Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17]CC4C=CC=CC=4)=[C:13]([F:25])[CH:12]=3)[N:6]=[CH:5][C:4]=2[C:3]=1[OH:26].B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:25])[CH:12]=3)[N:6]=[CH:5][C:4]=2[C:3]=1[OH:26]
Reactant: Oc1c(Cl)ccc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(-n2ncc3c(O)c(Cl)ccc32)cc1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
A solution of 5-chloro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazol-4-ol (D24) (0.072 g, 0.2 mmol) in dichloromethane (4 mL) was cooled to −78° C. and boron tribromide (0.4 mL of 1M solution in dichloromethane, 0.4 mmol) was added dropwise over 5 mins. After stirring at −78° C. for 3 hrs under argon, methanol (1 mL) was added and the mixture was diluted with dichloromethane (30 mL) and water (30 mL). The pH was adjusted to 7 with NaHCO3 solution and the aqueous layer was separated and extracted with ethyl acetate (35 mL×2). The combined extracts were washed with brine (25 mL), and evaporated. The product was purified by MDAP to give the title compound (E12) as a white solid (0.022 g).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][C@H:8]1[C:13]([OH:15])=[O:14])=[O:6])[CH:2]=[CH2:3].OS(O)(=O)=O.O>CC(C)=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C:10](=[O:12])[CH2:9][C@H:8]1[C:13]([OH:15])=[O:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: C=CCOC(=O)N1CC(=O)C[C@H]1C(=O)O
Reaction time: 0.75 h

Procedure:
The alloc protected hydroxy proline (13) (18 g, 83.72 mmol) was dissolved in acetone (1260 ml). The Jone's reagent [Cro3:26.6 g/H2SO4:21.3 ml and the solution was made up to 100 ml with water] (87 ml) was added over 10 min. The resulting mixture was stirred for a further 45 minutes when the excess oxidant was quenched with methanol (15 ml). The green chromium salts were removed by filtration through Celite and the filtrate was diluted in CHCl3(1000 ml). The combined organic phase was washed with brine several times (5×500 ml) and the solvent was evaporated under reduced pressure, to yield the ketone 14 which was used without any purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[O:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]
Reactant: CCOC(=O)CCCOc1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=Cc1cccc(OCCCC(=O)O)c1
Yield: 92.8 %

Procedure:
A solution of 385 mg (1.63 mmol) of 4-(3-formylphenoxy)butanoic acid, ethyl ester and 850 mg (6.15 mmol) of potassium carbonate is stirred in 6 mL of methanol/water (3:2) at room temperature for 8 hours. The solution is then concentrated in vacuo. The residue is dissolved in 10 mL of 0.1N sodium hydroxide solution and washed with 20 mL of ether. The aqueous layer is separated and acidified with sodium bisulfate and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, then dried over magnesium sulfate. The mixture is then filtered and concentrated in vacuo to give 315 mg of 4-(3-formylphenoxy)butanoic acid as a white solid. The product is utilized in the next reaction without further purification. m.p. 62°-63°; the 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 3400, 3000, 1700, 1690, 1590 cm-1 ; MS (CI low res) m/e 209 (M+H), 191, 123.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=3)=[S:28])=[CH:7][CH:6]=2)=[CH:10][CH:11]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Sc2ccnc3ccccc23)cc1
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3ccnc4ccccc34)cc2)ccc1Cl
Yield: 55.5 %

Procedure:
4-(4-aminophenylthio)quinoline (3.9 mmoles, 1.0 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (3.9 mmoles, 0.92 g) were reacted according to procedure A to yield of the title compound 1.06 g, 56%. Mass spec (FD) 490. Calculated for C23H15ClF3 N3S2 : C, 56.38; H, 3.09, N, 8.58. Found: C, 56.60; H, 3.11; N, 8.42.
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])C(=O)C=1)C1C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][O:37][C:38]2[CH:43]=[N:42][NH:41][C:40](=[O:44])[CH:39]=2)=[N:34][CH:35]=1>>[OH:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][N:41]2[C:40](=[O:44])[CH:39]=[C:38]([O:37][CH2:36][C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][N:34]=3)[CH:43]=[N:42]2)=[C:19]([CH3:26])[CH:20]=1
Reactant: COc1ccc(COc2cn[nH]c(=O)c2)nc1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: COc1ccc(COc2cnn(CC(=O)c3ccc(CO)cc3C)c(=O)c2)nc1
Yield: 70 %

