Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([N:18]2[CH2:22][CH2:21][C@H:20]([OH:23])[C:19]2=[O:24])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26].C(N(CC)CC)C.O>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([N:18]2[CH2:22][CH2:21][C@H:20]([O:23][S:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=3)(=[O:35])=[O:36])[C:19]2=[O:24])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1ccc(N2CC[C@H](O)C2=O)nc1Cc1ccccc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCOc1ccc(N2CC[C@H](OS(=O)(=O)c3cccc([N+](=O)[O-])c3)C2=O)nc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
2.2 g of 2-benzyl-3-methoxymethyloxy-6-[(3S)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine (Example 138a) was dissolved in 20 ml of ethyl acetate, and 2.3 g of 3-nitrobenzenesulfonyl chloride, 183 mg of 4-dimethylaminopyridine and 3 ml of triethylamine were added thereto, followed by stirring at room temperature overnight. Then, water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 25-33% ethyl acetate/hexane as an eluent, to give 3.5 g of the target compound.
Reaction SMILES: C([O-:4])(C)C.[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C:18]#[N:19].[CH:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26])=O>>[C:18](/[C:17](/[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([O:7][CH3:6])[CH:9]=2)[NH:13][CH:12]=1)=[CH:20]\[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]([NH2:26])=[O:4])#[N:19]
Reactant: CC(C)[O-]
Reactant: COc1ccc2[nH]cc(CC#N)c2c1
Reactant: N#Cc1cccc(C=O)c1
Agent: [Na+]
Product: COc1ccc2[nH]cc(/C(C#N)=C/c3cccc(C(N)=O)c3)c2c1
Temperature: 25 °C

Procedure:
To a solution of sodium isopropanolate [prepared from sodium (30 mg, 1.3 mmol, 1.2 eq.) and isopropanol (8 mL)] were added, under an argon atmosphere, (5-methoxy-1H-indol-3-yl)-acetonitrile (200 mg, 1.1 mmol, 1.0 eq.) and, after 10 minutes stirring, 3-formyl-benzonitrile (200 mg, 1.5 mmol, 1.4 eq.). The reaction apparatus was protected from light and the mixture stirred heated at reflux for 4 hours. The reaction was allowed to cool to room temperature and then, the solvent was removed under reduced pressure, and the crude purified by silica gel flash-column chromatography (eluent: CH2Cl2/MeOH, 100:0 à 97:3). The residue was triturated with ethanol and diethyl ether to the compound (32) as a yellow powder (80 mg, 24%). TLC: Rf=0.34 (CH2Cl2 96/MeOH 4); mp: 234° C.; IR νmax (cm−1): 1651 (νC═O), 2215 (νCN), 3172 (νN—H amide), 3326 (νN—H indole); 1H NMR (DMSO, 300 MHz) δ (ppm): 3.89 (3H, s, 5′-methoxy), 6.97 (1H, m, H6′), 7.48 (2H, s, H7′ and amide H), 7.53 (1H, s, H4′), 7.65 (1H, m, H5″), 7.83 (2H, s, H3 and H2′), 7.95 (1H, m, H4″), 8.12 (2H, m, H6″ and amide H), 8.39 (1H, m, H2″), 11.68 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 55.6 (5′-methoxy), 101.8 (C4′), 107.0 and 110.3 (C2 and C3′), 112.3 (C6′), 113.2 (C7′), 118.3 (C1), 124.1 (C3a′), 127.3 (C2′), 127.9 (C4″), 128.3 (C2″), 128.7 (C5″), 130.5 (C6″), 132.3 (C7a′), 134.9 (C1″ and C3″), 135.5 (C3), 154.5 (C5′), 167.7 (amide C); ESI-MS: m/z 340.1 ([M+Na]+), 316.1 ([M−H]−); HRESI-MS: m/z 340.1067 (calcd for C19H15N3O2Na), m/z 316.1117 (calcd for C19H14N3O2, 316.1086).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[F:12][C:13]([F:31])([F:30])[C:14]1[CH:29]=[CH:28][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOCC>C(#N)C.O>[F:12][C:13]([F:30])([F:31])[C:14]1[CH:29]=[CH:28][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][O:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[C:7](=[O:11])[CH2:6][CH2:5]4)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccc(COc2ccc(CCl)cc2)cc1
Reactant: O=C1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: O=C1CCc2cc(OCc3ccc(OCc4ccc(C(F)(F)F)cc4)cc3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 305.5 %

Procedure:
