Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH3:15].[Li]CCCC.CCCCCC.Cl[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:15])=[CH:7][CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[C:10]=1[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: COCOc1ccc(C)c(OCOC)c1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1c(OCOC)ccc(C)c1OCOC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a solution of 2,4-bis(methoxymethoxy)-1-methyl-benzene (Intermediate 7, 5.5 g, 25.94 mmol) in dry tetrahydrofuran (50 ml) at room temperature BuLi 1.6M in hexane (19.45 ml, 31.13 mmol) was added and the reaction mixture was stirred for 30 minutes at the same temperature. The mixture was cooled to −78° C. and it was added (via cannulation) to a solution of ethyl chlorooxoacetate (4.35 ml, 38.9 mmol) in dry tetrahydrofuran (30 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction was quenched with water (20 ml), diluted with brine (50 ml) and extracted with ethyl acetate (2×100 ml). Combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluent affording the title compound (4.65 g) as a light yellow oil.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[NH:17][C:16]=2[CH3:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[C:30]([N:17]1[C:18]2[C:23](=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:15]([CH2:14][CH2:13][N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[C:16]1[CH3:26])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCC3CC3CCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCC1CC1CCCCC1)c(C)n2C(=O)c1ccccc1

Procedure:
Reaction of 3-[2-(2-cyclohexylmethylpyrrolidino)ethyl]-5-methoxy-2-methylindole with a mineral oil dispersion of sodium hydride in DMF and reaction of the resulting sodium salt with benzoyl chloride affords 1-benzoyl-3-[2-(2-cyclohexylmethylpyrrolidino)ethyl]-5-methoxy-2-methylindole.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[C:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[CH:11]=[CH:10][C:9]3[O:8][CH2:7][C:6]4[CH:12]=[C:13]([C:15]([N:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH3:18])=[O:16])[S:14][C:5]=4[C:4]=3[CH:3]=2)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCNCC1
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Product: CC(=O)N1CCN(c2ccc3c(c2)-c2sc(C(=O)N(C)c4ccc(F)cc4F)cc2CO3)CC1

Procedure:
Following Example 70 and General Procedure D, 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp and 1-acetylpiperazine were reacted to give 120bp. 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 1H), 6.82-6.93 (m, 5H), 5.99 (s, 1H), 5.01 (s, 2H), 3.86 (m, 2H), 3.73 (m, 2H), 3.32 (s, 3H), 3.21 (m, 2H), 3.16 (m, 2H), 2.13 (s, 3H). LCMS (ESI) m/z: 484.1
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:2][C:3](=[O:4])[N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(CCl)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
To the solution of morpholine (10 mmol, 0.872 mL) and Et3N (15 mmol, 2.09 mL) in THF (20 mL) at 0° C. was dropped in chloroacetyl chloride 1 (12 mmol, 0.956 mL). The mixture was stirred at 0° C. for 4 h and then r.t. overnight. The reaction was quenched with H2O and evaporated to dryness. Purification by column chromatography (CH2Cl2/CH3OH=50/1) gave 2-chloro-1-morpholin-4-yl-ethanone 2 (1.62 g, 100%). 2 (1.6 g, 0.98 mmol) was treated with piperazine-1-carboxylic acid t-butyl ester (10 mmol, 1.86 g) in DMF (20 mL) at 70° C. for 12 h in the presence of K2CO3 (3 mmol, 4.14 g). Solvents were evaporated and the crude product was purified by flash chromatography (CH2Cl2/CH3OH=30/1) to give 4-(2-morpholin-4-yl oxo-ethyl)-piperazine-1-carboxylic acid t-butyl ester 4, which was treated with TFA (5 mL) in CH2Cl2 (5 mL) at r.t. for 2 h. Evaporation of all solvents furnished the TFA salt of 1-morpholin-4-yl-2-piperazin-1-yl-ethanone 4 (4.1 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=O)[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[CH2:27]([O:29][NH2:30])[CH3:28].O>C(O)C>[Cl:1][C:2]1[C:3]([C:12](=[N:30][O:29][CH2:27][CH3:28])[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CCON
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.4 %