Procedure:
2-[2-(4-Hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 1c employing 5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 9b) instead of 4-benzyloxy-1H-pyridin-2-one.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:32]=[CH:31][C:12]3[N:13]([CH3:30])[C:14]([N:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:33](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:33])[C:9]2[CH:32]=[CH:31][C:12]3[N:13]([CH3:30])[C:14]([N:16]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(N(C(=O)OC(C)(C)C)c2ccccc2)nc2cc(Nc3ccnc(Cl)n3)ccc21
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1ccc2c(c1)nc(N(C(=O)OC(C)(C)C)c1ccccc1)n2C)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
Tert-butyl 5-[(2-chloropyrimidin-4-yl)amino]-1-methyl-1H-benzimidazol-2-yl(phenyl)carbamate (0.97 g, 2.2 mmol) was dissolved in DMF (10 ml) and cesium carbonate (2.15 g, 6.6 mmol) was added. After 15 min, iodomethane (0.20 ml, 3.3 mmol) was added, and the reaction was stirred at rt. After TLC showed the starting material to be consumed, the reaction was diluted with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4 and concentrated to a red foam. The crude material was purified through silica gel to give the title compound as a white solid (0.80 g. 78% over two steps). 1H NMR (300 MHz, d6-DMSO) δ 7.90 (d, J=6.3 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.38 (m, 4H), 7.25-7.29 (m, 2H), 6.17 (d, J=5.7 Hz, 1H), 3.78 (s, 3H), 3.41 (s, 3H), 1.41 (s, 9H). MS (ESI) m/z=465 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:29][C:11]3=[N:12][C:13]([N:22]([CH2:27]C)[S:23]([CH3:26])(=[O:25])=[O:24])=[C:14]([CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH:15]=[C:10]3[C:9]=2[C:30](=[O:33])[NH:31][CH3:32])=[CH:4][CH:3]=1.[CH3:34][O:35][C:36]([C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1)=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:29][C:11]3=[N:12][C:13]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])=[C:14]([CH2:16][CH2:17][CH2:18][C:19]([N:39]4[CH2:40][CH2:41][CH2:42][C@H:38]4[C:36]([O:35][CH3:34])=[O:37])=[O:20])[CH:15]=[C:10]3[C:9]=2[C:30](=[O:33])[NH:31][CH3:32])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CCN(c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1CCCC(=O)O)S(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(CCCC(=O)N3CCC[C@H]3C(=O)OC)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-ethylmethylsulfonamido)furo[2,3-b]pyridin-5-yl)butanoic acid (15 mg) in DMF (1 ml) is added (S)-methylpyrrolidine-2-carboxylate (4.2 mg), HATU (18.5 mg) and DIPEA (17 μl), and the mixture is stirred at rt for 30 min, and purified by preparative HPLC to afford the title compound. (M+H)+=575.2; Retention time=1.26 min, Method A. 1H NMR (400 MHz, CD3CN) δ ppm 8.18 (m, 1H), 8.06-8.01 (m, 2H), 7.33-7.26 (m, 2H), 6.91 (br s, 1H), 4.33-4.29 (m, 1H), 3.67 (s, 3H), 3.61-3.50 (m, 2H), 3.27 (s, 3H), 3.16 (s, 3H), 2.98-2.90 (m, 2H), 2.92 (d, 3H), 2.51-2.36 (m, 2H), 2.32-1.78 (m, 6H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([N:14]=[N+]=[N-])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[H][H]>CO.[Re]>[CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:14]
Reactant: [H][H]
Reactant: COC(=O)C(CSCc1ccccc1)N=[N+]=[N-]
Agent: [Re]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](N)CSCc1ccccc1
Yield: 73.6 %

Procedure:
0.91 gram (3.62 mmoles) of the 2-azido-3-benzylmercapto-propionic acid methyl ester obtained in Example 4 was dissolved in 8 ml of methanol, treated with 0.27 gram (7.41 mmoles) of HCl gas and there was added 1 mole % of rhenium VII sulfide, based on the amount of azido compound employed. Hydrogen was led into this vigorously stirred reaction mixture for 45 hours. The working up according to Example 19 gave 0.60 gram (63% of theory) of S-benzyl-cysteine methyl ester.HCl having a melting point of 84° to 87° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][C:19]#[N:20])[C:5]2=O.O.[NH2:27][NH2:28]>>[Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[C:6]([C:13]3[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=3[O:15][CH2:16][CH2:17][CH2:18][C:19]#[N:20])=[CH:7][NH:28][N:27]=2)[CH:3]=1
Reactant: NN
Reactant: N#CCCCOc1ccccc1-c1coc2cc(O)c(Cl)cc2c1=O
Solvent: O
Product: N#CCCCOc1ccccc1-c1c[nH]nc1-c1cc(Cl)c(O)cc1O

