Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[S:3].Cl[CH2:17][CH:18]=O>C(O)C>[S:3]1[CH:18]=[CH:17][N:4]=[C:2]1[NH:1][C:5]1[CH:6]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)Nc1cccc(NC(N)=S)c1
Reactant: O=CCCl
Solvent: CCO
Product: CS(=O)(=O)Nc1cccc(Nc2nccs2)c1
Yield: 93.4 %

Procedure:
N-(3-thioureidophenyl)methanesulfonamide 54 (1.14 g, 4.65 mmol) and 50% aq. chloroacetaldehyde solution (3.65 mL, 23.25 mmol) were taken into ethanol and refluxed for 2 hours. Reaction mixture was concentrated and aq. Saturated NaHCO3 was added. Resulting light brown solid was filtered and washed with water, dried under high vacuum to obtain N-(3-(thiazol-2-ylamino)phenyl)methanesulfonamide 55 (1.17 g, 93% yield). Resulting product was further used without further purification. MS (ES) m/z 270 (M+H+).
Reaction SMILES: [F-].[Cs+].[O:3]1[CH2:8][CH2:7][CH2:6][O:5][CH:4]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[C:22]([N:23]=2)=[CH:21][CH:20]=[C:19](Cl)[N:18]=3)=[C:11]([F:25])[CH:10]=1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([Sn](CCCC)(CCCC)CCCC)=[CH2:41])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.CC(=O)OCC.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:3]1[CH2:8][CH2:7][CH2:6][O:5][CH:4]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[C:22]([N:23]=2)=[CH:21][CH:20]=[C:19]([C:40]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:35][CH:36]=2)=[CH2:41])[N:18]=3)=[C:11]([F:25])[CH:10]=1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(Cl)nc2s1
Reactant: C=C(c1ccc(OCc2ccccc2)cc1)[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Agent: [Pd]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(c1ccc(OCc2ccccc2)cc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Temperature: 55 °C

Procedure:
A slurry of cesium fluoride (0.325 g, 2.14 mmol), CuI 0.0271 g, 0.143 mmol), tetrakis(triphenylphosphine) palladium (0) (0.0824 g, 0.0713 mmol), 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-chlorothiazolo[5,4-b]pyridine (0.500 g, 1.43 mmol), and crude (1-(4-(benzyloxy)-phenyl)vinyl)tributylstannane (1.07 g, 2.14 mmol) in 5 mL DMF was flushed with argon, sealed, and heated to 55° C. overnight. The reaction mixture was diluted with EA, filtered through celite, rinsing with EA. The filtrate was washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was adsorbed onto 4 g silica gel from DCM, concentrated, and purified by ISCO 40 g, 0-100% EA/hexanes to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(4-(benzyloxy)phenyl)vinyl)thiazolo[5,4-b]pyridine as an orange solid. MS (ESI) m/z: calculated: 524.2; Observed: 525.1 (M++1).
Reaction SMILES: [C:1]([O:7][C@@H:8]1[C@@H:13]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:12]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@@H:11]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:10][C@H:9]1[O:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][C:44]=2/[CH:46]=[CH:47]/[C:48]2[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=2)[NH:39][N:38]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>O1CCCC1.[C].[Pd]>[C:1]([O:7][C@@H:8]1[C@@H:13]([O:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:18])[CH3:19])[C@H:12]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@@H:11]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:32])[CH3:33])[O:10][C@H:9]1[O:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][C:44]=2[CH2:46][CH2:47][C:48]2[CH:49]=[CH:50][N:51]=[CH:52][CH:53]=2)[NH:39][N:38]=1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(/C=C/c4ccncc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(CCc4ccncc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[(E)-2-(pyridin-4-yl)vinyl]-1H-indazole (0.13 g) in tetrahydrofuran (6 mL) was added 10% palladium-carbon powder (26 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(pyridin-4-yl)ethyl]-1H-indazole (0.13 g). This material was dissolved in methanol (6 mL). To the solution was added sodium methoxide (28% methanol solution, 0.12 mL), and the mixture was stirred at 50° C. overnight. To the reaction mixture was added acetic acid (0.05 mL), and the resulting mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=5/1 containing triethylamine at 3%) to give the title compound (70 mg).
Reaction SMILES: [CH2:1]([N:8]([C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:25]([N:27]([CH:41]([CH3:43])[CH3:42])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)=[O:26])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[O:14][C:13]([CH3:50])([CH2:44][O:45]S(C)(=O)=O)[C:12]1=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:62]1(O)[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([N:8]([C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:25]([N:27]([CH:41]([CH3:43])[CH3:42])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)=[O:26])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[O:14][C:13]([CH3:50])([CH2:44][O:45][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:12]1=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(COS(C)(=O)=O)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(COc1ccccc1)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 29.3 %

