Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:39][O:40][C:41](=[O:52])[C@H:42]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1)[NH2:43]>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:14]([NH:43][C@@H:42]([CH2:44][C:45]1[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=1)[C:41]([O:40][CH3:39])=[O:52])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-leucine (7 g) in acetonitrile (100 ml), under a nitrogen atmosphere, was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.9 g) and 1-hydroxybenzotriazole (4.2 g). After stirring for 30 mins at 20° C. L-tyrosine methyl ester (5.5 g) was added and stirring was continued for 18 h. The mixture was concentrated in vacuo to ca. 10 ml and the residue was partitioned between 1M hydrochloric acid (200 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous phase was further extracted with ethyl acetate (100 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (100 ml), water (2×100 ml) and brine (50 ml), dried over sodium sulphate and evaporated in vacuo. The residue was co-evaporated with chloroform to give the title compound as a white foam (11.3 g, 98%). LCMS: Rt 3.11 min; m/z 409 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37]OS(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH3:23])([CH3:14])[C:4]([OH:3])=[O:24])=[CH:8][CH:9]=3)[N:35]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1OC
Product: COc1ccccc1OC(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxy-phenyl)-2-(2-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3): δ 7.18 (d, 2H, J=8.21 Hz), 7.06 (t, 1H, J=7.82 Hz), 6.88 (d, 1H, J=8.21 Hz), 6.83-6.79 (m, 3H), 6.62 (d, 1H, J=7.82 Hz), 4.12 (t, 2H, J=6.65 Hz), 3.82 (s, 3H), 3.29 (d, 1H, J=14.08 Hz), 3.09 (d, 1H, J=14.08 Hz). 2.85 (t, 2H, J=6.65 Hz), 2.70-2.63 (m, 1H), 2.21 (s, 3H), 1.99 (d, 2H, J=12.51 Hz), 1.77 (d, 2H, J=12.90 Hz), 1.67 (d, 1H, J=11.73 Hz, 1.50 (q, 2H, J=12.51 Hz), 1.37-1.21 (m, 5H). MS [ES+] m/z exact mass calcd for C29H36NO6 494.2543, found 494.2562.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([O:16]C)=O)[CH2:3]1.[CH2:18]([NH2:20])[CH3:19]>CO>[CH2:18]([NH:20][C:14]([CH:4]1[CH2:3][C:2](=[O:1])[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5]1)=[O:16])[CH3:19]
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: CCN
Solvent: CO
Product: CCNC(=O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 100 °C
Yield: 49.4 %

Procedure:
A mixture of 200 g (0.86 mole) of methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate [J. Org. Chem., 26, 1519 (1961)], 1000 ml methanol and 200 g (4.4 mole) of ethylamine was heated at 100° C. in a pressure reactor for 17.2 hours. The reaction mixture was cooled and the excess ethylamine and methanol were removed under reduced pressure. The residue was taken up in dichloromethane and washed with 3×150 ml 1N sodium hydroxide. The organic layer was dried over magnesium sulfate and the solvent removed at reduced pressure to give 104.6 g of N-ethyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as a white solid, mp 97°-99° C.
Reaction SMILES: ON=[C:3]([CH3:19])[C:4](=[N:14][NH:15][C:16]([NH2:18])=[S:17])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[C:20](=O)([O-])[O-].[K+].[K+]>O>[CH3:19][C:3]1[N:18]=[C:16]([S:17][CH3:20])[N:15]=[N:14][C:4]=1[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(=NO)C(=NNC(N)=S)c1ccc([N+](=O)[O-])cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CSc1nnc(-c2ccc([N+](=O)[O-])cc2)c(C)n1
Yield: 44.1 %

