Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:47]([O:48]CC2C=CC=CC=2)[C@H:46]([O:56][C@@H:57]2[O:76][C@H:75]([CH2:77][OH:78])[C@@H:62]([O:63][C@@H:64]3[O:72][C@H:71]([CH2:73][OH:74])[C@@H:69]([OH:70])[C@H:67]([OH:68])[C@H:65]3[OH:66])[C@H:60]([OH:61])[C@H:58]2[OH:59])[C@@H:45]([CH2:79][O:80]CC2C=CC=CC=2)[O:44][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17]CC2C=CC=CC=2)[CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[C@@H:13]1[CH2:35][O:36]CC1C=CC=CC=1)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[C@@H:64]1([O:63][C@@H:62]2[C@@H:75]([CH2:77][OH:78])[O:76][C@@H:57]([O:56][C@@H:46]3[C@@H:45]([CH2:79][OH:80])[O:44][C@H:10]([O:11][C@H:12]4[C@H:16]([OH:17])[CH2:15][NH:14][C@@H:13]4[CH2:35][OH:36])[C@H:9]([OH:8])[C@H:47]3[OH:48])[C@H:58]([OH:59])[C@H:60]2[OH:61])[O:72][C@H:71]([CH2:73][OH:74])[C@@H:69]([OH:70])[C@H:67]([OH:68])[C@H:65]1[OH:66]
Reactant: O=C(OCc1ccccc1)N1C[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@H](O)[C@H]3O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: OC[C@H]1NC[C@@H](O)[C@@H]1O[C@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 19.2 %

Procedure:
The compound (100.7 mg, 0.084 mmol) synthesized in Example 19 (19f) was dissolved in methanol (10 mL) and 36% hydrochloric acid (280 μL) and palladium hydroxide (100 mg) were added thereto, followed by stirring of the mixture at room temperature under a hydrogen atmosphere for 4 hours. After celite filtration, 18% ammonia water (1 mL) was added thereto and the solvent was distilled off under reduced pressure. The residue was purified by ion exchange resin (Dowex 50w×8) column (water—1% ammonia water). Further, it was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired title compound (10.0 mg, 19.2%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(ON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of compound (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.193 g, 0.70 mmol) in dry DCM (20 mL) were added tert-butyl 3-(aminooxy)azetidine-1-carboxylate 36 (0.198 g, 1.05 mmol, J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.142 g, 1.05 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.201 g, 1.05 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl 3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate 37 (0.15 g, 48%) as a clear thick oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[F:26][C:27]1[CH:35]=[C:34]2[C:30]([C:31]([Sn](CCCC)(CCCC)CCCC)=[N:32][N:33]2[CH3:36])=[CH:29][CH:28]=1>CN(C=O)C.[Cu]I.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>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:31]3[C:30]4[C:34](=[CH:35][C:27]([F:26])=[CH:28][CH:29]=4)[N:33]([CH3:36])[N:32]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(F)ccc12
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Temperature: 90 °C
Yield: 5.4 %

