Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2S(C1C=CC=CC=1)(=O)=O.[CH3:20][CH:21]([N:23]1[C:27]([C:28]([NH:30][C:31]2[CH:39]=[C:38]([Sn](C)(C)C)[CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][N:35]3S(C2C=CC=CC=2)(=O)=O)=[O:29])=[CH:26][CH:25]=[N:24]1)[CH3:22].C1(S)C=CC=CC=1>CN(C=O)C>[NH:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([C:38]3[CH:37]=[C:36]4[C:32]([CH:33]=[N:34][NH:35]4)=[C:31]([NH:30][C:28]([C:27]4[N:23]([CH:21]([CH3:20])[CH3:22])[N:24]=[CH:25][CH:26]=4)=[O:29])[CH:39]=3)[C:3]=2[CH:4]=[N:5]1
Reactant: CC(C)n1nccc1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(Br)cccc21
Agent: Sc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2cccc3[nH]ncc23)cc2[nH]ncc12
Temperature: 135 °C
Reaction time: 8 h

Procedure:
4-Bromo-1-(phenylsulfonyl)-1H-indazole (61 mg) in DMF (0.4 ml) was added to 1-(1-Methylethyl)-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1H-pyrazole-5-carboxamide (100 mg) in DMF (0.4 ml). Solvias catalyst (4 mg) was added and the sealed vessel was heated in the Anton Paar microwave at 135° C. for 20 min. PS-thiophenol resin was added and the reaction was stirred overnight before being filtered onto a C18SPE cartridge, pre-washed with 0.1% TFA, with acetonitrile. The cartridge was washed with 0.1% TFA in acetonitrile and the collected solvent was removed under a stream of nitrogen. The residue was dissolved in DMSO (1 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo. The residue was dissolved in isopropanol (0.3 ml), 2M sodium hydroxide (aq) (0.3 ml) was added and the reaction was left at room temperature overnight, then heated to 60° C. for 2 h. The solvent was removed under a stream of nitrogen and the residue was dissolved in DMSO (0.5 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo to give title compound, 15 mg.
Reaction SMILES: [C:1]1([C:10]([OH:12])=O)[CH:2]=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:35]1([C@H:41]([NH2:44])[CH2:42][CH3:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[C:35]1([C@H:41]([NH:44][C:10]([C:1]2[CH:2]=[CH:3][N:4]3[C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]3)=[O:12])[CH2:42][CH3:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)c1ccn2c1CCCC2
Reactant: CC[C@@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1ccn2c1CCCC2)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid (Comp. No. 8b) (6.22 g, 37.7 mmol) in dimethylformamide (125 ml) was added 1-hydroxybenzotriazole (5.60 g, 41.4 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.94 g, 41.4 mmol). The mixture was stirred for 30 min at 25° C., then (R)-1-phenyl-propylamine (6.11 g, 45.2 mmol) was added and the mixture was stirred at 25° C. overnight and at 45° C. for additional 24 h. The mixture was concentrated in vacuo to 20% of its volume, 70 ml water and 30 ml ethyl acetate were added and the mixture was extracted 3 times with ethyl acetate, the combined organic layers were washed with 50 ml 1 N aqueous hydrochloric acid, then 50 ml aqueous sodium hydrogencarbonate, and evaporated to dryness. The crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 9.33 g (88%) of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid ((R)-1-phenyl-propyl)-amide as a white solid. LC/MS (method 5): Rt=3.15 min; m/z=283.15 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20].O1CCCC1.[H-].[Na+].Cl[C:29]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:30]>C(OCC)C>[CH2:32]([O:31][C:29]([O:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20])=[O:30])[CH:33]([CH3:35])[CH3:34]
Reactant: COC1C(O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reactant: CC(C)COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC1C(OC(=O)OCC(C)C)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Yield: 26.7 %

Procedure:
To a solution of 6-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (14.1 mg) in freshly distilled tetrahydrofuran (0.5 ml) was added sodium hydride (6.0 mg, 60% oil dispersion) in one portion at 5° C. The mixture was stirred for half an hour at the same temperature and then isobutyl chloroformate (7 mg) was added thereto. The reaction mixture was stirred for 2 hours at ambient temperature and then diluted with diethyl ether. The organic layer was washed with brine, dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (elution by diethyl ether/n-hexane =1/3) to yield 6-isobutoxycarbonyloxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (5.1 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:9]([O:11][C:12]1[C:13](=O)[C:14](=[O:19])[C:15]=1[O:16]CC)[CH3:10]>C(O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:13]2[C:14](=[O:19])[C:15](=[O:16])[C:12]=2[O:11][CH2:9][CH3:10])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2ccc(Cl)nc2)c(=O)c1=O
Temperature: 80 °C
Yield: 43.5 %