Procedure:
A mixture of 2-hydroxyimino-4'-nitropropiophenone thiosemicarbazone (15.8 g) and potassium carbonate (17.09 g) in water (145 ml) was refluxed for 30 minutes with stirring. After cooling, the mixture was filtered by suction and then methyl iodide (10.37 g) was added dropwise to the filtrate at room temperature with stirring. The resulting precipitates were collected by filtration, washed with water, and dried. The residue was purified by column chromatography on silica gel (100 g) with methylene chloride as an eluent to give yellow powder of 5-methyl-3-methylthio-6-(4-nitrophenyl)-1,2,4-triazine (6.49 g).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[C:11](N)(=[NH:14])[CH2:12][CH3:13]>>[CH2:12]([C:11]1[N:14]=[C:7]([OH:9])[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[N:1]=1)[CH3:13]
Reactant: CCC(=N)N
Reactant: COC(=O)c1sccc1N
Product: CCc1nc(O)c2sccc2n1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Methyl 3-amino-2-thiophenecarboxylate (4.67 g,) and propionamidine (3 g, were combined and heated in an oil both for 1/2 hour at 60° C.; 1/2 hour at 80° C.; 1/2 hour at 100° C. and finally for 4 hours at 120° C. The mixture was cooled, triturated with ether, filtered and washed with ether to obtain 0.67 g of the product; m.p. 233°-237° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.[CH3:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][NH:19][CH3:18])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Reactant: CN
Solvent: CCO
Product: CNCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
A solution containing 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (5.5 g, 20.4 mmol), obtained as explained in EP 106515, a 40% solution of methylamine in ethanol (60 mL) and ethanol is stirred at 100° C. for 16 h in a closed vessel. The product is isolated by flash chromatography as a white solid. mp 98°-101° C.; 1H NMR (80 MHz, CDCl3)δ(TMS) 8.12 (s, 1H, N=CH), 7.81 (s, 1H, N=CH), 7.73 (d, J=8.5 Hz, 1H, arom), 7.5-7.1 (m, 2H, arom), 4.78 (s, 2H, CH2 -Tr), 3.28 (AB system, Δv=0.49, J=12.3 Hz, 2H, NCH2), 2.29 (s, 3H, NMe).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:13][CH3:14])[CH:3]=1.[I:15]Cl.CC(O)=O>C(O)(=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:12]([I:15])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:13][CH3:14])[CH:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1SC
Reactant: ClI
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(I)c(N)cc1SC
Temperature: 60 °C
Yield: 62.4 %

Procedure:
To a solution of ethyl 4-amino-2-fluorobenzoate (12 g, 65.5 mmol) in DMF (100 mL) was added NaSMe (9.17 g, 131 mmol) and the mixture was stirred at 60° C. for 20 h. After cooling to rt, the reaction was diluted with H2O and extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford ethyl 4-amino-2-(methylthio)benzoate. To a pre-heated 60° C. solution of ethyl 4-amino-2-(methylthio)benzoate (65 mmol) in acetic acid (150 mL) was added ICl/AcOH solution (1M, 72 mL, 72 mmol) dropwise during 40 min and the temperature was maintained at 60° C. for 3 h. After cooling to rt the reaction was diluted with EtOAc (500 mL) and washed with 5% sodium thiosulfate solution (3×100 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-20% EtOAc/Hexanes) to afford ethyl 4-amino-5-iodo-2-(methylthio)benzoate (13.67 g, 53% yield). For ethyl 4-amino-2-(methylthio)benzoate: LC-MS m/z 212 [M+H]+. For ethyl 4-amino-5-iodo-2-(methylthio)benzoate: LC-MS m/z 338 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H), 6.47 (s, 1H), 4.49 (br s, 2H), 4.31 (q, J=7.2 Hz, 2H), 2.38 (s, 3H), 1.37 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[O:14][C:13]1=[O:21])CC1C=CC=CC=1.C>CO>[CH3:1][NH:2][CH2:10][CH2:11][N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[O:14][C:13]1=[O:21]
Reactant: CN(CCn1c(=O)oc2cccnc21)Cc1ccccc1
Solvent: CO
Product: CNCCn1c(=O)oc2cccnc21
Temperature: 25 °C