Procedure:
This compounds was synthesised in the same manner as described above. 4-[2-(6-Chloro-7-hydroxy-4-oxo-4H-chromen-3-yl)-phenoxy]-butyronitrile (0.1 g, 0.28 mmol), Hydrazine hydrate (6 ml). The quenched reaction was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a clear oil which was purified by column chromatograpy to give 4-{2-[3-(5-chloro-2,4-dihydroxy-phenyl)-1H-pyrazol-4-yl]-phenoxy}-butyronitrile as an off white soild Rf 0.65 ethyl acetate/hexane (70/30).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:11][CH3:12])[CH3:10])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1.[CH3:17][SH:18].[H-].[Na+]>C(N(CC)CC)C>[CH3:17][S:18][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:11][CH3:12])[CH3:10])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1
Reactant: CCC(C)Nc1nc(Cl)nc(C)c1[N+](=O)[O-]
Reactant: CS
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCC(C)Nc1nc(SC)nc(C)c1[N+](=O)[O-]
Yield: 91.3 %

Procedure:
12.2 g of 2-chloro-4-sec. butylamino-5-nitro-6-methylpyrimidine (0.05 mole) are dissolved in 200 ml of alcohol and 10 ml of triethylamine are added to this solution. The reaction mixture is heated to reflux temperature and then 4.5 g of methylmercaptan (0.094 mole) are passed in. Subsequently 1.2 g of sodium hydride (0.05 mole) are added at 70° C and the mixture is refluxed for 1 hour. After the reaction mixture has cooled, the sodium chloride precipitate is filtered off with suction and the filtrate is evaporated to yield 11.7 g of 2-methylthio-4-sec.butylamino-5-nitro-6-methylpyrimidine of m.p. 37°-41° C (= 91.5% yield). On recrystallisation from petroleum ether, the melting point of the product rises to 48°-50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[F:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>>[F:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[CH:5]=2)=[O:40])=[CH:37][CH:36]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(F)cc3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 1-(3) and 4-fluorobenzoyl chloride were treated in a manner similar to Example 2-(4) to give 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl 4-fluorophenyl ketone as a colorless powder. APCI-Mass m/Z 604/606 (M+H). 1H-NMR (DMSO-d6) δ 1.69 (s, 3H), 1.79 (s, 3H), 1.98 (s, 3H), 2.04 (s, 3H), 4.11 (d, J=3.9 Hz, 2H), 4.27-4.33 (m, 1H), 5.29 (t, J=9.8 Hz, 1H), 5.54 (t, J=9.6 Hz, 1H), 5.72 (t, J=9.4 Hz, 1H), 6.33 (d, J=9.0 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.35-7.42 (m, 3H), 7.80 (d, J=8.3 Hz, 1H), 7.89 (dd, J=8.4, 5.7 Hz, 2H), 8.16 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.C([Li])CCC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O1CCCC1>[F:10][C:9]1[CH:8]=[C:5]([C:6]#[N:7])[C:4]([F:11])=[CH:3][C:2]=1[NH:1][S:18]([CH3:17])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cc(F)c(N)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(F)c(C#N)cc1F
Temperature: 0 °C
Yield: 79.6 %