5-Hydroxyindanone (1.0 g, 1.1 mmol) was dissolved in acetonitrile (40 mL) with 5E (1.8 g, 1.0 mmol) and Cs2CO3 (4.4 g, 2.2 mmol). The reaction mixture was stirred at RT for 3 h. Ether (25 mL) and water were added and the stirring was continued for another 5 min. The layers were separated and the aqueous layer was extracted with ether (2×20 mL). The combined organics was dried over MgSO4 and concentrated to a tan solid. The crude product was purified by column chromatography eluted with EtOAc and hexanes to give the desired product, compound 52A as a tan solid (1.26 g, 50%). MS m/z 413 (M+1). Step 2. Preparation of {5-[4-(4-Trifluoromethyl-benzyloxy)-benzyloxy]-indan-1-yl}-acetic acid ethyl ester (Compound 52B).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:9]=2[O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([S:18]([N:21](CC3C=CC(OC)=CC=3OC)[C:22]3[S:26][N:25]=[CH:24][N:23]=3)(=[O:20])=[O:19])=[C:13]([F:38])[CH:12]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:50][CH:51]=O>C(O)C.O.ClCCl>[Cl:43][C:41]1[CH:40]=[CH:39][C:9]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([S:18]([NH:21][C:22]3[S:26][N:25]=[CH:24][N:23]=3)(=[O:19])=[O:20])=[C:13]([F:38])[CH:12]=2)=[C:8]([C:6]2[N:7]3[CH:50]=[CH:51][N:1]=[C:2]3[CH:3]=[CH:4][CH:5]=2)[CH:42]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3cccc(N)n3)cc2F)c(OC)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(Oc2ccc(Cl)cc2-c2cccc3nccn23)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
To a stirred solution of 4-(2-(6-aminopyridin-2-yl)-4-chlorophenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (2.43 g, 3.75 mmol) in ethanol (75 mL) and water (9 mL) was added sodium bicarbonate (0.41 g, 4.9 mmol) and chloroacetaldehyde (50% w/w in water, 0.63 mL, 4.9 mmol) at ambient temperature. The mixture was heated at reflux for 16 h, allowed to cool to ambient temperature and diluted with dichloromethane (200 mL) and water (20 mL). The organic layer washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred for 5 h at ambient temperature and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-10% gradient of methanol in ethyl acetate to afford 4-(4-chloro-2-(imidazo[1,2-a]pyridin-5-yl)phenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a pale yellow solid in 43% yield (0.84 g): 1H NMR (300 MHz, DMSO-d6) δ8.14 (s, 1H), 7.93 (d, J=1.5 Hz, 2H), 7.87-7.78 (m, 2H), 7.76-7.66 (m, 2H), 7.62-7.52 (m, 1H), 7.42-7.30 (m, 3H); MS (ES+) m/z 519.8 (M+1), 521.8 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([NH2:14])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(=O)C.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C@H:4]([NH:14][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=1)[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](N)COCc1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](COCc1ccccc1)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A solution of (2R)-3-benzyloxy-2-aminopropanoic acid methyl ester (19 g, 78 mmol) in methanol (350 mL) under N2 was cooled to 0° C. and acetic acid (2 g, pH 2) was added, followed by the addition of 4-fluorobenzaldehyde, a compound of formula (N) (12.5 mL, 117 mmol) and sodium cyanoborohydride (7.3 g, 117 mmol) and 3 Å molecular sieves (15 g). The resulting mixture was stirred at ambient temperature for 3 hours, then filtered through Celite (MeOH). The filtrate was concentrated in vacuo to afford a clear liquid. This was taken up in ethyl acetate and washed sequentially with 10% aqueous Na2CO3 solution, water, then brine. The organic phase was then dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel afforded 14.7 g (60% yield) of (2R)-3-benzyloxy-2-(N-(4-fluorobenzyl)amino)propanoic acid methyl ester, a compound of formula (O), as a clear, colorless oil; NMR (CDCl3) 7.4-7.2 (m, 7), 7.0 (dd, 2), 4.5 (d, 2), 3.9-3.5 (m, 8) ppm, MS (LSIMS) 317.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]([C:43]2[CH:44]=[C:45]([CH2:60]OS(C)(=O)=O)[C:46](=[O:59])[N:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[N:48]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42].N1(C(OC(C)(C)C)=O)CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:60][C:45]2[C:46](=[O:59])[N:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:53]=[CH:54][C:55]([F:58])=[CH:56][CH:57]=3)[N:48]=[C:43]([C:37]3[CH:38]=[CH:39][C:40]([O:41][CH3:42])=[C:35]([F:34])[CH:36]=3)[CH:44]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Yield: 72.6 %