Procedure:
In a 1,000-cm3 ground-necked flask, 0.02 mol of 3-[2-(N-methyl-N-b-enzylamino)ethyl]-3H-oxazolo[4,5-b]-pyridin-2-one is dissolved in 250 cm3 of methanol. 0.2 g of palladinized charcoal is introduced and the mixture is stirred under a hydrogen atmosphere at room temperature and atmospheric pressure After absorption of the theoretical quantity of hydrogen, the reaction medium is filtered. The filtrate is concentrated on a water bath under vacuum and acidified with a stream of gaseous hydrochloric acid The precipitate obtained is drained, dried and recrystallize.
Reaction SMILES: [N+:1]([C:4]1([N+:10]([O-:12])=[O:11])[CH2:9][O:8]C(=O)[CH2:5]1)([O-:3])=[O:2].[N+](C(C)C(O)=O)([O-])=[O:14]>>[N+:1]([C:4]([N+:10]([O-:12])=[O:11])([CH3:5])[C:9]([OH:14])=[O:8])([O-:3])=[O:2]
Reactant: CC(C(=O)O)[N+](=O)[O-]
Reactant: O=C1CC([N+](=O)[O-])([N+](=O)[O-])CO1
Product: CC(C(=O)O)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
A unique synthesis involving the latter substrates covers the synthesis of 3,3-dinitrobutyrolactone. 2-nitropropionic acid can be nitrated to provide 2,2-dinitropropionic acid, which is formylated to give the corresponding methylol derivative, which is then cyclized to the lactone.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][N:25]4[CH2:30][C:31](O)=[O:32])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][C@@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50].O>CN(C=O)C>[CH3:48][S:49]([NH:52][C:31](=[O:32])[CH2:30][N:25]1[C:26]2[C:22](=[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][C@@H:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])=[C:3]([C:2]([F:34])([F:1])[F:35])[CH:4]=4)[O:20][N:19]=3)[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1)(=[O:51])=[O:50]
Reactant: C[C@H](Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(=O)O)no2)cc1C(F)(F)F)C(F)(F)F
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(=O)NS(C)(=O)=O)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
To a solution of [4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetic acid (100 mg) in DMF (1 ml) was added CDI (39 mg), and after 30 min, methanesulfonamide (23 mg) and 2,3,4,6,7,8,9,10-octahydropyrimide[1,2-a]azepine (37 mg) were added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture was added with water to complete the reaction. It was extracted with EtOAc, the obtained organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 90:10) to obtain N-(methylsulfonyl)-2-[4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetamide (56.4 mg) as a white solid.
Reaction SMILES: N#N.[C:3]([NH:7][C:8]1[N:13]=[C:12]([C:14]#[CH:15])[CH:11]=[CH:10][N:9]=1)([CH3:6])([CH3:5])[CH3:4].I[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>CCN(CC)CC.C1COCC1>[C:3]([NH:7][C:8]1[N:13]=[C:12]([C:14]#[C:15][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:11]=[CH:10][N:9]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Fc1ccc(I)cc1
Reactant: C#Cc1ccnc(NC(C)(C)C)n1
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1nccc(C#Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.4 %

Procedure:
To a mixture of Pd(PPh3)Cl2 (0.4 g) in Et3N (150 mL) and THF (150 mL) under a stream of N2, was added tert-butylamino-4-ethynylpyrimidine (18.6 g, 0.11 mol). After bubbling N2 into the solution for 15 min, 4-iodo-fluorobenzene (23.6 g, 0.11 mol) and Cul (0.22 g) were added sequentially. The mixture was stirred at rt for 2.5 h. The precipitate was filtered and washed with EtOAc. The filtrate was concentrated and the residue was diluted with EtOAc and loaded directly onto a short pad of silica gel. The product was eluted with 10% EtOAc in hexanes to afford the crude product, which was recrystallized from EtOAc/hexanes to give the title compound as a light yellow solid (25 g, 84%). TLC: Rf=0.30. mp 97-99° C. IR: 3287 (w), 2964 (w), 2222 (w), 1566 (s). 1H NMR: 8.26 (d, J=4.2 Hz, 1H), 7.60-7.55 (m, 2H), 7.10-7.00 (m, 2H), 6.65 (d, J=4.9 Hz, 1H), 5.22 (s, 1H), 1.45 (s, 9H). 13C NMR: 164.19, (162.19, 162.03), 157.77, 150.83, (134.35, 134.29), (117.84, 117.81), (115.94, 115.76), 112.37, 89.91, 87.24, 51.07, 28.86. Anal. Calcd for C16H16FN3: C, 71.36; H, 5.99; N, 15.60. Found: C, 71.25; H, 5.95; N, 15.66.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[CH2:13]([N:15]([CH2:30][CH3:31])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[NH:23][C:24]([CH:28]=O)=[CH:25][C:26]=1[CH3:27])=[O:21])[CH3:14]>>[CH2:30]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[NH:23][C:24]([CH:28]=[C:7]2[C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:9][C:8]2=[O:12])=[CH:25][C:26]=1[CH3:27])=[O:21])[CH3:31]
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)cc1C
Reactant: COc1ccc2c(c1)NC(=O)C2
Product: CCN(CC)CCCNC(=O)c1[nH]c(C=C2C(=O)Nc3cc(OC)ccc32)cc1C
Yield: 31 %