Procedure:
To 214 mg of the N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-oxoethyl]phthalimide prepared in Step 2 in Synthetic Example 6 in 3 ml of ethanol, 84 mg of ethoxyamine hydrochloride was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 5 ml of water and extracted with ethyl acetate (5 ml×3), and the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure liquid chromatography (preparative medium pressure chromatograph: YFLC-Wprep manufactured by Yamazen Science, Inc.) using ethyl acetate-hexane (with a gradient of from 2:18 to 5:15) as the eluent to obtain 111 mg of the desired product as a brown resinous substance.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22](I)=[C:21]([CH3:26])[CH:20]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[CH2:32]([O:34]C=C[Sn](CCCC)(CCCC)CCCC)[CH3:33].Cl>C1(C)C=CC=CC=1>[CH3:26][C:21]1[CH:20]=[C:19]([O:18][C:15]2[CH:16]=[CH:17][C:12]([C:3]([O:8][CH2:9][O:10][CH3:11])([C:4]([F:7])([F:6])[F:5])[C:2]([F:31])([F:30])[F:1])=[CH:13][C:14]=2[CH2:27][CH2:28][CH3:29])[CH:24]=[CH:23][C:22]=1[C:32](=[O:34])[CH3:33]
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(I)c(C)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(C(C)=O)c(C)c1
Yield: 87 %

Procedure:
To a solution of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-1-(4-iodo-3-methylphenoxy)-2-propylbenzene (393 mg, 0.699 mmol) in toluene (7.0 mL), ethoxyvinyltributyl tin (473 μL, 1.40 mmol) and tetrakis triphenylphosphine palladium (162 mg, 0.140 mmol) were added sequentially, and the resultant mixture was heated to reflux for 1 hour. Then, ethoxyvinyltributyl tin (946 μL, 2.80 mmol) was added and heated to reflux for 1.5 hours. After completion of the reaction, 5% aqueous solution of hydrochloric acid was added under ice-cold conditions, and the resultant mixture was stirred overnight. The reaction solution was filtered using celite and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane/ethyl acetate), and 1-{2-methyl-4-[2-propyl-4-(2,2,2-trifluoro-1-methoxymethoxy-1-trifluoromethyl-ethyl)-phenoxy]-phenyl}-ethanone (291 mg, yield 80%) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11](Cl)=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CN(C=O)C>O>[CH2:1]([C:8]1[S:12][C:11]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: COc1ccc(-c2nc(Cl)sc2Cc2ccccc2)cc1
Agent: [Li]O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(N3CCOCC3)sc2Cc2ccccc2)cc1
Temperature: 100 °C
Yield: 62.8 %

Procedure:
To 25 ml eggplant-shaped bottle were added 1.00 g (3.17 mmol) 5-benzyl-2-chloro-4-(4-methoxy-phenyl)-thiazole prepared in the step 1, 0.27 g (6.34 mmol) LiOH.H2O, 20 mg KI, 0.55 g (6.34 mmol) morpholine, 5 ml DMF and 0.5 ml water. The mixture was stirred until homogeneous, heated to 100° C., stirred for 20 hours, added 20 ml water, and extracted with ethyl acetate 3×10 ml. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a thick crude product, which was purified under a reduced pressure by silica gel column chromatography eluted with petroleum ether and ethyl acetate at a ratio 4:1-3:1 (V:V) to give a 0.73 g product as a white solid in a yield of 62.9%, mp: 88-89 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.47 (4H, m, 2×CH2), 3.80 (4H, t, J=5.2 Hz, 2×CH2), 3.82 (3H, s, OCH3), 4.12 (2H, s, CH2), 6.92 (2H, d, J=8.40 Hz, ArH), 7.18˜7.32 (5H, m, ArH), 7.53 (2H, d, J=8.40 Hz, ArH); EI-MS m/e (%): 366.1 (M+, 100), 309.1 (23); HREI-MS Calcd. for C21H22N2O2S: 366.1402. found: 366.1404. Anal. Calcd. for C21H22N2O2S: C, 68.83; H, 6.05; N, 7.64. found: C, 68.73; H, 6.26; N, 7.83.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13]1([CH3:20])[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1>>[CH3:20][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: Cc1cccc(C)c1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Product: Cc1cccc(CON2C(C)(C)CC(O)CC2(C)C)c1
Temperature: 135.5 °C
Yield: 25.2 %

