Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[CH3:6][C:7]([CH3:13])([CH:11]=[CH2:12])[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O>[CH3:6][C:7]([CH3:13])([CH:11]=[CH2:12])[CH2:8][CH2:9][O:10][S:22]([CH3:21])(=[O:24])=[O:23]
Reactant: C=CC(C)(C)CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C=CC(C)(C)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
In a tetrahydrofuran (30 ml) solution of 3,3-dimethyl-4-penten-1-ol (3.6 g), triethylamine (4.1 g) and methanesulfonyl chloride (4.3 g) were added at 0° C., followed by raising the temperature to room temperature and further stirring for 30 minutes. Water was added thereto and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to obtain a crude product (5.7 g) of methanesulfonic acid 3,3-dimethyl-4-pentenyl ester. This crude product was subjected to a subsequent reaction without being purified.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.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.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[N:14]=1)[N:11]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Temperature: 120 °C
Yield: 57.1 %

Procedure:
A mixture of 8-bromo-5-hydroxy-2-oxo-1-phenethyl-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (54 mg, 0.11 mmol), 3-tributylstannanyl-pyridine (0.054 mL, 0.17 mmol) and PdCl2(PPh3)2 (16 mg, 0.023 mmol) in 3 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and water were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (10-90% EtOAc/hexanes) to give 30 mg of the title compound as a yellow solid. MS: (+) m/z 478.39 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[C:3]=1[CH3:26].[CH3:27][O:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:33]5[CH:32]=[CH:31][N:30]=[C:29]([O:28][CH3:27])[CH:34]=5)[C:3]([CH3:26])=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1cc(B(O)O)ccn1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C
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: COCCOC
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C)ccn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
A solution of N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (38 mg, 0.1 mmol) in DME (1 mL) was added to a reaction tube containing 2-methoxypyridin-4-ylboronic acid (46 mg, 0.15 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol). Saturated Na2CO3 solution was added (100 μL) and the reaction was stirred at 80° C. overnight. The reaction was filtered, concentrated and purified by column chromatography (0-50% ethyl acetate in hexanes) to obtain 40 mg (44%) of a clear oil. ESI-MS m/z calc. 453.4. found 454.3 (M+1)+. Retention times: 2.06 minutes. H NMR (400 MHz, DMSO) 8.85 (s, 1H), 8.20 (d, J=5.2 Hz, 1H), 7.86 (s, 1H), 7.54 (d, J=1.5 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.32 (dd, J=1.6, 8.3 Hz, 1H), 6.97 (dd, J=1.2, 5.2 Hz, 1H), 6.77 (s, 1H), 3.87 (s, 3H), 2.31 (s, 3H), 2.09 (s, 3H), 1.51-1.48 (m, 2H), 1.17-1.15 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.ClC[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(Cl)[Cl:65].CO>CN(C)C=O>[Cl:65][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:28]
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: ClCCl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1cccc(Cl)c1
Yield: 33 %

Procedure:
Preparation of example 44 from the title compound of Example 7 (0.03 g, 0.11 mmol), 3-Chloromethyl-benzoic acid (0.025 g, 0.16 mmol), triethylamine (0.078 mL, 0.43 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.062 g, 0.11 mmol) and N,N-dimethylformamide (0.05 M, 2.0 mL) was carried out analogously to Example 11. Silica gel chromatography (95:5 CH2Cl2/methanol) afforded the title compound (0.015 g) as a yellow powder in 33% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH:14]1([C:20]([N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(C1CCCCC1)N1CCN(Cc2ccccc2)CC1
Reaction time: 0.75 h
Yield: 74 %