Procedure:
A solution of tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-2-{[(methylsulfonyl)oxy]methyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate (170 mg), phenol (18 mg) and cesium carbonate (186 mg) in N,N-dimethylformamide (2 ml) was stirred at 80° C. for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (49 mg).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:44])[C:7]([O:31][C:32]1[CH:33]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=[CH:36][CH:37]=1)([CH3:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)C.C(OC(=O)C(C)(OC1C=CC=CC=1)CC1C=CC(OCCC2N=C(C3CCCCC3)OC=2C)=CC=1)C>C(O)C>[C:34]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=[CH:36][CH:37]=[C:32]([O:31][C:7]([CH3:30])([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][C:18]3[N:19]=[C:20]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[O:21][C:22]=3[CH3:23])=[CH:13][CH:14]=2)[C:6]([OH:44])=[O:5])[CH:33]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)Oc1cccc(-c2ccccc2)c1
Agent: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2cccc(-c3ccccc3)c2)C(=O)O)cc1
Temperature: 25 °C

Procedure:
5N NaOH (0.5 mL) was added to a solution of 2-(Biphenyl-3-yloxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionic acid ethyl ester and 3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionic acid ethyl ester in ethanol (4 mL). The resultant mixture was refluxed under an atmosphere of nitrogen for 2 h, then cooled to ambient temperature. The reaction mixture was concentrated in vacuo, diluted with 1N HCl, and extracted with CH2Cl2. The organic layer was dried through a Varian ChemElut cartridge, concentrated in vacuo, and purified by LCMS. 1H NMR (400 MHz, CDCl3): δ 7.51 (d, 2H, J=7.82 Hz), 7.41 (t, 2H, J=7.04 Hz), 7.35-7.24 (m, 2H), 7.18 (d, 3H, J=8.21 Hz), 7.12-7.11 (m, 1H), 6.86 (d, 1H, J=8.60 Hz), 7.82 (d, 2H, J=8.60 Hz), 4.13 (t, 2H, J=5.47 Hz), 3.26 (d, 1H, J=14.08 Hz), 3.14 (d, 1H, J=14.08 Hz), 2.95 (t, 3H, J=5.47 Hz), 2.29 (s, 3H), 2.00 (d, 2H, J=12.51 Hz), 1.79 (d, 2H, J=13.30 Hz), 1.70-1.21 (m, 8H). MS [EI+] 540 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH2:4]O.C1OC2C=CC(C[Cl:19])=CC=2O1.S(Cl)(Cl)=O>CCOCC>[CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH2:4][Cl:19]
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: COc1ccc(CO)c(C)c1C
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: COc1ccc(CCl)c(C)c1C