Procedure:
A mixture of 8.60 g (0.05 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 106.17 g (1.0 mol) of m-xylene under a nitrogen atmosphere is heated at 135-136° C. for 69 hours. The reaction mixture is filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate is washed with 10 w/v % ascorbic acid (3×33 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous sodium sulfate and the volatiles are removed in vacuo. The residue is recrystallized from heptane to give 3.50 g (51% yield) of a white solid melting at 66-67° C.
Reaction SMILES: [O:1]1[CH:5]([CH2:6][NH2:7])[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][C:14]=3[C:2]1=2.C(N(C(C)C)CC)(C)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O1CCCC1>[O:1]1[CH:5]([CH2:6][NH:7][C:25](=[O:26])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][C:14]=3[C:2]1=2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2ccc3c(c2O1)CCC3
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2ccc3c(c2O1)CCC3)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of (±)-1-(3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine (0.568 g, 3.00 mmol) in tetrahydrofuran (30 mL) cooled to 0° C. was added diisopropylethylamine (0.427 g, 3.30 mmol) followed by benzyl chloroformate (0.538 g, 3.15 mmol) and the reaction mixture was allowed to stir at 0° C. for 1 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (100 mL) and extracted with diethyl ether (2×150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) afforded 0.663 g (68%) of (±)-benzyl 3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-ylmethylcarbamate as a white solid. Rf=0.30 (silica, ethyl acetate:hexanes 1:9); mp 99-101° C.; Anal. calcd. for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C, 73.82; H, 6.53; N, 4.25. Chiral HPLC separation of (±)-benzyl 3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-ylmethylcarbamate (Chiralcel OJ, isopropanol:hexane 7:3) provided two fractions. Fraction 1 (Rt=13.237 min, Chiralcel OJ, isopropanol:hexanes 3:7); Fraction 2 (Rt=16.526 min, Chiralcel OJ, isopropanol:hexanes 3:7).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:32][C:33]([O:35]CC)=[O:34]>CN(C=O)C>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:32][C:33]([OH:35])=[O:34])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
To a solution of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (203 mg, 0.535 mmol) in DMF (5 mL), NaH (43 mg, 1.07 mmol, 60% in mineral oil) is added at 0° C. The mixture is stirred at 0° C. and ethyl bromoacetate (98 mg, 0.588 mmol) is added. Stirring is continued at 0° C. for 30 min, then at rt for 72 h. The reaction is quenched by adding water (2 mL) and the mixture is concentrated. The residue is dissolved in THF (10 mL), methanol (10 mL) and 2 N aq. LiOH (10 mL). The mixture is stirred at 60° C. for 2 h before it is cooled to rt, acidified by adding 2 N aq. HCl and extracted three times with EA (3×20 mL). The combined org. extracts are concentrated and the crude product is purified by prep. HPLC to give the title compound (146 mg) as a white solid; LC-MS: tR=1.14 min, [M+H]+=438.07; 1H NMR (CDCl3): δ 7.90 (s, 1H), 7.88 (s, 1H), 7.79 (s br, 1H), 7.50 (s, 1H), 7.29 (s, 1H), 4.57 (s, 2H), 4.01 (s, 3H), 3.20-3.29 (m, 1H), 2.79 (q, J=7.5 Hz, 2H), 2.42 (s, 3H), 2.04-2.16 (m, 2H), 1.82-1.95 (m, 4H), 1.68-1.80 (m, 2H), 1.34 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>CC(C)=O>[Cl:10][CH2:11][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:8][CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ccccc1
Solvent: CC(C)=O
Product: ClCc1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
Thiobenzamide (10.0 g) and 1,3-dichloroacetone (9.25 g) were dissolved in acetone (200 mL), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, methanol (200 mL) was added, and the mixture was refluxed for 1.5 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:1) to give the title compound (5.1 g) as a brown oil.
Reaction SMILES: C([O:4][CH2:5][C:6](=O)[CH2:7][S:8][C:9]1[C:18]([C:19]([O:21]CC)=[O:20])=[C:17]([OH:24])[C:16]2[C:11](=[C:12]([F:27])[C:13]([F:26])=[C:14]([F:25])[CH:15]=2)[N:10]=1)(=O)C>S(=O)(=O)(O)O>[F:25][C:14]1[CH:15]=[C:16]2[C:11](=[C:12]([F:27])[C:13]=1[F:26])[N:10]1[C:6]([CH2:5][OH:4])=[CH:7][S:8][C:9]1=[C:18]([C:19]([OH:21])=[O:20])[C:17]2=[O:24]
Reactant: CCOC(=O)c1c(SCC(=O)COC(C)=O)nc2c(F)c(F)c(F)cc2c1O
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(=O)c2cc(F)c(F)c(F)c2n2c(CO)csc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50 %