Procedure:
To a solution of 21.2 g (0.12 mole) of 1-benzylpiperazine in 100 ml of CHCl3 was added dropwise over a period of 30 minutes a solution of 15.0 g (0.10 mole) of cyclohexanecarbonyl chloride in 50 ml of CHCl3. The mixture was allowed to stand at room temperature during 45 minutes and was made basic with 5 g of sodium hydroxide in 50 ml of water. The nonaqueous layer was separated, dried over sodium sulphate and concentrated. The residue was distilled b.p. 150°-56° C. at 0.1-0.2 mmHg to give 21.2 g of 1-cyclohexanecarbonyl-4-benzylpiperazine.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O.[CH2:14]([NH2:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(O)(C)C>[CH2:14]([NH:32][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
60 g of D-galactose were suspended in 330 ml of isopropanol and 170 ml of water and heated to 50°. After addition of 90 g of stearylamine, the mixture was stirred until all the amine had gone into solution. On cooling, the glycosylamine crystallised out. The solid material was filtered off with suction, washed consecutively with ethanol and with ether and dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][NH:6]2.Cl.CN(C)CCCN=C=NCC.[N:25]1([C:31]2[N:32]=[C:33]([CH2:38][C:39]([O-])=[O:40])[NH:34][C:35](=[O:37])[CH:36]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[Na+].O>CN(C)C=O.N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][N:6]2[C:39](=[O:40])[CH2:38][C:33]1[NH:34][C:35](=[O:37])[CH:36]=[C:31]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:32]=1
Reactant: CC1(C)CNc2cccc(F)c21
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
150 mg of 4-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole [reference example 2c] and 279 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 261 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (obtained in step 2c of example 1c) in 5 ml of N,N-dimethylformamide and 5 ml of pyridine. The reaction mixture is stirred at ambient temperature for 16 hours and then 30 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by trituration from a mixture of ethyl acetate and diisopropyl ether, so as to give 194 mg of 2-[2-(4-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one, the characteristics of which are the following:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17](O)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH:22]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([C:23]5[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=5)=[CH:32][CH:31]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: Nc1ccc(-c2cccnc2)cc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(-c5cccnc5)cc4)nn23)c1

Procedure:
[7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-pyridin-3-yl-phenyl)-amine was prepared from 7-(3-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 4-pyridin-3-yl-phenylamine in an analogous manner to Example 1052a. Product isolated as a yellow solid (66 mg, 49%). m.p.=216-218° C.; LCMS (m/e) 442 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.87 (s, 1H), 8.79 (s, 1H), 8.71 (s, 1H), 8.56 (d, 1H, J=4.3 Hz), 8.42 (d, 1H, J=7.9 Hz), 7.95 (d, 1H, J=7.8 Hz), 7.90 (d, 1H, J=8.0 Hz), 7.78-7.68 (m, 3H), 7.64 (d, 2H, J=8.6 Hz), 7.36 (dd, 1H, J=4.9 and 7.7 Hz), 7.09 (d, 1H, J=4.8 Hz), 6.98 (s, 1H), 6.90 (d, 1H, J=4.8 Hz), 3.08 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[Cl:8][S:9]([C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([CH3:22])=[CH:15][N:16]=[CH:17]2)(=[O:11])=[O:10]>>[ClH:8].[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:9]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[C:14]([CH3:22])=[CH:15][N:16]=[CH:17]3)(=[O:10])=[O:11])[CH2:7]1
Reactant: C[C@H]1CNCCN1
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Product: Cc1cncc2cccc(S(=O)(=O)N3CCN[C@@H](C)C3)c12
Product: Cl
Yield: 95.2 %

Procedure:
Using 0.60 g of (S)-2-methylpiperazine and 0.49 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.66 g of the objective compound (white crystals).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]3[CH2:15][CH2:14][N:13]=[C:11]3[S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.N.[H][H]>[Pt].CO>[N:13]1[CH2:14][CH2:15][N:10]2[C:9]3=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=[C:8]3[S:12][C:11]=12
Reactant: O=[N+]([O-])c1cccc2c1N1CCN=C1S2
Reactant: [H][H]
Agent: [Pt]
Agent: N
Solvent: CO
Product: Nc1cccc2c1N1CCN=C1S2