Procedure:
Following the procedure of Example 1 (10), 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 72.6%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH:36]C(=O)OCC2C=CC=CC=2)[C@H:18]([OH:35])[CH2:19][NH:20][CH2:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34])[CH:12]=[C:13]([F:15])[CH:14]=1.O.[OH-].[Ba+2].[OH-]>COCCOC.O>[NH2:36][C@@H:17]([CH2:16][C:11]1[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([F:8])[CH:10]=1)[C@H:18]([OH:35])[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34]
Reactant: C=CCCCc1ccc(OC)cc1CNC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: COCCOC
Product: C=CCCCc1ccc(OC)cc1CNC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
Step AH (6): To a solution of benzyl (2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-(5-methoxy-2-(pent-4-enyl)benzylamino)butan-2-ylcarbamate trifluoroacetate salt (91.3 mg, 0.140 mmol) in DME (9.0 mL) and water (6.0 mL) was added barium hydroxide monohydrate (831.2 mg, 4.389 mmol). The reaction mixture was stirred at 110° C. in a high-pressure vial for 18 h. The reaction was filtered through a pad of celite and the filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography to give (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-(5-methoxy-2-(pent-4-enyl)benzylamino)butan-2-ol double trifluoroacetate salt (45.8 mg, 52%) as colorless oil. LC-MS (M+H)+=405.42. 1H NMR (CD3OD, 500 MHz) δ 7.30-6.75 (m, 6H) 5.86 (m, 1H) 5.02 (m, 2H) 4.33 (m, 1H) 3.81 (s, 3H) 3.72 (m, 2H) 3.37 (m, 1H) 3.12-2.92 (m, 2H) 2.75-2.60 (m, 2H) 2.14 (m, 2H) 1.65 (m, 2H) 1.53 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[C:9]([NH2:13])(=[O:12])[CH:10]=[CH2:11].S(=O)(=O)(O)O>>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][CH2:11][CH2:10][C:9]([NH2:13])=[O:12]
Reactant: CN(C)CCO
Reactant: C=CC(N)=O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCOCCC(N)=O
Yield: 60 %

Procedure:
A 100 ml 3 neck round bottom flask was fitted with the following: magnetic stirrer, reflux condenser, air bubbler, and a temperature controlled oil bath. The flask was charged with 22.25 g of 2-dimethylamino ethanol. Sodium hydride, 0.05 g, was then added carefully to 2-dimethylamino ethanol solution with stirring. After stirring at a constant rate for two minutes, 17.75 g of acrylamide was added. The reaction mixture was stirred at 45° C. for 6 hours. The mixture was cooled to ambient temperature and neutralized with 0.11 g of concentrated sulfuric acid. The resulting mixture was filtered through a Celite layer. The filtrate was collected for foam application. Quantitative 1H NMR shows that the product had ˜90% purity. The product could be further purified by reduced pressure distillation. Fraction collected at 135° C./1 mm Hg gives a colorless needle shape crystal (60% yield, >96% in purity).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[F:20].C(=O)([O-])[O-].[K+].[K+].[CH3:27][C:28](=O)CC>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:27][CH3:28])=[CH:15][C:14]=1[F:20]
Reactant: CCC(C)=O
Reactant: Oc1ccc(Br)c(F)c1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCCCCCOc1ccc(Br)c(F)c1

Procedure:
1-Bromodecane (12.01 g, 48.2 mmol) in butanone (20 ml) was added dropwise to a stirred, refluxing mixture of 4-bromo-3-fluorophenol (1) (9.04 g, 47.4 mmol), potassium carbonate (10.12 g, 73.2 mmol) and butanone (100 ml). The resulting reaction mixture was refluxed for a further 20 hours. The cooled reaction mixture was then filtered to remove the excess potassium carbonate and precipitated potassium bromide. The filtrate was washed with 5% (v/v) sodium hydroxide (2×50 ml) then water (50 ml) and the organic layer then dried (MgSO4), filtered and evaporated under reduced pressure to give a colourless oil which was purified by column chromatography [silica gel: 1:1 dichloromethane-petrol (bp 40°-60° C.)] to give a colourless liquid. This was then dried in vacuo (P2O5, 0.20 mm Hg, RT, 5 h).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[C:23]([CH:26]=O)[CH:22]=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH3:36]N.C1COCC1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:61](#[N:63])C>>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[C:23]([CH2:26][N:63]([CH3:61])[CH3:36])[CH:22]=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: COc1cc(-c2cc3c(C=O)cccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Reactant: CN
Reactant: CC#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(-c2cc3c(CN(C)C)cccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 30 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-4-formylindol-2-yl]isoindolinone (0.262 g, 1.17 mmol) was dissolved in acetonitrile (15.0 mL), and the solution was treated with 2.0 mol/L methylamine-THF solution (5.20 mL, 10.5 mmol), acetic acid (0.600 mL, 10.5 mmol) and sodium triacetoxyborohydride (0.555 g, 2.62 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=3/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-4-(dimethylaminomethyl)indol-2-yl]isoindolinone (0.0839 g, 30%).
Reaction SMILES: N12CCCCC1C=NCCC2.O([C:19]([NH:21][C:22]1[N:27]=[C:26]([O:28][CH:29]([F:31])[F:30])[CH:25]=[C:24]([CH3:32])[N:23]=1)=[O:20])C1C=CC=CC=1.[CH2:33]([O:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45]([NH2:48])(=[O:47])=[O:46])[CH3:34].Cl>C(#N)C.O.C(OCC)(=O)C>[CH2:33]([O:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45]([NH:48][C:19]([NH:21][C:22]1[N:27]=[C:26]([O:28][CH:29]([F:30])[F:31])[CH:25]=[C:24]([CH3:32])[N:23]=1)=[O:20])(=[O:46])=[O:47])[CH3:34]
Reactant: CCOCCOc1ccccc1S(N)(=O)=O
Reactant: Cc1cc(OC(F)F)nc(NC(=O)Oc2ccccc2)n1
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOCCOc1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC(F)F)n1
Reaction time: 1 h

Procedure:
1.8 g (0.012 mol) of 1,5-diazabicyclo(5.4.0)undec-5-ene are added to a solution of 3.5 g (0.012 mol) of 2-phenoxycarbonylamino-4-difluoromethoxy-6-methyl-pyrimidine, in the form of the crude product, and 2.9 g (0.012 mol) of 2-(2-ethoxy-ethoxy)-benzenesulfonamide in 100 ml of absolute acetonitrile and the mixture is stirred at 20°-25° C. for 1 hour and then diluted with 500 ml of water and acidified with hydrochloric acid. The oil which separates out is taken up in 200 ml of ethyl acetate and the mixture is dried over sodium sulfate and evaporated. The oily residue is crystallised from diethyl ether and acetone to give N-[2-(2-ethoxyethoxy)-phenyl-sulfonyl]-N'-(4-difluoromethoxy-6-methylpyrimidin-2-yl)-urea of melting point 90°-95° C. (decomposition) as colourless crystals in a yield of 2.7 g.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([OH:11])[CH:2]=1.[OH-:12].[Na+].ClCCl.[CH3:17]O>C(Cl)(Cl)Cl.O>[OH:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([C:4]=1[CH:17]=[O:12])=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: [OH-]
Reactant: Oc1cnc2ccccc2c1
Reactant: CO
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1c(O)cnc2ccccc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