Procedure:
2-Bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 0.187 mmol) and 6-fluoro-1-methyl-3-(tributylstannyl)-1H-indazole (0.1 g, 0.228 mmol) were dissolved in DMF (3 mL). The reaction mixture was evacuated and filled with nitrogen. Copper(I) iodide (6.71 mg, 0.0749 mmol) and tetrakis(triphenylphosphine)palladium (0) (10.8 mg, 0.00936 mmol) were added. The reaction mixture was heated at 90° C. for 2 h. The mixture was cooled and partitioned between ethyl acetate and water, the organic phase washed with brine, then dried over magnesium sulfate. The crude compound was purified by chromatography using 25% ethyl acetate/hexanes to obtain 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (5 mg, 38%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH:27]1([N:32]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:34]=[N:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CO.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>[CH:27]1([N:32]2[CH:36]=[C:35]([C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]5[CH:17]=[C:16]([N:18]6[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]6)[N:15]=[C:14]([NH2:25])[N:13]=5)[CH2:9]4)=[CH:4][CH:3]=3)[CH:34]=[N:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC1(C)OB(c2cnn(C3CCCC3)c2)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(C4CCCC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.5 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in 1,4-dioxane (0.2 mL) and water (0.1 mL) was stirred at 90° C. overnight. After cooling, it was diluted with methanol, and purified with RP-HPLC (pH=10) to afford the desired product (4.7 mg). LCMS (M+H)+: m/z=473.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[C:6]([OH:8])[CH:7]=1.[Br:13]C1C=CC(O)=CC=1.C(O)(C)(C)C.S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl>[Br:13][C:3]1[CH:2]=[CH:7][C:6]([OH:8])=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)c1ccc(Br)cc1O
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Using the same general procedure as for the preparation of 5-bromo-2-t-butylphenol (Compound D), but instead using 50.00 g (289.0 mmol) of 4-bromophenol, 21.40 g (27.25 ml, 289.0 mmol) of t-butanol, 14.0 ml of conc. sulfuric acid (added slowly) and 140 ml of distilled carbon tetrachloride, stirred at room temperature for 24 hours produced a dull green-colored solution and a white precipitate. At this time an additional 3.5 ml of conc. sulfuric acid was added and the solution was allowed to stir for 4 days at room temperature. After aqueous workup, a dark yellow oil was isolated. Purification by flash chromatography (silica, 2% ethyl acetate in hexane) yielded the title compound as a clear, light yellow oil. PMR (CDCl3):d 1.38 (9H, s), 4.79 (1H, s), 6.54 (1H, d, J=8.5 Hz), 7.16 (1H, dd, J=8.5, 2.5 Hz), 7.35 (1H, d, J=2.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:18])[C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[OH:18])[N:14]=1)=[O:17])[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[NH2:23]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1cccc(C(O)c2ccc(F)cc2)n1
Product: CC(C)C[C@H](NC(=O)c1cccc(C(O)c2ccc(F)cc2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-((4-fluorophenyl)(hydroxy)methyl)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=360.1 [M+H]+.
Reaction SMILES: [CH:1]1([C@@H:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[S:28][C:27]5[C:22](=[N:23][CH:24]=[CH:25][C:26]=5[O:29][CH3:30])[CH: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])[C:5]([OH:7])=O)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH:47]1[CH2:50][CH:49]([C:51]#[N:52])[CH2:48]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:51]([CH:49]1[CH2:50][N:47]([C:5](=[O:7])[C@H:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[S:28][C:27]5[C:22](=[N:23][CH:24]=[CH:25][C:26]=5[O:29][CH3:30])[CH:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:36])[CH3:37])[CH:12]=2)=[O:10])[CH:1]2[CH2:2][CH2:3]2)[CH2:48]1)#[N:52]
Reactant: N#CC1CNC1
Reactant: COc1ccnc2cc(-c3cnc4c(n3)c(C(=O)N[C@@H](C(=O)O)C3CC3)cn4COCC[Si](C)(C)C)sc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccnc2cc(-c3cnc4c(n3)c(C(=O)N[C@@H](C(=O)N3CC(C#N)C3)C3CC3)cn4COCC[Si](C)(C)C)sc12
Reaction time: 16 h
Yield: 64 %

Procedure:
To a solution of (R)-cyclopropyl-{[2-(7-methoxy-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-acetic acid (27 mg, 0.049 mmol) in DMF (2 mL) at room temperature was added triethylamine (34.0 μL, 0.24 mmol), azetidine-3-carbonitrile hydrochloride (6 mg, 0.049 mmol and PyBOP (31 mg, 0.059 mmol). The reaction mixture was stirred for 16 h at the same temperature then poured into EtOAc (25 mL) and washed with water (4×30 mL). The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude residue was purified by column chromatography (SiO2, 23 g, hex:EtOAc, 9:1 to 100% in 30 min) to give 26 mg (64%) of 2-(7-methoxy-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[CH3:35][O:36][CH2:37][CH2:38][NH2:39].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([NH:39][CH2:38][CH2:37][O:36][CH3:35])=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Reactant: COCCN
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCNc1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 150 °C
Yield: 19.8 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (470 mg, 1.0 mmol), from the procedure for 249, 2-Methoxy-ethylamine (90 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 341 (105.5 mg, yield: 20%). 1HNMR (DMSO-d6, 400 MHz): δ8.63 (s, 1H), 8.31 (s, 1H), 7.94-7.88 (m, 2H), 7.76-7.68 (m, 2H), 7.46-7.38 (m, 2H), 7.21 (s, 2H), 6.99 (s, 1H), 6.63 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.49 (s, 4H), 3.29 (s, 3H), 3.15 (s, 2H). ESI-MS: m/z=533 [M+H+]
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:23]2[CH:24]=[N:25][C:26]4[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:16][CH2:15]3)[CH2:8]1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: Brc1cnc2ccccc2c1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2cnc4ccccc4c2)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 3-bromo-quinoline.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].C(O)(=O)C.[CH3:22][C:23](=O)[CH2:24][CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:23]([N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH3:2])(=[O:5])=[O:4])[CH:7]=2)[CH2:13][CH2:14]1)([CH2:24][CH3:25])[CH3:22]
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Reactant: CCC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCC(C)N1CCC(c2cccc(S(C)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-(3-methanesulfonyl-phenyl)-piperidine hydrochloride (20 mg), glacial acetic acid (4.4 mg) and 2-butanone (5.1 mg) were mixed in 1,2-dichloroethane (5 mL). Sodium triacetoxyborohydride (23.5 mg) was added to the solution and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 5 h (G.L.C. analysis indicated a complete reaction). The reaction was quenched with saturated aqueous NaHCO3 and the product was extracted with CH2Cl2. The combined organic phases were dried (MgSO4), filtered, and the solvent was evaporated to afford 1-sec-butyl-4-(3-methanesulfonyl-phenyl)piperidine as an oily residue. The product was chromatographed on a silica column with CH2Cl2:MeOH (9:1 (v/v)) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded pure amine (15 mg, 71%); MS m/z (relative intensity, 70 eV) 295 (M+, 1), 280 (7), 266 (bp), 187 (4), 129 (4).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15].C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CN2C(=O)c3ccccc3C2=O)CC1
Yield: 66.5 %