Procedure:
5-Amino-2-chloropyridine (2.32 g, 18.0 mmol) in ethanol (50 mL) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione 3.07 g, 18.0 mmol) in ethanol (200 mL) at 70° C. over a period of 6 hours. The mixture was then heated at 80° C. for an additional 18 hours, filtered, and the solvents removed in vacuo. The crude product was suspended in 10% EtOH/EtOAc (30 mL) and adsorbed onto silica gel (15 g). Purification by flash chromatography on silica gel (eluted with 5% EtOH/EtOAc) provided 1.98 g of the desired product as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([S:9][CH2:10]C)[N:3]=1.CCO[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[NH2:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:1][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]=1
Reactant: CCSc1nc(N)cc(N)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1cc(N)nc(SC)n1)C(=O)OCC
Temperature: 135 °C
Reaction time: 0.67 h

Procedure:
A mixture of 4,6-diamino-2-ethylmercaptopyrimidine (9.95 g) and diethyl ethoxymethylene malonate (13.77 g) at 165° C. was stirred for 40 minutes, cooled to 135° C., stirred for 60 minutes, cooled to 25° C., and added to refluxing ethanol (700 mL). This mixture was treated with decolorizing carbon (NORIT®) stirred for 30 minutes, cooled, filtered, concentrated to 300 mL, heated until homogeneous, cooled, treated with water until cloudy, stored at 0° C. for 18 hours, and filtered. 1H NMR (300 MHz, DMSO-d6) δ 10.41 (d, 1H), 8.96 (d, 1H), 6.98 (s, 2H), 5.97 (s, 1H), 4.21 (q, 2H), 4.12 (q, 2H), 2.43 (s, 3H), 1.26 (t, 3H), 1.23 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>ClCCCl.CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: OC1CCc2ccc(F)cc21
Yield: 97.6 %

Procedure:
To a solution of 6-fluoro-indan-1-one (0.50 g, 3.3 mmol) in DCE (10 mL) and MeOH (10 mL) was added NaBH4 (0.25 g, 6.6 mmol). After 30 min the reaction was quenched with H2O (10 mL) and extracted with CH2Cl2 (3×20 mL). The organic layers were combined and dried to give the title compound (0.49 g, 97%). MS (ESI): mass calcd. for C9H7FO, 150.1; m/z found, 151.4 [M+H]+. 1H NMR (CDCl3): 7.23-7.13 (m, 1H), 7.09 (dd, J=8.6, 2.5 Hz, 1H), 6.99-6.90 (m, 1H), 5.21 (t, J=6.3 Hz, 1H), 3.13-2.91 (m, 1H), 2.85-2.68 (m, 1H), 2.63-2.44 (m, 1H), 2.09-1.74 (m, 2H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][CH:7]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:9][OH:10]>O.CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:6][CH:7]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][C:9]([OH:2])=[O:10]
Reactant: CC(C)CCCC(C)CCO
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)CCCC(C)CC(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of chromium trioxide (55.5 g, 0.555 mol) in water (68 ml) and 2M-sulphuric acid (12 ml) was added dropwise to a solution of 3,7-dimethyloctanol (43.7 g, 0.308 mol) in acetone (100 ml), the temperature was maintained at 40-60° C. and the reaction mixture was left stirring overnight. Acetone was carefully removed in vacuo, the reaction mixture was diluted in water and washed with diethyl ether (2×200 ml). The ethereal solution was washed with 10% sodium hydroxyde solution (200 ml); and the aqueous phase was acidified with 36% HCl (200 ml) and washed once more with diethyl ether (2×200 ml). The organic layer was dried (MgSO4) and the diethyl ether was removed in vacuo. The crude product was distilled to give a colourless oil.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:56])[CH2:14][N:12]2[CH2:13][C@@H:5]([CH2:6][C@:7]([C:52]([O:54][CH3:55])=[O:53])([C:22]3[CH:27]=[C:26]4[C:28]56[C@@H:39]([N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:50][CH3:51])[C@@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@H:37]([OH:47])[C@:33]3([CH2:48][CH3:49])[CH:34]=[CH:35][CH2:36][N:31]([C@H:32]53)[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH2:10][CH2:11]2)[CH2:4]1.[C:57](OC(=O)C)(=[O:59])[CH3:58]>>[CH3:1][CH2:2][C@@:3]1([OH:56])[CH2:14][N:12]2[CH2:13][C@H:5]([CH2:6][C@:7]([C:52]([O:54][CH3:55])=[O:53])([C:22]3[CH:27]=[C:26]4[C@:28]56[C@@H:32]7[C@:33]([CH2:48][CH3:49])([C@@H:37]([O:47][C:57]([CH3:58])=[O:59])[C@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@@H:39]5[N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:50][CH3:51])[CH:34]=[CH:35][CH2:36][N:31]7[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:9]=3[CH2:10][CH2:11]2)[CH2:4]1
Reactant: CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@@H]3C45CCN4CC=C[C@](CC)([C@H]45)[C@@H](O)[C@]3(O)C(=O)OC)C2)C1
Reactant: CC(=O)OC(C)=O
Product: CC[C@]1(O)C[C@@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Reaction time: 1 h

