Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C@@H:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16](O)=[O:17])=[O:13])[CH:9]=[N:8][C:7]=2[N:23]2[CH2:26][C:25]([F:28])([F:27])[CH2:24]2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[F:61][C:62]([F:66])([F:65])[CH2:63][NH2:64]>CN(C=O)C>[CH3:22][CH:20]([CH3:21])[CH2:19][C@H:15]([NH:14][C:12]([C:10]1[CH:9]=[N:8][C:7]([N:23]2[CH2:26][C:25]([F:27])([F:28])[CH2:24]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:13])[C:16](=[O:17])[NH:64][CH2:63][C:62]([F:66])([F:65])[F:61]
Reactant: CC(C)C[C@H](NC(=O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)O
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
(S)-2-{[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-amino}-4-methyl-pentanoic acid (40 mg, 100 μmol) was suspended in DMF (2 mL). TBTU (35.5 mg, 110 μmol), DIEA (85.9 μl, 0.5 mmol) and 2,2,2-trifluoro-ethanamine hydrochloride (1:1) (CAN 373-88-6, 15 mg, 135 μmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo; ethyl acetate (3 mL) and 2N NaOH solution (2 mL) were added before eluting with ethyl acetate through ChemElut (10 g). The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, 10 g, 0% to 100% ethyl acetate in n-heptane) to give the desired product (36 mg, 75%) as white solid; LC-MS (UV peak area, ESI) 100%, 480.2035 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[C:23]([F:28])[CH:22]=2)=[N:16]1.[CH3:29][C:30]([CH3:34])([CH3:33])[C:31]#[CH:32].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:32]#[C:31][C:30]([CH3:34])([CH3:33])[CH3:29])=[C:23]([F:28])[CH:22]=2)=[N:16]1
Reactant: C#CC(C)(C)C
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)c(F)c3)[nH]c2=O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC(C)(C)C)c(F)c3)[nH]c2=O)c1
Yield: 12.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 by using N-(4-chloro-3-(3-(3-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide (0.080 g, 0.155 mmol), 3,3-dimethylbut-1-yne (0.019 g, 0.233 mmol), TBAF (0.121 g, 0.466 mmol), bis(triphenylphosphine)palladium(II) chloride (0.004 g, 0.006 mmol) and DMSO (3.0 mL) to afford 0.009 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.02 (d, J=6.9 Hz, 6H), 1.31 (s, 9H), 2.39-2.42 (m, 1H), 4.29 (d, J=5.7 Hz, 2H), 7.35 (d, J=7.5 Hz, 1H), 7.43 (s, 1H), 7.57-7.67 (m, 4H), 8.37 (m, 1H), 13.0 (br s, 1H); MS (m/z): 469.31 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:48])[C:5]([C@@:7]1([CH3:47])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[O:37][C@@H:38]1[O:43][CH2:42][C@@H:41]([OH:44])[C@H:40]([OH:45])[C@H:39]1[OH:46])=[O:6].CC1[C@@H](O)C[C@]2(O)C(C)(C)C=1[C@@H:52](O)[C:53]([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=[O:54]>>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:48][C:53]([CH3:52])=[O:54])[C:5]([C@@:7]1([CH3:47])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[O:37][C@@H:38]1[O:43][CH2:42][C@@H:41]([OH:44])[C@H:40]([OH:45])[C@H:39]1[OH:46])=[O:6]
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Product: CC(=O)O[C@H]1C(=O)[C@]2(C)[C@@H](O[C@@H]3OC[C@@H](O)[C@H](O)[C@H]3O)C[C@H]3OC[C@@]3(OC(C)=O)[C@H]2[C@H](OC(=O)c2ccccc2)[C@]2(O)C[C@H](O)C(C)=C1C2(C)C
Reaction time: 24 h

Procedure:
The strain was the same as that in Example 6 and the substrate was 7-xylosyl-10-deacetylbaccatin III (XDB). 1.5 ml cell reaction solution contained 16 mg dry cells per milliliter and 8 mg XDB per milliliter. The mixture was incubated in a water shaking bath for 24 h at 30˜55° C. HPLC analysis results showed that the conversion ratio of XDB was 86.54% and the yield of the product, 10-deacetylbaccatin III (DB), was 5.57 mg/ml (FIG. 7).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:3]1=[O:22].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO.O>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]([S:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)(=[O:33])=[O:32])[C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:14])=[O:15])=[CH:9][CH:8]=2)[C:3]1=[O:22]