Procedure:
Phthalimide (33 mg, 0.23 mmol) was treated with tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate (80.5 mg, 0.32 mmol), tetrabutylammonium iodide (TBAI, 84 mg, 2.3 mmol), diisopropylethylamine (DIEA, 0.20 mg, 1.14 mmol) in anhydrous CH2Cl2 (10 mL) for 24 h at 40° C. The mixture was partitioned between CH2Cl2 and water. The organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by flash chromatography on a silica gel column with elution of EtOAc/hexane (1:1) to give the title compound (57.1 mg, 67% yield). C19H23N3O5; white solid; TLC (EtOAc/hexane=1:1) Rf=0.2; 1H NMR (400 MHz, CDCl3) δ 7.85-7.87 (2H, m), 7.70-7.72 (2H, m), 4.49 (2H, s), 3.51-3.57 (6H, m), 3.44 (2H, d, J=5.2 Hz), 1.46 (9H, d, J=4.8 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C1C=CC=CC=1>CCO.O1CCOCC1.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)COc1cc(C)nc2c(OCc3ccccc3)cccc12
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)COc1cc(C)nc2c(O)cccc12
Reaction time: 8 h
Yield: 46.2 %

Procedure:
To a mixture of give 8-(benzyloxy)-2-methylquinolin-4-ol (2.34 g, 8.83 mmol) and potassium carbonate (1.83 g, 13.2 mmol) in anhydrous DMF (50 mL) was added ethyl bromoacetate (1.77 g, 10.6 mmol) with stirring under nitrogen. The mixture was heated at 80° C. for 1 h, cooled, mixed with a saturated aqueous sodium bicarbonate and extracted with EtOAc. Evaporation gave a crude product that was dissolved in dichloromethane and precipitated by the addition of a mixture of Hex/EtOAc (10/1). The precipitate was filtered and dried to give ethyl 2-((8-(benzyloxy)-2-methylquinolin-4-yl)oxy)acetate (2.13 g, 69%). A mixture of ethyl 2-((8-(benzyloxy)-2-methylquinolin-4-yl)oxy)acetate (0.70 g, 1.99 mmol), Pd/C (10%, 0.07 g) in EtOH/dioxane (20 mL/20 mL) was placed under hydrogen atmosphere with stirring overnight. The mixture was filtered and evaporated to give ethyl 2-((8-hydroxy-2-methylquinolin-4-yl)oxy)acetate (0.24 g, 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:16]2[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]3[C:19]([C:20]4[CH:32]=[CH:31][O:30][C:21]=4[CH2:22][O:23]3)=[CH:18][CH:17]=2)C(OC)=O)(=[O:10])=[O:9])=[C:4](/[CH:33]=[CH:34]\[CH2:35]O)[CH:3]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.FC(F)(F)C(O)=O.[NH:58]1[CH2:61][CH:60]([O:62][C:63](=[O:65])[CH3:64])[CH2:59]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:16]2[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]3[C:19]([C:20]4[CH:32]=[CH:31][O:30][C:21]=4[CH2:22][O:23]3)=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[C:4](/[CH:33]=[CH:34]\[CH2:35][N:58]2[CH2:61][CH:60]([O:62][C:63](=[O:65])[CH3:64])[CH2:59]2)[CH:3]=1
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCc1occc1-2
Reactant: CC(=O)OC1CNC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CC(OC(C)=O)C2)ccc2c1OCc1occc1-2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.1 %