Procedure:
0.29 g of deacetyl-vinblastine is dissolved in 3 ml of acetic anhydride and the solution is allowed to stand for one hour at room temperature. The thus obtained vinblastine is isolated from the reaction mixture in the usual way and then converted into the sulfate salt. 0.28 g of vinblastine sulfate is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([F:39])[CH2:18][N:19]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[S:20]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH3:53]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([F:39])[CH2:18][N:19]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH3:53])=[CH:34][CH:33]=3)[S:20]([C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N(CC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c2ccc(O)cc2)cc1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCCOc1ccc(N(CC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 43 %

Procedure:
A solution of the product of Step 3 (15.9 mg, 0.023 mmol), potassium carbonate (13.6 mg, 0.098 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (8.5 mg, 0.041 mmol) in dimethylformamide (1.0 ml) was heated at 70° C. overnight. The reaction was diluted with EtOAc and washed with water several times, then brine. Column chromatography in 100% DCM (+0.2% TEA)-1% MeOH/DCM (+0.2% TEA) gave the pure product. Yield=43%.
Reaction SMILES: C1([C@H]([N:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)C)C=CC=CC=1.[C:20](Cl)(=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:21][C:20]([N:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C[C@H]1CCN([C@H](C)c2ccccc2)C1
Reactant: O=C(Cl)OCc1ccccc1
Product: CCOC(=O)C[C@H]1CCN(C(=O)OCc2ccccc2)C1

Procedure:
(3R)-Ethyl 1-[(R)-1-phenylethyl]pyrrolidine-3-acetate described in U.S. Pat. No. 621,101 is allowed to react with benzyl chlorocarbonate to give (3R)-ethyl 1-benzyloxycarbonylpyrrolidine-3-acetate.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].[CH3:20]I>CN(C=O)C.O>[CH3:20][N:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 2.1 g, 41.8 mmol) in DMF (80 mL) at 0° C. was added a solution of tert-butyl 3-nitrophenylcarbamate (18) (8.3 g, 34.9 mmol) in DMF (50 mL). The mixture was stirred at 0° C. for 0.5 hour before CH3I (4.9 mL, 52.35 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, diluted with water (200 mL), and extracted with DCM (60 mL×3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to afford tert-butyl methyl(3-nitrophenyl)carbamate (19) 8.8 g as yellow solid (yield 100%). LC-MS (ESI): m/z (M+1) 253.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([C:12]1[N:13]=[C:14]3[C:20]([CH:21]=[O:22])=[CH:19][N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]3=[N:16][CH:17]=1)=[N:5][NH:6]2.[H-].[Na+].I[CH3:34]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([C:12]1[N:13]=[C:14]3[C:20]([CH:21]=[O:22])=[CH:19][N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]3=[N:16][CH:17]=1)=[N:5][N:6]2[CH3:34]
Reactant: CI
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(F)cc(F)c34)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2c(F)cc(F)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
To a solution of 2-(4,6-difluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (890 mg, 2.1 mmol) in DMF (9 ml) at 0° C. was added sodium hydride (60% in mineral oil, 279 mg, 2.49 mmol). The reaction mixture was stirred at 0° C. for 10 min then iodomethane (0.18 ml, 2.9 mmol) was slowly added. The mixture was stirred at 0° C. for 30 min then at room temperature for 30 min. The reaction was quenched with sat'd NH4Cl, diluted with water and extracted with EtOAc (2×). The combined organics were washed with sat LiCl and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 20% to 100% EtOAc/heptane to provide 226 mg (22%) of 2-(4,6-difluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a yellow solid.
Reaction SMILES: [OH:1][NH:2][C:3]([NH2:5])=[O:4].Cl[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:17]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[C:20]([F:22])[CH:21]=2)=[CH:11][CH:10]=1)[CH3:8]>>[F:22][C:20]1[CH:19]=[C:18]([C:23]2([O:29][CH3:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:17]=[C:16]([S:15][C:12]2[CH:11]=[CH:10][C:9]([CH:7]([CH3:8])[O:1][NH:2][C:3]([NH2:5])=[O:4])=[CH:14][CH:13]=2)[CH:21]=1
Reactant: NC(=O)NO
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)Cl)cc3)c2)CCOCC1
Product: COC1(c2cc(F)cc(Sc3ccc(C(C)ONC(N)=O)cc3)c2)CCOCC1
Temperature: 60 °C
Yield: 32 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reactants were heated to 60° C. for 2 hours, hydroxyurea was reacted with 4-{3-[4-(1-chloroethyl)phenylthio]-5-fluorophenyl}-4-methoxytetrahydropyran to give N-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-methylbenzyloxy}urea in 32% yield, m.p. 84°-85° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[S:12](Cl)(=[O:14])=[O:13].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[S:12]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)(=[O:14])=[O:13]
Reactant: C1CCNCC1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.7 %