Quinolin-3-ol (500 mg, 3.44 mmol, 1.0 eq) is added at room temperature to a stirred solution of sodium hydroxide (1.6 g, 40.0 mmol, 11.6 eq) in chloroform (1 mL) and water (10 mL). After 2 hours stirring at 100° C., the reaction mixture is extracted with dichloromethane (3×20 mL) and water (20 mL) and the pH is adjusted to 4 by the addition of a 1N hydrochloric acid aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 200:1, v/v) to afford 3-hydroxy-quinoline-4-carbaldehyde as a yellow solid (60 mg, 10% yield).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:11]#[C:12][CH:13]=[C:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:6](F)[C:7]=1OC.[N+]([C:32]1C(N2CCC(=CC#C)CC2)=NC=CC=1)([O-])=O.IC1C=[C:50]([C:54](=[O:56])C)C=CC=1.BrC1C=C(F)C(OC)=C(F)C=1>>[CH3:32][C:22]1[N:21]=[C:20]([N:17]2[CH2:16][CH2:15][C:14](=[CH:13][C:12]#[C:11][C:4]3[CH:5]=[C:6]([C:54](=[O:56])[CH3:50])[CH:7]=[CH:2][CH:3]=3)[CH2:19][CH2:18]2)[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: CC(=O)c1cccc(I)c1
Reactant: COc1c(F)cc(C#CC=C2CCN(c3ncccc3[N+](=O)[O-])CC2)cc1F
Agent: COc1c(F)cc(Br)cc1F
Product: CC(=O)c1cccc(C#CC=C2CCN(c3nc(C)ccc3[N+](=O)[O-])CC2)c1
Yield: 84.3 %

Procedure:
The title compound was prepared in the same way as the Compound of Example 199 but substituting Compound 274c for Compound 1c and 1-(3-iodophenyl)ethanone for 4-bromo-2,6-difluoranisole. After the work-up, the residue was purified by automated flash liquid chromatography (SP1™-Biotage) eluting with PE-EtOAc gradient from 9:1 to 8:2 affording the title product. Yellow oil. Yield: 84.3%.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH:9]([CH3:12])[C:10]#[CH:11])(=O)=O.[F:13][C:14]([F:24])([F:23])[CH2:15][CH2:16][S:17]([CH2:20][C:21]#[N:22])(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH3:12][CH:9]([C:10]#[CH:11])[CH2:8][CH2:7][CH2:6][CH:20]([S:17]([CH2:16][CH2:15][C:14]([F:24])([F:13])[F:23])(=[O:19])=[O:18])[C:21]#[N:22]
Reactant: C#CC(C)CCCOS(C)(=O)=O
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CC(C)CCCC(C#N)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 48 h
Yield: 29 %

Procedure:
To a solution of 1.0 g of 4-methyl-5-hexynyl methanesulfonate and 1.1 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 30 ml of dimethyl sulfoxide was added 0.7 g of potassium carbonate at room temperature. The reaction mixture was stirred at 60° C. for 2 days. The reaction mixture was allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.45 g of 6-methyl-2-(3,3,3-trifluoropropylsulfonyl)-7-octynenitrile (hereinafter referred to as the present compound (28)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[N:26]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH:20]3[CH2:24][CH2:23][N:22]([CH2:30][C:27]4[CH:28]=[CH:29][O:25][N:26]=4)[CH2:21]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCNC2)n1
Reactant: O=Cc1ccon1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ccon3)C2)n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[4(4-fluorophenyl)-1-pyrrolidin-3-yl-1H-imidazol-5-yl]pyrimidin-2-amine (C18) (300 mg, 0.925 mmol) and isoxazole-3-carbaldehyde (90 mg, 0.93 mmol) in toluene (5 mL) was added triethylamine (0.5 mL, 3.6 mmol), and the mixture was heated at 80° C. for 16 hours. After cooling to room temperature, the reaction was treated with sodium triacetoxyborohydride (500 mg, 2.36 mmol) and stirred for an additional 3 hours at 80° C. Solvents were removed in vacuo, and the residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by preparative thin layer chromatography on silica gel (Eluant: ethyl acetate) provided the product as a solid. Yield: 60 mg, 0.15 mmol, 16%. LCMS m/z 406.6 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.10 (m, 1H), 2.50-2.59 (m, 2H), 2.84 (dd, J=10.5, 6.7 Hz, 1H), 3.09 (dd, J=10.4, 2.4 Hz, 1H), 3.16 (m, 1H), 3.85 (AB quartet, JAB=14.0 Hz, ΔνAB=23.1 Hz, 2H), 5.29 (m, 1H), 6.40 (d, J=4.9 Hz, 1H), 6.55 (br s, 1H), 7.07 (dd, J=8.7, 8.7 Hz, 2H), 7.41 (dd, J=8.5, 5.5 Hz, 2H), 8.12 (d, J=5.2 Hz, 1H), 8.21 (s, 1H), 8.63 (br s, 1H).