Procedure:
To an ice-cold solution of 4-amino-2,5-difluorobenzonitrile (1.0 g) in anhydrous tetrahydrofuran (50 ml) was slowly added n-butyl lithium (2.6 ml) through an injector with stirring, followed by stirring 30 minutes. To the mixture was slowly added methanesulfonyl chloride (550 μl), followed by stirring at room temperature for 24 hours. After confirming the completion of the reaction using TLC, the resulting mixture was concentrated under reduced pressure, diluted with 1 N aqueous hydrochloric acid (100 ml), extracted with dichloromethane (50 ml×3). The combined organic layer was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by column-chromatography (ethyl acetate/hexane 2/3) to yield 2,5-difluoro-4-cyano-1-methanesulfonylaminobenzene (1.2 g, 79.6%).
Reaction SMILES: C(OC([NH:8][C:9]1[C:14](I)=[C:13]([CH3:16])[N:12]=[CH:11][N:10]=1)=O)(C)(C)C.[Br-].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][Zn+])=[CH:22][CH:21]=1.O1CCCC1.FC(F)(F)C(O)=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.CN(C)C=O>[NH2:8][C:9]1[C:14]([C:27]#[C:26][C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:21][CH:22]=2)=[C:13]([CH3:16])[N:12]=[CH:11][N:10]=1
Reactant: FC(F)(F)c1ccc(C#C[Zn+])cc1
Reactant: Cc1ncnc(NC(=O)OC(C)(C)C)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
4-(tert-Butoxycarbonylamino)-5-iodo-6-methylpyrimidine and {4-(trifluoromethyl)phenyl]ethynylzinc bromide were reacted in a solvent mixture of tetrahydrofuran and N,N-dimethylformamide (1:1) in the presence of tetrakis(triphenylphosphine)palladium while stirring under room temperature to heating to obtain a compound. To the compound, trifluoroacetic acid was added to remove a tert-butoxycarbonyl group serving as a protecting group to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: CC1(C)N([Br:9])C(=O)N(Br)C1=O.[CH3:12][CH:13]([CH3:26])[CH2:14][O:15][C:16](=[O:25])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.S([O-])([O-])=O.[Na+].[Na+]>O>[Br:9][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:16](=[O:25])[O:15][CH2:14][CH:13]([CH3:26])[CH3:12])=[CH:19][C:20]=1[F:24]
Reactant: CC(C)COC(=O)Nc1cccc(F)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)COC(=O)Nc1ccc(Br)c(F)c1
Reaction time: 12 h

Procedure:
To a mixture of 3-fluoroaniline (I, 29.058 g, 261.5 mmol) in methylene chloride (116 ml) is added a mixture of potassium carbonate (27.26 g, 197.3 mmol, 0.75 eq) in water (116 ml) at 20-25°. The mixture is warmed to 32°, and isobutyl chloroformate (38.5 g, 282 mmol, 1.08 eq) is added over 13 min while maintaining 30-35° with mild cooling. The mixture is stirred at 30-35° for 2.5 hr until the reaction is complete to give 2-methylpropyl-(3-fluorophenyl)carbamate as determined by GC [GC method A, <0.1 area % 3-fluoroaniline; RT (3-fluoroaniline)=3.97 min, RT=14.2 min]. Aqueous ammonia (29.3 wt %, 4.20 ml, 65.0 mmol, 0.25 eq) is added and the mixture stirred at 30-35° for 15 min. The mixture is cooled to 20-25° and the pH adjusted from 8.7 to 1.9 with hydrochloric acid (37 wt %, 6.36 g, 64.5 mmol, 0.25 eq). The phases are separated and the aqueous washed with methylene chloride (58 ml). The combined organics are washed with water (118 ml) and the water wash back extracted with methylene chloride (58 ml). [In a prior experiment crystallization at this point from heptane at −30° gave 2-methylpropyl-(3-fluorophenyl)carbamate analytically pure in 98.1% yield.]. Dibromantin (57.37 g;, 200.6 mmol, 0.767 eq) and water (174 ml) are added to the combined organics and the mixture stirred at 40° for 12 hr until complete as measured by HPLC (<0.1 2-methylpropyl-(3-fluorophenyl)carbamate). The mixture is cooled to 20-25° and clarified on a “C” frit by vacuum filtration. The phases are separated and the organic (lower) phase added to a mixture of sodium sulfite (33.06 g, 262.3 mmol, 1.00 eq) in water (220 ml) with good agitation. The phases are separated and the organic phase washed with water (150 ml). Serial back-extracted the clarified solids and all aqueous with a single portion of methylene chloride (150 ml). Added heptane (520 ml) to the combined organic phases and concentrated under reduced pressure. Heptane (240 ml) is added, the mixture cooled to −30°, the precipitate is collected by vacuum filtration, washed with cold heptane (150 ml) and dried in a nitrogen stream to give the title compound; mp=79-82°; TLC Rf=0.41 (ethyl acetate/hexanes, 5/95); HPLC (method A) rt=6.75 min; NMR (CDCl3, 400 MHz) d 7.41, 6.96, 6.87, 3.96, 1.97 and 0.96; CMR (CDCl3, 75 MHz) d 159.2, 153.4, 139.0, 133.3, 115.1, 107.1, 102.0, 71.8, 27.9 and 19.0; MS (CI, NH3) m/Z (relative intensity) 310 (9.3), 309 (100), 308 (6.1), 307 (100), 292 (11), 291 (18), 290 (7.5) and 289 (19)
Reaction SMILES: [CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=[O:24])[CH3:23])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:33]O>C(O)C.CO>[CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:21]=[C:22]([CH3:23])[O:24][N:33]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(C)=O)SC)nc21
Reactant: NO
Solvent: CO
Solvent: CCO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(C)on3)nc21
Yield: 43.8 %