Procedure:
To a mixture of 2-methoxy-4-nitrobenzenesulfonylchloride (600 mg) and THF (5 mL), a mixture of piperidine (406 mg) and THF (1 mL) was added and stirred at room temperature for 12 hours. After addition of 10% hydrochloric acid, the reaction liquid was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 1-[(2-methoxy-4-nitrophenyl)sulfonyl]piperidine (714 mg) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH2:16][CH2:17][C:18](O)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC.B>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1COCCC(=O)O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1COCCCO
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 120.3 %

Procedure:
In THF (100 ml) was dissolved 3-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinylmethoxy)propionic acid (2.48 g, 8.51 mmol). At room temperature, a 10.0M borane-dimethyl sulfide solution (2.79 ml, 27.9 mmol) was added and the mixture was stirred at room temperature for 3.5 hours and then, at 60° C. for 30 minutes. After cooling to room temperature, the reaction mixture was poured in ice water (100 ml), followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby from chloroform/methanol (20/1) eluate fractions, the title compound (2.84 g, 100%) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:12])([CH3:11])[CH3:10].C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1>C1COCC1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]([CH3:10])([CH3:11])[O:12][C:18](=[O:19])[NH:1][C:2]=2[CH:7]=1
Reactant: CC(C)(O)c1ccc(Br)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)Nc2cc(Br)ccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
Into the solution of 2-(2-amino-4-bromophenyl)propan-2-ol (2.3 g) in THF (50 mL) was added CDI (1.95 g) at rt., then the mixture was warmed to 60° C. and stirred for overnight. After solvent removal, the residue was dissolved in ethyl acetate and washed with 1M of HCl(aq) and brine, and dried with dry agent. After removal of the solvent, the residue was crystallized from DCM and hexane to provide 2.3 g of 7-bromo-4,4-dimethyl-1H-benzo[d][1,3]oxazin-2(4H)-one 7.37 was synthesized. LCMS [M+H]+: 252.71. 1H NMR (400 MHz, Chloroform-d) δ 9.30 (s, 1H), 7.18 (d, d, J=8.2, 1.8 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 1.71 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.C(N(CC)CC)C.Cl.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:36]([C:33]2[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=2)[N:37]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
1.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 0.5 ml of triethylamine and 0.7 g of 4-nitrophenylhydrazine hydrochloride are boiled under reflux for 1 h in 10 ml of ethanol. On cooling, the product precipitates in crystalline form. It is filtered off and washed with ethanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-(4-nitrophenyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 180-183° C.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].BrBr.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Br-].[Zn+2].[Br-].O1CCOCC1>[OH:16][C:10]1[CH:15]=[CH:14][C:13]([CH:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: BrBr
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: O=C1NC(=O)C(c2ccc(O)cc2)N1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
4.0 g (40 mmol) of hydantoin, 50 ml of dioxane, 0.025 g of zinc bromide, and 2.0 ml (40 mmol) of bromine were mixed at room temperature. The reaction mixture was then vigorously stirred at a temperature of 60° C. for 30 minutes. The reaction system was then allowed to cool to room temperature. To the reaction system was then added 7.6 g (80 mmol) of phenol. The reaction mixture was then allowed to undergo reaction at a temperature of 50° C. for 4 hours. The resulting precipitate was recovered by filtration, washed with water, and then dried to obtain 4.69 g (yield: 61%) of 5-(p-hydroxyphenyl)hydantoin.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(C(F)(F)F)c(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M104) (0.23 g, 0.43 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light orange solid (150 mg, 84%).