Procedure:
A mixture of 5.5 parts of 2,3-dihydro-5-nitroimidazo[2,1-b]benzothiazole and 160 parts of methanol, saturated with ammonia is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from 1-butanol. The product is filtered off and dried, yielding 3 parts of 2,3-dihydroimidazo[2,1-b]benzothiazol-5-amine; mp. 229.2° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:11](OC(OCC)OCC)C.[N-:21]=[N+:22]=[N-:23].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[N:4]1[CH:11]=[N:23][N:22]=[N:21]1
Reactant: COc1ccc(N)c(Br)c1
Reactant: CCOC(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-n2cnnn2)c(Br)c1
Temperature: 75 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
2-Bromo-4-methoxyaniline (1.2 g, 6 mmol; Desc. 7a) was dissolved in glacial acetic acid (10 ml) and heated to 75° C. To this solution was added triethylorthoformate (2.5 ml, 15 mmol) and heated at 75° C. for 1 hour. Sodium azide (1.16 g, 18 mmol) was added portionwise and reaction heated at 75° C. for a further 3 hours and stirred at ambient temperature for 24 hours. The reaction was diluted with water (100 ml) and product extracted into ethyl acetate (3×70 ml). The combined organics were washed with brine (100 ml), dried over magnesium sulphate and the solvent removed in vacuo. Medium pressure chromatography eluting with 40% ethyl acetate/hexane afforded the title compound as a white solid (1.5 g, 90%). 1H NMR (360 MHz, d6 -DMSO) δ 3.88 (3H, s), 7.20 (1H, dd, J 2.7 Hz, J 8.8 Hz), 7.51 (1H, d, J 2.7 Hz), 7.68 (1H, d, J 8.8 Hz), 9.83 (1H, s).
Reaction SMILES: [C:1]([O-])(=[O:13])[CH2:2]CCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.CC(CCCCN=C=O)C(N=C=O)(C)C.[N-:53]=[C:54]=[O:55].[C:56]([O:61]CCO)(=[O:60])[C:57]([CH3:59])=[CH2:58]>CC(C)=O>[C:56]([OH:61])(=[O:60])[C:57]([CH3:59])=[CH2:58].[NH2:53][C:54]([O:13][CH2:1][CH3:2])=[O:55]
Reactant: [N-]=C=O
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: C=C(C)C(=O)OCCO
Agent: CC(CCCCN=C=O)C(C)(C)N=C=O
Agent: CCCC[Sn+2]CCCC
Solvent: CC(C)=O
Product: C=C(C)C(=O)O
Product: CCOC(N)=O
Reaction time: 72 h

Procedure:
212 g (approx. 0.2 mol) Tego-Diol BD-1000, 140 g acetone and 0.1 g dibutyltin dilaurate are introduced first into a 2I 3-neck flask equipped with thermometer, reflux cooler, mechanical stirrer and drying tube, and 84 g (0.4 mol) trimethyl-hexamethylene diisocyanate added in measured does, accompanied by cooling, over a period of 30 minutes. The reaction mixture is stirred for 20 hours at room temperature until the isocyanate content has fallen to 3.7%. 53 g hydroxyethyl methacrylate is added, accompanied by cooling. After 72 hours at room temperature, an isocyanate value of 0.1 is recorded, at which the reaction is ended. The ethyl acetate can be distilled off in fine vacuum.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([NH:10][C:11]2[C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[F:28])=[C:18]([F:29])[C:14]3[N:15]=[CH:16][O:17][C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C[N+]1([O-])CC[O:34]CC1.[OH2:38]>C1COCC1.[Os](=O)(=O)(=O)=O>[OH:38][CH:2]([CH2:3][OH:34])[CH2:1][C:4]1([S:7]([NH:10][C:11]2[C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[F:28])=[C:18]([F:29])[C:14]3[N:15]=[CH:16][O:17][C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH2:6][CH2:5]1
Reactant: O
Reactant: C=CCC1(S(=O)(=O)Nc2cc3ocnc3c(F)c2Nc2ccc(I)cc2F)CC1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc2ocnc2c(F)c1Nc1ccc(I)cc1F)C1(CC(O)CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
To a solution of 1-allyl-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide (100 mg, 0.38 mmol) in THF (10 mL) was added N-methylmorpholine-N-oxide (44 mg, 0.38 mmol) followed by osmium tetraoxide (10 mg, 0.04 mmol) and water (0.5 mL). The resultant was stirred at room temperature overnight. The mixture was concentrated and then diluted with ethyl acetate. The organic layer was washed with water, saturated NaHCO3 (aq.) and brine sequentially, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel to give the product as white solid (30 mg, 28.2% yield). 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.46-7.36 (m, 2H), 7.30-7.20 (m, 1H), 6.82 (s, 1H), 6.45-6.32 (m, 1H), 4.40-4.26 (m, 2H), 4.20-4.10 (m, 1H), 3.75-3.60 (m, 1H), 2.86-2.79 (m, 1H), 1.30-1.25 (m, 2H), 1.15-1.20 (m, 4H). MS APCI (+) m/z: 566.3, [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])N.S(=O)(=O)(O)[OH:11].N([O-])=O.[Na+].CCCCCC>O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Cl
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: Cc1ccc(O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
283 g of 3-chloro-4-methylaniline, 1000 ml of water and 500 ml of concentrated sulfuric acid were mixed, initially at room temperature. The temperature of the mixture rose to 95° C. The mixture was stirred at room temperature for 30 minutes, cooled to 5° C. and a solution of 145 g of sodium nitrite in 500 ml of water was slowly added (1.5 hours) to the stirred mixture at 5°-10° C., then the mixture was stirred at about 5° C. for one hour. The resulting solution was added over two hours to a stirred solution of 1.2 liters of concentrated sulfuric acid in 2 liters of water, at 105°-110° C., and the resulting mixture was stirred at 110° C. for one hour, then held at room temperature for 18 hours. Then 3.5 liters of hexane was added, the mixture was stirred for 30 minutes, allowed to stand, and the two liquid phases were separated. The hexane phase was filtered, washed with water, dried (MgSO4) and concentrated to dryness to give crude (91%) 3-chloro-4-methylphenol (1A).
Reaction SMILES: N#N.[C:3]1([CH3:17])[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:32]([Si:36]([CH3:53])([CH3:52])[O:37][CH:38]([C:40]1[O:41][C:42]([CH2:45][N:46]2[N:50]=[C:49]([NH2:51])[CH:48]=[N:47]2)=[CH:43][N:44]=1)[CH3:39])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:32]([Si:36]([CH3:53])([CH3:52])[O:37][CH:38]([C:40]1[O:41][C:42]([CH2:45][N:46]2[N:50]=[C:49]([NH:51][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:5]3[CH:4]=[C:3]([CH3:17])[CH:8]=[CH:7][CH:6]=3)=[O:16])[CH:48]=[N:47]2)=[CH:43][N:44]=1)[CH3:39])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc(N)n2)o1
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-m-tolyl-oxazole-4-carboxylic acid (31 mg, 0.16 mmol) in CH2Cl2 (1.0 mL) was treated at rt with HOBt (25 mg, 0.19 mmol), EDC (74 mg, 0.38 mmol), DMAP (5 mg, 0.04 mmol) and the resulting mixture was stirred at rt for 30 min. 2-{2-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-ylamine (50 mg, 0.16 mmol) in CH2Cl2 (0.6 mL) was then added and the resulting mixture was stirred at rt for 16 h. CH2Cl2 (20 mL) followed by water (15 mL) were added and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with water, brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a brown oil. LC-MS-conditions 02: tR=1.20 min, [M+H]+=509.55.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>C(#N)C>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 97.2 %