Procedure:
1 g (6.016 mmol) of 2,3-dimethyl-4-methoxybenzyl alcohol (Aldrich, Steinheim, FRG) and 4.8 g of diisopropylaminomethylpolystyrene (polyhunig base, see Ex. 44a) in 21 ml of abs. ether are treated dropwise, at from 0° C. to 5° C. and over the space of approximately 25 min, with 0.482 ml of thionyl chloride. After the reaction has ended, the mixture is filtered with suction and the solvent and the excess reagent are removed. The residue, which is the desired title compound, is subjected, without purification, to further processing. TLC Rf (hexane:ethyl acetate 4:1)=0.59. IR(CH2Cl2) inter alia: 1599, 1485, 1466 und 1107 cm-1. 1H-NMR (200 MHz, CDCl3): 7.14 (d, 1H); 6.69 (d, 1H); 4.64 (s, 2H); 3.82, 2.34 and 2.18 (each s, each 3H).
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@H:9]2[O:14][C@H:13]([CH2:15][NH2:16])[C@@H:12](O)[C@H:11](O)[C@H:10]2O)[C@H:4]([OH:20])[C@@H:3]([O:21][C@H:22]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([NH2:31])[C@H:23]2[OH:32])[C@@H:2]1[NH2:33].O.C([N:37](CC)CC)C.C(OC(N=[N+]=[N-])=O)(C)(C)C>N1C=CC=CC=1>[CH2:12]1[C@@H:13]([CH2:15][NH2:16])[O:14][C@H:9]([O:8][C@H:5]2[C@H:4]([OH:20])[C@@H:3]([O:21][C@H:22]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([NH2:31])[C@H:23]3[OH:32])[C@H:2]([NH2:33])[CH2:1][C@@H:6]2[NH2:7])[C@H:10]([NH2:37])[CH2:11]1
Reactant: CCN(CC)CC
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CC(C)(C)OC(=O)N=[N+]=[N-]
Solvent: O
Solvent: c1ccncc1
Product: NC[C@@H]1CC[C@@H](N)[C@@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
For instance, 6'-N-t-butoxycarbonylkanamycin may be prepared in a high yield by reacting kanamycin in solution in a mixture of pyridine, water and triethylamine with a 1 to 3 molar proportion of t-butoxycarbonyl azide added dropwise thereto under agitation, stirring the admixture at ambient temperature overnight, concentrating the reaction mixture to dryness in vacuo and then purifying the solid residue in a column chromatography with a cation-exchange resin such as Amberlite CG 50 (NH4 form), while recovering the unreacted kanamycin. Moreover, 2',6'-di-N-t-butoxycarbonylkanamycin B or 3',4'-dideoxykanamycin B may be prepared in a high yield, for example, by reacting kanamycin B or 3',4'-dideoxykanamycin B in solution in a mixture of pyridine, water and triethylamine with a 2-3 molar proportion of t-butoxycarbonyl azide added dropwise thereto under agitation, stirring the admixture at ambient temperature overnight, concentrating the reaction mixture to dryness in vacuo, and then purifying the solid residue in column chromatography with a cation-exchange resin such as Amberlite CG 50 (NH4 form). When this preparation procedure is repeated with 2 molar proportions or less of t-butoxycarbonyl azide, there may be obtained 6'-N-t-butoxycarbonyl-kanamycin B or 3',4'-dideoxykanamycin B in a high yield. 6'-N-t-butoxycarbonyl-kanamycin B or 3',4'-dideoxykanamycin B once isolated may also be converted into the 2',6'-di-N-t-butoxycarbonyl derivative by further reacting with 1 to 2 molar proportions of t-butoxycarbonyl azide in a similar manner. The compounds of the formula (IV) prepared in the above procedures may be employed as a starting compound in the process of this invention without purification.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:21]=[C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[S:19][C:18]=3[S:26]([NH:29]C(C)(C)C)(=[O:28])=[O:27])[CH:14]=[CH:15][CH:16]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.B(Cl)(Cl)Cl.N1(C2C=CC=CN=2)CCCC1.Cl[C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:53]([O:52][C:50]([NH:29][S:26]([C:18]1[S:19][C:20]([CH2:22][CH:23]([CH3:24])[CH3:25])=[CH:21][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[CH:12]=1)(=[O:28])=[O:27])=[O:51])[CH2:54][CH2:55][CH3:56]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(Cn3cnc4ccccc43)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2cnc3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 3-(3-benzoimidazol-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (67.6 mg, 0.14 mmol; see step (a)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (41.6 mg, 0.28 mmol) and butyl chloroformate (178.4 μL, 1.40 mmol) and the reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq.) was added to the reaction mixture, which was then extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the title compound in 70% yield, over two steps, (51.6 mg, 0.098 mmol).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]#[C:31][C:32]([CH3:35])([OH:34])[CH3:33])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]#[C:31][C:32]([OH:34])([CH3:33])[CH3:35])=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1C#CC(C)(C)O
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1C#CC(C)(C)O