Procedure:
A mixture of (Z)-N,N-dicyclopropyl-6-ethyl-1-methyl-4-(1-(methylthio)-3-oxobut-1-enylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (22 mg, 0.049 mmol) and hydroxylamine (50% aqueous solution, 3.13 μL, 0.051 mmol) in ethanol (1 mL) was heated at reflux for 3 h and LC/MS showed completion of reaction. The reaction mixture was diluted with methanol and purified by preparative HPLC to furnish N,N-dicyclopropyl-6-ethyl-1-methyl-4-(5-methylisoxazol-3-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (9 mg, 43.3% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]([F:16])([F:15])[C:3]([Cl:14])([F:13])[C:4]([F:12])([F:11])[C:5]([F:10])([F:9])[CH2:6][CH2:7]I.C(O)C.[OH-].[K+]>O>[Cl:14][C:3]([F:13])([C:2]([Cl:1])([F:15])[F:16])[C:4]([F:11])([F:12])[C:5]([F:10])([F:9])[CH:6]=[CH2:7]
Reactant: FC(F)(Cl)C(F)(Cl)C(F)(F)C(F)(F)CCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CC(F)(F)C(F)(F)C(F)(Cl)C(F)(F)Cl
Yield: 92 %

Procedure:
To a stirred solution of 1,2-dichloro-1,1,2,3,3,4,4,-heptafluoro-6-iodohexane (370.0 g) and ethanol (400 mL) was added dropwise a solution of potassium hydroxide (56.0 g), ethanol (300 mL) and water (20 mL) at 80°-90° C. over 40 minutes. After the addition was complete, the reaction mixture was refluxed for 1 hour and then poured into water. Lower layer was separated and washed with water to give desired product (233.5 g) . 19F NMR: -63.9 (m, 2F) , -111.9 (m, 2F) , -116.2 (m, 2F) , -130.5 (m, 1F); 1H NMR: 5.72 to 6.10 (m) . IR: 1651 (m) , 1422 (s) , 1180 (s) , 1055 (s) , 1019 (s) , 1002 (s) , 980 (s) .
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=2)[C:10]([CH3:22])=[C:9]1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=2)[CH:10]([CH3:22])[CH:9]1[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)C(C)C(C)N2Cc1ccccc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A 460 mg portion of ethyl 1-benzyl-2,3-dimethyl-1H-indole-5-carboxylate was dissolved in 15 ml of trifluoroacetic acid, and 1.19 ml of triethylsilane was added at room temperature, followed by stirring at 50° C. for 3 hours. After evaporation of the solvent, ethyl acetate was added, followed by washing with a 1 M sodium hydroxide aqueous solution and saturated brine and subsequent drying over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:30 to 1:20) to obtain 437 mg of ethyl 1-benzyl-2,3-dimethylindoline-5-carboxylate as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3[N:9]2[CH:12]([CH3:17])[C:13](=[O:16])[NH:14][N:15]=3)=[CH:4][CH:3]=1.O=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1.C([BH3-])#N.[Na+]>CO.CC(O)=O>[CH3:17][CH:12]1[N:9]2[C:10]3[C:5]([CH2:6][CH2:7][C:8]2=[N:15][NH:14][C:13]1=[O:16])=[CH:4][CH:3]=[C:2]([NH:1][CH:19]1[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22]1)[CH:11]=3
Reactant: CC1C(=O)NN=C2CCc3ccc(N)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1C(=O)NN=C2CCc3ccc(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
A solution of 9-amino-1-methyl-5,6-dihydro-1H-[1,2,4]triazino[4,3-a]quinolin-2(3H)-one (0.035 g, 0.152 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (0.078 g, 0.45 mmol) in MeOH (5 mL) and AcOH (0.5 mL) was stirred for 1 h at rt. Sodium cyanoborohydride (0.028 g, 0.456 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. The solution was concentrated in vacuo and the residue was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give tert-butyl 3-(1-methyl-2-oxo-2,3,5,6-tetrahydro-1H-[1,2,4]triazino[4,3-a]quinolin-9-ylamino)azetidine-1-carboxylate (0.020 g, 34%). LC/MS (Table 1, Method 2) Rt=1.104 min; MS m/z: 386 [M+H]+.