Reactant: O=C1[C@@H](O)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N(c2nccs2)S(=O)(=O)c2ccc(N3CC[C@H](O)C3=O)cc2)cc1
Yield: 89.2 %

Procedure:
Synthesized according to General Procedure 8. A solution of (S)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (150 mg, 0.44 mmol), 4-methoxybenzenesulfonyl chloride (91 mg, 0.44 mmol) and DIEA (57 mg, 77 μL, 0.44 mmol) in DMF (0.75 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with MeOH (1 mL) and water (10 mL), and the resulting precipitated solid was collected by vacuum filtration. The precipitate was washed with water followed by cold Et2O to afford the product, (S)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(4-methoxyphenylsulfonyl)-N-(thiazol-2-yl)benzenesulfonamide (200 mg, 0.3925 mmol) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.86-7.80 (m, 4H), 7.70 (d, J=5.1 Hz, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.03-6.98 (m, 3H), 5.88 (d, J=5.9 Hz, 1H), 4.38-4.32 (m, 1H), 3.85-3.77 (m, 1H), 3.81 (s, 3H), 3.70 (td, J=9.4, 5.4 Hz, 1H), 2.48-2.41 (m, 1H) and 1.92-1.82 (m, 1H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=510.0; tR=1.22 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]([F:10])([F:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.CC([O-])=O.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CCOC(C)=O.C1COCC1>[CH:11]1([NH:1][CH2:2][C:3]([F:10])([F:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)C(F)(F)CN
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CNC1CCCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a round bottom flask was added Ethyl 3-amino-2,2-difluoropropanoate (1.31 g, 4.9 mmol), THF (50 mL), cyclopentanone (0.46 mL, 5.1 mmol), and NaOAc (400 mg, 4.9 mmol). To this mixture was added sodium triacetoxyborohydride (1.6 g, 7.3 mmol) portionwise over 15 minutes. The reaction was left to stir overnight. It was then added slowly to a stirring solution of ice (30 mL), NaHCO3 (sat., 10 mL), and EtOAc (100 mL) cooled in an ice-salt bath. The layers were then separated and the aqueous pH further adjusted to 11 using 25% NaOH while cooling in the bath. The aqueous layer was washed with EtOAc (2×50 mL), the organic extracts combined, washed with cold NaHCO3, (sat. 20 mL×2) brine (20 mL), dried over MgSO4, filtered and concentrated to yield the desired product as a clear syrup (960 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (t, J=7.07 Hz, 2H) 1.34-1.74 (m, 8H) 3.00 (q, 1H) 3.11 (t, J=14.15 Hz, 2H) 4.27 (q, J=7.07 Hz, 2H). [M+H] calc'd for C10H17F2NO2, 222. found 222.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(N1CCN(C2C=C(N[C:31]([C:33]3[C:34]4[N:35]=[CH:36][CH:37]=[N:38][C:39]=4[C:40]([C:43]4[C:52]5[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=5)[CH:46]=[N:45][CH:44]=4)=[CH:41][CH:42]=3)=[O:32])C=CC=2)CC1)C>>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:31]([C:33]3[C:34]4[N:35]=[CH:36][CH:37]=[N:38][C:39]=4[C:40]([C:43]4[C:52]5[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=5)[CH:46]=[N:45][CH:44]=4)=[CH:41][CH:42]=3)=[O:32])=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Product: CCN1CCN(c2ccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)cc2)CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 4-(4-ethylpiperazin-1-yl)-aniline (Step 1.9) and 8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid (Example 52). Title compound: ESI-MS: 489.1 [M+H]+; tR=10.58 min (System 2).