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.32 mmol) and 4-(6-chloro-2-methylpyridin-3-yl)-2-methylbut-3-yn-2-ol (67 mg, 0.32 mmol) as starting materials.
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:15])([F:14])[C:8](=[O:13])[CH2:9][CH2:10][CH2:11]O.[Br:16]Br>CCOCC>[F:6][C:7]([F:15])([F:14])[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][Br:16]
Reactant: O=C(CCCO)C(F)(F)F
Reactant: BrBr
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(CCCBr)C(F)(F)F
Temperature: -5 °C
Reaction time: 8 h

Procedure:
A 500 mL three neck round bottom flask, fitted with dropping funnel, magnetic stirrer, ice-salt bath, and argon inlet is charged with 125 mL of dry dimethylformamide, 29 g(35.7 mM) of trifluoro-5-hydroxy-2-pentanone. This mixture was cooled to -5° C. and 11.5 g(71.6 mM) of bromine was added dropwise over a two hour period. After stirring overnight at ambient temperature the reaction mixture was distilled through a 30 cm vigreaux column at 2.0 mm of pressure. Two fractions were collected; the first fraction from 27°-35° C. and the second fraction at 35°-70° C. The second fraction was partitioned between water and ethyl ether, the organic layer was washed with water (3×100 mL, dried (anhydrous MgSO4), and evaporated under reduced pressure at ambient temperature to give 40 g of a colorless oil mixture of dimethyl formamide, ether, and the desired product which was used in the next reaction without further purification.
Reaction SMILES: C([O-])(O)=O.[Na+].Cl.[NH2:7][OH:8].ClCCl.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>O.C(OCC)(=O)C>[C:16]1([O:15][C:13](=[O:14])[NH:7][OH:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C(NO)Oc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
To a stirred solution of NaHCO3 (60.5 g) in water (200 mL) in a 2 L beaker was added portion-wise over 15 min 27.5 g of hydroxylamine hydrochloride. Once the bubbling subsided, dichloromethane (200 mL) was added to the reaction mixture and cooled to 5° C. Phenyl chloroformate (50 g) was then added at a steady rate to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. Ethyl acetate (100 mL) was employed to bring the reaction mixture to a transparent solution. The organic layer was separated, washed with brine (200 mL) and dried over MgSO4. The organic solvent was removed under reduced pressure to give the title compound (38.20 g) as a white solid melting at 104-107° C.
Reaction SMILES: [Li+].[OH-].[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([NH2:29])[C:22]([N+:26]([O-:28])=[O:27])=[N:23][C:24]=1I.[Cl-].[NH4+]>O1CCOCC1.O>[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]([C:24]2[N:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]([NH2:29])=[CH:20][C:19]=2[Cl:18])=[CH:5][CH:4]=1
Reactant: Nc1cc(Cl)c(I)nc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(Cl)c(-c2ccc(-c3ccccc3)cc2)nc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
LiOH (5.73 ml, 17.19 mmol) was added to a stirred mixture of 4-biphenylboronic acid (1.498 g, 7.57 mmol), 5-chloro-6-iodo-2-nitropyridin-3-amine (2.0595 g, 6.88 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.562 g, 0.688 mmol) in dioxane (15 ml)/water (4 ml) and the mixture was stirred under N2 at 80° C. for 2 h. The mixture was cooled, then aqueous ammonium chloride (saturated, 100 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic fractions were washed with brine (saturated, 80 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel Biotage™40M, eluting with 0-20% EtOAc/hexane to give the title compound. LC-MS: calculated for C17H12ClN3O2 325.06 observed m/e: 326.09 (M+H)+ (Rt 1.28/2 min).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][NH2:23].[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22]/[N:23]=[CH:12]/[C:11]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:10]=1[NH:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=Cc1cccc(F)c1NCCN1CCOCC1
Reactant: CC(C)(C)CCN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC/N=C/c1cccc(F)c1NCCN1CCOCC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
2-(2-Morpholinoethylamino)-3-fluorobenzaldehyde (495 mg, 1.962 mmol), 3,3-dimethylbutan-1-amine (400 μL, 2.973 mmol), and MgSO4 were added to toluene (15 mL) and the reaction stirred in a 70° C. oil bath overnight. The oil bath temperature was raised to 100° C. for 2.5 hours, then heat was removed, solvent and volatiles removed under high vacuum on a rotary evaporator at 35° C. to give 2-((E)-(3,3-dimethylbutylimino)methyl)-6-fluoro-N-(2-morpholinoethyl)benzenamine. The crude material was carried on to the next reaction. FIA: 336.49 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[C:25]([Br:29])(Br)(Br)Br.OC[CH2:32][S:33][C:34]1[S:38][C:37]([NH2:39])=[N:36][CH:35]=1>C(Cl)Cl.O>[Br:29][CH2:25][CH2:32][S:33][C:34]1[S:38][C:37]([NH2:39])=[N:36][CH:35]=1
Reactant: BrC(Br)(Br)Br
Reactant: Nc1ncc(SCCO)s1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Nc1ncc(SCCBr)s1