Procedure:
To a suspension of methyl 7-{N-[4-fluoro-2-((Z)-3-hydroxy-prop-1-enyl)-benzenesulfonyl]-N-(methoxycarbonyl)amino}-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 92, 0.220 g) in DCM (10 mL) was added N,N-di-isopropyl-N-ethylamine (1.10 g) and methanesulfonyl chloride (0.059 g). The mixture was stirred at room temperature for 1.5 hours. A solution of acetic acid azetidin-3-yl ester trifluoroacetate salt (1.40 g) in DCM (5 mL) was added and the resultant mixture was stirred at room temperature for 30 minutes. The mixture was diluted with DCM and washed with water, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10% to give methyl 7-{4-fluoro-2-[(Z)-3-(3-acetoxyazetidin-1-yl)-prop-1-enyl]-benzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (0.095 g) as a white foam.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[F:14][C:15]1[N:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C.[BH4-].[Na+]>CO>[F:14][C:15]1[N:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][C@H:23]([NH:26][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=3)[CH2:22]2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: NC1CCN(c2ccc(F)nc2)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: Fc1ccc(N2CC[C@H](NCc3ccc(C(F)(F)F)cc3)C2)cn1
Reaction time: 18 h

Procedure:
Add 4-(trifluoromethyl)benzaldehyde (30 μL, 0.22 mmol) to a solution of 1-(6-fluoropyridin-3-yl)-pyrrolidin-3-ylamine hydrochloride (43 mg, 0.2 mmol) and triethylamine (90 μL, 0.66 mmol) in methanol (1 mL). Vortex the resulting mixture and allow to sit for 18 h. Add sodium borohydride (12-15 mg, 0.3-0.4 mmol). When the bubbling begins to subside, vortex and allow to sit for 1 h. Dilute the reaction mixture with methanol (2 mL) and pour onto a column of Dowex® 50Wx2 (H+ form). Rinse the column with methanol, elute the product with 5% triethylamine in methanol and concentrate. Redissolve the residue in methanol, dilute with acetonitrile and concentrate to dryness to give the title compound as a residue.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]([NH2:15])=[S:14]>CCO>[C:8]1([CH3:11])[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]([NH2:15])[S:14][CH:2]=2)=[CH:6][CH:7]=1
Reactant: NC(N)=S
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: Cc1ccc(-c2csc(N)n2)cc1
Yield: 98.4 %

Procedure:
A mixture of 2-bromo-1-(p-tolyl)ethanone (5.00 g, 23.5 mmol) and thiourea (1.97 g, 25.9 mmol) in 95% EtOH (33.5 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and washed with hot water. The solids were filtered and dried under vacuum to give 4-(p-tolyl)thiazol-2-amine (4.40 g) as white solids in 99% yield: 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J=8.0 Hz, 2 H), 7.18 (d, J=7.5 Hz, 2 H), 6.66 (s, 1 H), 5.25 (bs, 2 H), 2.36 (s, 6 H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:20][CH:19]([O:21][CH3:22])[CH2:18]2)=[O:16])[CH:12]=[C:11]([Cl:23])[C:10]=1[F:24])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:18][CH:19]([O:21][CH3:22])[CH2:20]2)=[O:16])[CH:12]=[C:11]([Cl:23])[C:10]=1[F:24]
Reactant: COC1CN(C(=O)c2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1CN(C(=O)c2cc(Cl)c(F)c(CN)c2)C1

Procedure:
was prepared according to Scheme C3 (step B) from [3-chloro-2-fluoro-5-(3-methoxy-azetidine-1-carbonyl)-benzyl]-carbamic acid tert-butyl ester (99 mg, 0.3 mmol) and TFA (0.5 mL) in CH2Cl2. MS (LC-MS): 273.0 [M]+; tR (HPLC conditions c): 2.73 min.