Procedure:
Concd. sulfuric acid (300 ml) was added to ethyl 2-(3-acetoxy-2-oxopropylthio)-6,7,8-trifluoro-4-hydroxyquinoline-3-carboxylate (36.0 g) and the mixture was stirred at room temperature for 45 minutes and then at 85° C. for 19 hours. After adding ice-water (250 g) with cooling, the mixture was stirred at room temperature for 3 hours and the reaction mixture was then poured into ice-water. After precipitated crystal was filtered and washed with water, the resultant was recrystallized from a mixed solvent of chloroform-methanol to give the title compound (14.2 g) as light brown crystals, m.p. 220° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=3)=[CH:8][C:6]=2[N:7]=1.[C:28]([O:32][C:33]([NH:35][C:36]1[N:41]=[CH:40][C:39](B(O)O)=[CH:38][N:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>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.O>[C:19]([NH:18][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[N:11][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:39]4[CH:40]=[N:41][C:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[N:37][CH:38]=4)=[N:7][C:6]=3[CH:8]=2)[CH:17]=[CH:16][CH:15]=1)(=[O:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)Nc1ncc(B(O)O)cn1
Reactant: CC(=O)Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cccc(-c2cnc3c(N4CCOCC4)nc(-c4cnc(NC(=O)OC(C)(C)C)nc4)nc3c2)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a 50 mL sealed tube, N-(3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-phenyl)acetamide (1.30 g, 0.0033 mol), (2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid (1.21 g, 0.0050 mol), potassium phosphate (K3PO4) (1.43 g, 0.0067 mol), DMF (35 mL) and water (9 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)4 (0.274 g, 0.00023 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 105° C. for 2 hours. The reaction mass was cooled and added to ice cold water. The precipitate was obtained and was collected by filtration. The solid was dissolved in chloroform, dried over anhydrous sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by column chromatography (60-120 silica gel, 3% methanol in chloroform) to provide the title compound (1.6 g, 87.4%). NMR (300 MHz, DMSO-d6): δ 10.42 (s, 1H), 10.15 (s, 1H), 9.47 (s, 1H), 9.05 (d, J=2.4 Hz, 1H), 8.29 (d, J=2.1 Hz, 1H), 8.17 (s, 1H), 7.63 (t, J=8.4 Hz, 2H), 7.49 (t, J=7.8 Hz, 1H), 4.56 (br s, 4H), 3.85 (t, J=3.9 Hz, 4H), 2.10 (s, 3H), 1.49 (s, 9H): LC-MS (ESI): Calculated mass: 542.2; Observed mass [M+H]+: 542.9. (RT=1.39 min).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[Br:13]Br>CC(O)=O.O>[Br:13][C:9]1[CH:10]=[C:2]([Cl:1])[C:3]([O:11][CH3:12])=[CH:4][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1Cl
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(=O)O)c(Br)cc1Cl
Temperature: 60 °C
Yield: 70.5 %

Procedure:
A solution of 4-chloro-3-methoxybenzoic acid (5.0 g, 26.7 mmol) in HOAc (25 mL) and water (25 mL) was treated slowly with Br2 (1.6 mL 32 mmol). After heating to 60° C. for 2 h, the reaction was stirred cooled to rt overnight. It was quenched with water (300 mL), and the precipitate was filtered and dried to yield 2-bromo-4-chloro-5-methoxybenzoic acid (5.0 g, 70%). (264.87 [M−H]) 1H NMR: (400 MHz, DMSO) δ: 3.90 (s, 3H), 7.46 (s, 1H), 7.82 (s, 1H), 13.63 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])=[CH:15][CH:14]=3)[CH2:10]2)[CH:5]=[CH:4][N:3]=1.[CH:25]1([CH2:28][OH:29])[CH2:27][CH2:26]1.[H-].[Na+]>O1CCOCC1>[CH:25]1([CH2:28][O:29][C:2]2[CH:7]=[C:6]([O:8][CH:9]3[CH2:12][N:11]([C:13]4[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])=[CH:15][CH:14]=4)[CH2:10]3)[CH:5]=[CH:4][N:3]=2)[CH2:27][CH2:26]1
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccnc(F)c3)C2)cc1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccnc(OCC4CC4)c3)C2)cc1
Temperature: 130 °C
Reaction time: 15 h

Procedure:
To 55 mg (0.17 mmol) (S)—N-(1-{4-[3-(2-Fluoro-pyridin-4-yloxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide (XI.1) in 5 mL 1,4-dioxane is added 0.14 mL (1.73 mmol) cyclopropanemethanol. 38 mg (0.95 mmol, 60% suspension in mineral oil) NaH is added and the mixture is stirred for 15 h at 130° C. After concentration in vacuo the residue is purified by chormotography (silica, ethylacetate) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:8][C:4]1[CH:3]=[C:2]([NH:1][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(N)c1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CNc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of m-toluidine (10 g), ethyl bromoacetate (10.3 ml), sodium acetate (7.6 g) and water (5 ml in ethanol (50 ml) was stirred at room temperature overnight. The product was filtered off as the hydrobromide salt. Yield 11.6 g.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[CH3:46][S:47]([NH:2][CH:3]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH2:4]1)(=[O:49])=[O:48]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCC(N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCC(NS(C)(=O)=O)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-amino-cyclopentyl)-amide hydrochloride (145 mg, 0.23 mmol) was suspended in dichloromethane (2.5 ml). The suspension was cooled to 0° C. and triethylamine (0.10 ml, 0.72 mmol) was added followed by methanesulfonyl chloride (0.02 ml, 0.26 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with dichloromethane (2×). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-5% MeOH) to afford 111 mg (79%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-methanesulfonylamino-cyclopentyl)-amide as a light yellow solid.