Procedure:
Triphenylphosphine (12.1 g), imidazole (3.86 g), and carbon tetrabromide (4.44 g) were added to a suspension of 5-(2-hydroxyethylthio)thiazol-2-amine (2.00 g) in methylene chloride (74.6 mL) under cooling with ice, and the mixture was stirred under cooling with ice for 4 hours. Methylene chloride (200 mL) and water (100 mL) were added to the reaction mixture, and the mixture was extracted. The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (neutral spherical silica gel, ethyl acetate:hexane=1:10 and then 1:2) and washed with hexane to give the title compound as white powder crystals (1.06 g, yield: 39%).
Reaction SMILES: [F:1][CH:2]([F:42])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:41])=[C:21]([NH:23][C:24]([N:26]4[CH2:33][C:30]5([CH2:32][CH2:31]5)[N:29](CC5C=CC=CC=5)[CH2:28][CH2:27]4)=[O:25])[CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[H][H]>CO.[Pd]>[F:42][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:41])=[C:21]([NH:23][C:24]([N:26]4[CH2:33][C:30]5([CH2:32][CH2:31]5)[NH:29][CH2:28][CH2:27]4)=[O:25])[CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1NC(=O)N1CCN(Cc2ccccc2)C2(CC2)C1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1NC(=O)N1CCNC2(CC2)C1

Procedure:
N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(phenylmethyl)-4,7-diazaspiro[2.5]octane-7-carboxamide D8a (prepared as described for D1; 0.2 mmol) is dissolved in 10 mL MeOH followed by addition of 5% mol of Pd/C (10% in weight). The flask is charged with a hydrogen balloon for 12 h stiffing. The mixture is filtered over a celite pad and the filtrate is concentrated to afford N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4,7-diazaspiro[2.5]octane-7-carboxamide D8, which is used without further purification. MS (m/z) (M+1)+: 523.1.