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)([CH3:10])[CH2:8][N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6]1)=[O:4].[Li+].[OH-].CO>C1COCC1>[CH2:18]([N:7]1[CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)([CH3:10])[CH:5]([C:3]([OH:4])=[O:2])[CH2:6]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1(C)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(c2ccc(Cl)cc2)CN(Cc2ccccc2)CC1C(=O)O
Yield: 97.1 %

Procedure:
A mixture of 9.56 g (27.8 mmol) rac-(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-4-methyl-pyrrolidine-3-carboxylic acid methyl ester and 3.5 g (83.4 mmol) LiOH.H20 in 50 mL THF/50 mL water and 5 mL methanol was heated to reflux and stirred over night. The organic solvents were removed under vacuum and the aqueous phase was adjusted to pH=4-5 with 1N HCl aq. Water was decanted off the residue and THF was added. The mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate/THF (1:1) and the organic layers were evaporated to yield 8.9 g (97%) of the title compounds as off-white solid. MS m/e: 328.3 [M−H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH3:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CCOC(C)=O.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>[F:21][C:22]1[N:23]=[CH:24][C:25]([C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH3:17])=[CH:10][CH:9]=3)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=2)=[CH:26][CH:27]=1
Reactant: COCOc1ccc(-c2ncc(Br)cc2[N+](=O)[O-])cc1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
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: CCOC(C)=O
Solvent: C1COCCO1
Product: COCOc1ccc(-c2ncc(-c3ccc(F)nc3)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 67.5 %

Procedure:
A mixture of 5-bromo-2-(4-(methoxymethoxy)phenyl)-3-nitropyridine (68 mg, 0.2 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (45 mg, 0.2 mg), tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol), Na2CO3 (0.5 mL, 1 M aqueous solution) and dioxane (1.5 mL) was heated at 100° C. for 10 min in a microwave reactor. After cooling to rt, the reaction was diluted with EtOAc (20 mL) and washed with brine (20 mL) and water (2×20 mL) and dried over MgSO4. Solvent was removed under reduced pressure and the residue was purified by silica chromatography (EtOAc in hexane, 5% to 40%) to afford 6′-fluoro-6-(4-(methoxymethoxy)phenyl)-5-nitro-3,3′-bipyridine as a yellow solid (48 mg, 67%). MS (ESI) m/z [M+H]+356.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH2:7]([O:9][C:10]([O:12][CH2:13][CH3:14])=[CH2:11])[CH3:8]>CCCCC>[CH2:7]([O:9][C:10]1([O:12][CH2:13][CH3:14])[CH2:11][CH:5]2[CH:4]1[CH2:3][CH2:2][C:1]2=[O:6])[CH3:8]
Reactant: C=C(OCC)OCC
Reactant: O=C1C=CCC1
Solvent: CCCCC
Product: CCOC1(OCC)CC2C(=O)CCC21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of cyclopent-2-enone (3.7 g, 45 mmol) in pentane (80 mL) was added 1,1-diethoxyethene (89 mL, 677 mmol). The mixture was put in an ACE Photo Reactor (450 W lamp), and stirred at RT for 20 hr. It was concentrated to give the title compound as a pale yellow oil.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH2:24][C:25]2[N:26]=[C:27]([NH:30][C:31](=[O:39])[C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[S:28][CH:29]=2)=[O:23])=[C:17]([F:40])[CH:16]=1)(=[O:8])=[O:7])(C)(C)C.Cl>C(Cl)(Cl)Cl.CO>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C:31]([NH:30][C:27]2[S:28][CH:29]=[C:25]([CH2:24][C:22](=[O:23])[NH:21][C:18]3[CH:19]=[CH:20][C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:6](=[O:7])(=[O:8])[NH2:5])=[CH:16][C:17]=3[F:40])[N:26]=2)=[O:39])=[CH:37][CH:36]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)c(F)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)c(F)c1