Procedure:
To a stirred solution of compound ethyl 2-(4-hydroxyphenyl)acetate (30 g, 0.16 mol) in acetonitrile (300 mL) was added K2CO3 (114.9 g, 0.83 mol) and 2-(chloromethyl) quinoline (42.7 g, 0.19 mol) at RT. The reaction mixture was refluxed for 16 h, filtered and the resulting solid residue was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (50 g, 93%) as a solid.
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([CH:18]([C:24](OCC)=[O:25])[C:19](OCC)=[O:20])[CH:16]=[CH2:17].[Na]>>[CH2:15]([CH:18]1[C:19](=[O:20])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:24]1=[O:25])[CH:16]=[CH2:17]
Reactant: c1ccc(NNc2ccccc2)cc1
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Agent: [Na]
Product: C=CCC1C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Yield: 30.2 %

Procedure:
Prepared from 1,2-diphenylhydrazine (5.2 g; 28.0 mmol), diethyl allylmalonate (5.0 g; 25.0 mmol), and sodium (0.58 g; 25.0 mmol) using the procedure of Example 3. The crude product was recrystallized from absolute ethanol to give 2.21 g (30%) tan crystals, mp 135-137° C.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[CH2:3][C:4]#[N:5].[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C.O>[OH:17][N:16]=[C:3]([C:2](=[O:1])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=1)[C:4]#[N:5]
Reactant: O=N[O-]
Reactant: N#CCC(=O)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(=NO)C(=O)c1cccc(C(F)(F)F)c1
Temperature: 15 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of 30.0 g of the title compound of Step A in 200 mL of glacial acetic acid was added dropwise a solution of 11.7 g of sodium nitrite in 35 mL of water while maintaining the reaction temperature at about 15° C. with external cooling. Following addition, the external cooling was removed and the suspension was stirred at room temperature overnight and then poured into excess water (about 400 mL). The aqueous suspension was acidified by dropwise addition of concentrated hydrochloric acid (until red to litmus paper) and then extracted with methylene chloride. The organic solution was dried (MgSO4), filtered and concentrated to give 32.5 g of the title compound of Step B as an oil. 1H NMR (CDCl3): δ 8.3 (s,1H), 8.2 (m,1H), 7.9 (m,1H), 7.65 (m,1H); IR (neat) 1670.2 cm-1.