro-3-formyl-2H-chromene-2-carboxylic acid ethyl ester as a solid (2.08 g, 49.5%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH3:10].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].N12CCCN=C1CCCCC2.Cl>CN(C)C=O.CC(C)=O>[CH2:9]([C:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[CH3:10]
Reactant: COC(=O)CBr
Reactant: CCC(=O)c1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCc1c(C(=O)OC)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of 1-(2-hydroxyphenyl)propan-1-one (10.0 g), methyl bromoacetate (5.11 mL) and acetone (100 mL) was added potassium carbonate (18.4 g), and the mixture was stirred overnight at room temperature. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give a colorless oil. To a solution (150 mL) of the obtained oil in N,N-dimethylformamide was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8.12 mL), and the mixture was stirred at 120° C. for 2 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9, volume ratio) to give the title object compound (7.14 g, 52%) as a white solid.
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH2:18])=O)[CH:12]=[N:11]2)[CH:5]=1.N1C=CC=CC=1.O1CCOCC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O>[F:19][CH:2]([F:1])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]#[N:18])[CH:12]=[N:11]2)[CH:5]=1
Reactant: Cc1c(C(N)=O)cnn1-c1cc(OC(F)F)n(C)n1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: Cc1c(C#N)cnn1-c1cc(OC(F)F)n(C)n1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
A mixture of 0.79 g (2.91 mmol) 1-(5-difluoromethoxy-1-methyl-3-pyrazolyl)-5-methyl-4-pyrazolecarboxamide, 0.46 g (5.85 mmol) pyridine and 20 ml 1,4-dioxane was cooled to 5° C. and 0.74 g (3.51 mmol) trifluoroacetic anhydride was added dropwise. The mixture was stirred for 3 hours at room temperature. It was then added to 100 ml water and extracted 4 times with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated.
Reaction SMILES: CO.[O-2].[Ba+2].O.[NH2:6][NH2:7].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC>[CH:8](=[N:6][NH2:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NN
Reactant: O=Cc1ccccc1
Agent: [Ba+2]
Agent: [O-2]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: NN=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 7.8 %

Procedure:
A 1 L flask equipped with a mechanical stirrer, thermometer, and addition funnel was charged with 250 mL of methanol and cooled to 0° C. Barium oxide (9.8 g, 64 mmol) was added portion-wise with exotherm. The reaction was cooled to 0° C., and hydrazine monohydrate (64.1 g, 1.28 mol) was slowly added. The reaction mixture was stirred for 10 minutes, after which time benzaldehyde (135.8 g, 1.28 mol) was added drop-wise over a 30 minute period. The reaction was then stirred for 1 hour, while maintaining a temperature below 8° C. 1H NMR indicated the absence of ketone and a complete reaction. Ether (200 mL) was added, and the BaO was filtered through a bed of silica gel. The resultant clear filtrate was liberated of methanol on a rotary evaporator at or below room temperature. A large mass of bright yellow solid azine (1H-NMR (300 MHz, CDCl3)δ(ppm): 8.67 (s, 2H), 7.85 (m, 4H), 7.47 (m, 6H)), was removed by filtration, and the filtrate was distilled to provide ca. 12 g of distillate benzylidene-hydrazine. The material was stored under refrigeration. 1H-NMR (300 MHz, CDCl3)δ(ppm): 7.74 (s, 1H), 7.53 (m, 2H), 7.35 (m, 3H), 5.5 (br, 2H).
Reaction SMILES: [CH2:1]([C@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:33][CH2:32][CH2:31]1>C(Cl)(=O)C.CCN(CC)CC>[C:32]([N:10]1[CH2:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=2)[C@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)(=[O:33])[CH3:31]
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2Cc2ccccc2)cc(C(F)(F)F)c1
Reactant: C1CCOC1
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of the compound (0.40 g) obtained in Example 404 in THF (4 ml), acetyl chloride (0.075 ml) and Et3N (0.147 ml) were added at room temperature, and the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N hydrogen chloride and brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography to obtain the title compound as pale yellow oil (0.275 g, 79%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:19])[C:14]=2[NH2:18])[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]([CH2:32][C:33](O)=[O:34])[CH:25]=[CH:26][C:27]=1[C:28]([F:31])([F:30])[F:29].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:19])[C:14]=2[NH:18][C:33](=[O:34])[CH2:32][C:24]2[CH:25]=[CH:26][C:27]([C:28]([F:29])([F:30])[F:31])=[C:22]([F:21])[CH:23]=2)[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(C)ccc2c1=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[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: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A round bottom flask was charged with (R)-2-(5-amino-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (175 mg, 0.000638 mol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (210 mg, 0.00096 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (610 mg, 0.0016 mol), N,N-diisopropylethylamine (0.28 mL, 0.0016 mol) and N,N-dimethylformamide (8 mL, 0.1 mol) and the reaction stirred at 45° C. for 24 hours. The reaction did not go to completion. The reaction was then quenched with water and extracted with ethyl acetate, washed with NaHCO3, brine and dried. The solvent was removed under reduced pressure and the residue purified by flash chromatography to obtain the product as a light yellow oil. MS m/z=479.3 (M+H)
Reaction SMILES: NOS(O)(=O)=O.C(OC(=O)[NH:13][CH2:14][CH2:15][C:16](=[S:23])[N:17]=[C:18]([N:20](C)C)[CH3:19])(C)(C)C.N1C=CC=CC=1.Cl>CO.C(O)C>[CH3:19][C:18]1[N:17]=[C:16]([CH2:15][CH2:14][NH2:13])[S:23][N:20]=1
Reactant: CC(=NC(=S)CCNC(=O)OC(C)(C)C)N(C)C
Agent: Cl
Agent: NOS(=O)(=O)O
Solvent: CCO
Solvent: c1ccncc1
Solvent: CO
Product: Cc1nsc(CCN)n1
Temperature: 25 °C

Procedure:
Hydroxylamine-O-sulfonic acid (0.68 g, 6.0 mmol) in methanol (5 ml) is added to a stirred solution of [2-(1-Dimethylamino-ethylidenethiocarbamoyl)-ethyl]-carbamic acid tert-butyl ester (1.43 g, 5.0 mmol) and pyridine (0.83 ml, 10 mmol) in ethanol (25 ml). After stirring the reaction for 18 hours at room temperature the solvent is removed in vacuo and the residue is partitioned between water and DCM. The organic extract is separated, dried (MgSO4), and the solvent is removed to give a colourless oil which is dissolved in ethanol (20 ml). Aqueous HCl (2M, 10 ml) is added and the mixture is heated at reflux for 1 hour. After cooling to room temperature the solvent is removed. The product is dissolved in aqueous NaHCO3 and the free base is extracted with ethyl acetate. The organic extract is dried (MgSO4) and the solvent removed to give the titled compound.