Yield: 75.8 %

Procedure:
A solution of 163 mg N-{4-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-methyl]-thiazol-2-yl}-4-chloro-benzamide in 8 ml CHCl3/MeOH 3:1 was cooled to −11° C. A stream of HCl gas was passed over the stirred solution for 10 min. The reaction mixture was kept at 4° C. over night, then concentrated. The crude product was purified by chromatography on silica using a gradient from CH2Cl2 to CH2Cl2/MeOH 9:1 in 20 minutes to give 112 mg 4-chloro-N-{4-[(3-fluoro-2′-sulfamoyl-biphenyl-4-ylcarbamoyl)-methyl]-thiazol-2-yl}-benzamide as white solid. MS 545.3 ([M+H]+)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Oc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
To a stirred solution of 2-naphthol (2.9 g) and 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (4 g) in tetrahydrofuran (30 ml) at 0° C. was added triphenylphosphine (5.2 g) and diethyl azodicarboxylate (3.2 ml). The reaction was allowed to warm to room temperature and stirred for 16 h. The solvent was removed in vacuo and the slurry taken up in EtOAc (30 ml) and washed with aqueous sodium hydroxide (1M, 2×30 ml), water (30 ml) and brine (30 ml). The organic extract was diluted with hexane (50 ml), and the precipitates were removed by filtration, and the filtrate dried over magnesium sulphate (1 g). The solvent was removed in vacuo to yield the title compound as a white solid (3.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: BrCCCCCCBr
Reactant: COc1ccc(CCO)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc(CCOCCCCCCBr)cc1
Yield: 237.5 %

Procedure:
4-Methoxybenzeneethanol (5.0 g) and 1,6-dibromohexane (23.7 g) were stirred rapidly at RT with tetra-n-butyl ammonium bisulphate (0.94 g) and 12.5 M aqueous NaOH (30 ml) for 16 h. The mixture was diluted with H2O (125 ml), extracted with ER (3×150 ml) and the combined organic extracts were washed consecutively with H2O (125 ml), BR (125 ml), dried and evaporated to give an oil (24.6 g). The oil was purified by [FCS] eluting with ER-CX (0:100→4:96) to give the title compound as a colourless oil (8.30 g). T.l.c. (CX-ER (40:1)) Rf 0.33.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8](S(CCCCl)(=O)=O)[C:9]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[CH2:22][CH3:23])(=[O:7])=[O:6].CCN(CC)CC>CCO>[O:6]=[S:5]1(=[O:7])[CH2:4][CH2:3][CH2:2][N:8]1[C:9]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[CH2:22][CH3:23]
Reactant: CCn1ncc2c(N(S(=O)(=O)CCCCl)S(=O)(=O)CCCCl)cc(C(=O)OC)cc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1ncc2c(N3CCCS3(=O)=O)cc(C(=O)OC)cc21
Temperature: 25 °C

Procedure:
To a solution of methyl 4-{bis[(3-chloropropyl)sulfonyl]amino}-1-ethyl-1H-indazole-6-carboxylate (D237) (1.5 g, 3 mmol, 1 equiv) in EtOH (20 ml) was added NEt3 (920 μl, 6.6 mmol, 2.2 equiv) and the resulting solution was refluxed for 3 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase was washed with a 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with AcOEt/iso-hexane to give methyl 4-(1,1-dioxido-2-isothiazolidinyl)-1-ethyl-1H-indazole-6-carboxylate (B153) as a light brown solid which was used in the next step without further purification. [M+H]+=324.5, RT=2.35 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[C:9]1([CH2:15][O-:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+]>>[CH2:15]([O:16][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [O-]Cc1ccccc1
Reactant: Nc1cc(Cl)ncn1
Agent: [Na+]
Product: Nc1cc(OCc2ccccc2)ncn1
Yield: 27 %

Procedure:
6-Chloropyrimidin-4-amine (500 mg, 3.86 mmol) and sodium phenylmethanolate (1 M solution in benzyl alcohol, 4.67 mL, 4.67 mmol) were heated at 120° C. for 16 hrs. 6-(Benzyloxy)pyrimidin-4-amine (210 mg, 27% yield) was isolated as clear oil following HPLC purification (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA). The purified material (a TFA salt) was converted to its free base by dissolving in ethyl acetate (20 mL) and washing with saturated NaHCO3 (20 mL) for use in the next step. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=0.96 (M+H=202.24).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[S:11][C:7]=2[CH:6]=1)=[NH:4].[C:23](Cl)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(=O)C>[CH:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]2[S:11][C:7]3[CH:6]=[C:5]([C:3]4[N:4]=[C:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:1][N:2]=4)[CH:22]=[CH:21][C:8]=3[N:9]=2)[CH2:17][CH2:16]1)([CH3:19])[CH3:20]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)N1CCN(c2nc3ccc(C(=N)NO)cc3s2)CC1
Solvent: CC(=O)O
Product: CC(C)N1CCN(c2nc3ccc(-c4noc(-c5ccccc5)n4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of N-hydroxy-2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxamidine (650 mg, 2.04 mmol) in acetic acid (40 mL) was added benzoylchloride (3 mL). The reaction mixture was stirred overnight at room temperature and then refluxed for 2 h. The reaction mixture was concentrated in vacuo and the residue was dissolved into 0.5 N hydrochloric acid (30 mL). The aqueous solution was extracted with diethyl ether (3×15 mL). The organic layer was discarded and the aqueous phase was basified to pH 13 with 4 N sodium hydroxide and then extracted with ethyl acetate (4×10 mL). The combined organic extracts were evaporated and the residue was recrystallized three times from a mixture of CH2Cl2 and MeOH to give 189 mg (26%) of 2-(4-isopropylpiperazin-1-yl)-6-(5-phenyl-[1,2,4]oxadiazol-3-yl)benzothiazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12]Br)[CH:3]=1.[OH:14][CH2:15][C:16]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[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.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH2:12][O:14][CH2:15][C:16]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: FC(F)(F)c1cc(Br)cc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (1.0 g, 3.14 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.70 g, 2.4 mmol) were combined in dimethylformamide (8 mL) and cooled to 0° C. The reaction was treated with sodium hydride (115 mg, 4.8 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.6 g (96%). 1H-NMR (CDCl3, 500 MHz) δ 7.61 (s, 1H), 7.39 (s, 1H), 7.34-7.37 (m, 4H), 7.25-7.28 (m, 2H), 4.35 (s, 2H), 3.75-3.77 (m, 2H), 3.41 (s, 2H), 3.01-3.06 (m, 2H), 2.19-2.22 (m, 2H), 1.83-1.89 (m, 2H), 1.44 (s, 9H). Mass spec.: 530.21 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.Cl>CC(C)=O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:11][S:8]([C:6]2[O:7][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)(=[O:9])=[O:10])=[O:23])=[CH:17][CH:16]=1
Reactant: CCc1ccc(S(N)(=O)=O)o1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of 5-ethyl-2-furansulfonamide (4.5 g, 25.7 mmole) in 40 ml of acetone was added aqueous sodium hydroxide (25.7 ml of 1N, 25.7 mmole) followed by a solution of 4-chlorophenylisocyanate (3.9 g, 25.7 mmole) dissolved in 40 ml of acetone. The reaction was stirred at room temperature overnight and filtered through a plug of celite. The filtrate was acidified with hydrochloric acid (25.7 ml of 1N, 25.7 mmole) and the resulting precipitate filtered to produce 8.3 g of solid.