Procedure:
6-Methoxy-1,3-dihydroindol-2-one (82.5 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide to give 63 mg (31%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N+:12]([O-])=[C:11]([CH3:16])[C:10]=2[CH3:17])[CH2:4][O:3]1.C(OC(=O)C)(=[O:21])C>>[CH3:1][C:2]1([CH3:18])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:16][OH:21])[C:10]=2[CH3:17])[CH2:4][O:3]1
Reactant: Cc1c(OC[C@@H]2COC(C)(C)O2)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Product: Cc1c(OC[C@@H]2COC(C)(C)O2)ccnc1CO
Temperature: 80 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
The 4-(((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,3-dimethylpyridine 1-oxide (10.5 g, 41.5 mmol) obtained in the step (14a) was mixed with acetic anhydride (20 ml). The mixture was stirred at 80° C. for one hour. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue, methanol (40 ml) and a 5N aqueous sodium hydroxide solution (20 ml) were added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and the residue was partitioned between a saturated saline solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol) to obtain the title compound (3.77 g, yield: 41.9%) as a yellow oil.
Reaction SMILES: Br[C:2]1(Br)[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]1=O.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[NH:21][C:22]([NH2:24])=[S:23]>C(O)C>[CH3:11][C:10]1([CH3:12])[CH2:9][C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]2[N:24]=[C:22]([NH:21][C:16]3[N:17]=[CH:18][CH:19]=[CH:20][N:15]=3)[S:23][C:2]1=2
Reactant: NC(=S)Nc1ncccn1
Reactant: CC1(C)Cc2[nH]ncc2C(=O)C1(Br)Br
Solvent: CCO
Product: CC1(C)Cc2[nH]ncc2-c2nc(Nc3ncccn3)sc21
Reaction time: 0.67 h
Yield: 1.6 %

Procedure:
According to Scheme 2 Step 4: A solution of 5,5-dibromo-6,6-dimethyl-6,7-dihydro-1H-indazol-4(5H)-one (6.09 mmol, 1.96 g) and of 1-(pyrimidin-2-yl)thiourea (7.31 mmol, 1.13 g) in ethanol (15 mL) was microwaved at 150° C. for 90 minutes and then at 140° C. for 40 minutes. After filtration, the reaction mixture was concentrated to dryness. The crude residue was partitioned between DCM and a saturated solution of Na2CO3. The aqueous phase was extracted with DCM. The organic phase was dried over Na2SO4 and concentrated. The crude residue was purified by flash chromatography over silica gel using DCM/MeOH (98:2 to 90:10) as eluent to yield 4,4-dimethyl-N-(pyrimidin-2-yl)-5,6-dihydro-4H-thiazolo[4,5-e]indazol-2-amine (0.10 mmol, 31 mg) as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:40]1([CH3:49])[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([C:43]3[CH:44]=[CH:45][C:40]([CH3:49])=[CH:41][CH:42]=3)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(-c3ccc(C)cc3)nc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 86, step 86.1, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester replacing 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester and 4-tolylboronic acid replacing phenylboronic acid.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:26][C:27]3C=C(O)[C:30]([Cl:34])=[CH:29][C:28]=3[F:35])=[CH:21][N:22]=[N:23]2)=[CH:18][C:17]=1[O:36][CH3:37])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:5]([O:4][C:1]1[C:30]([Cl:34])=[CH:29][C:28]([F:35])=[C:27]([CH:2]=1)[NH:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([O:15][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:17]([O:36][CH3:37])[CH:18]=2)[N:23]=[N:22][CH:21]=1)(=[O:7])[CH3:6]
Reactant: COc1cc2c(Nc3cc(O)c(Cl)cc3F)cnnc2cc1OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1cc2c(Nc3cc(OC(C)=O)c(Cl)cc3F)cnnc2cc1OCc1ccccc1
Temperature: 110 °C

Procedure:
Acetic anhydride (920 μl, 9.7 mmol) and 4-dimethylaminopyridine (80 mg, 0.65 mmol) were added to a suspension of 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxycinnoline (3 g, 6.5 mmol), (prepared as described in Example 6), in pyridine (50 ml). After heating at 110° C. for 25 minutes, the solid was filtered off, washed with water and ether and dried under vacuum. The solid was suspended in 2M ethereal hydrogen chloride and the volatiles removed by evaporation to give 4-(5-acetoxy-4-chloro-2-fluoroanilino)-7-benzyloxy-6-methoxycinnoline as the hydrochloride salt (yellow solid, 3.1 g, 94%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([NH:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:4][C:3]1=2.[BH4-].[Na+].O>CO>[OH:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([NH:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc2c(c1)CCCC2O

Procedure:
To a solution of N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (1.00 g, 4.94 mmol) in methanol (20 mL) at 0° C. is added sodium borohydride (0.50 g, 7.41 mmol). The reaction is stirred for 1.5 hours, whereupon water is added and the volatiles are removed in vacuo. The mixture is extracted with dichloromethane and the organic phase is dried over sodium sulfate, filtered, and concentrated to give N-(5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide, which is used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7](=[O:10])[NH:8][CH:9]=1.[CH3:11]I>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7](=[O:10])[N:8]([CH3:11])[CH:9]=1
Reactant: CI
Reactant: O=c1ccc(Br)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(Br)ccc1=O
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a suspension of NaH (4.8 g, 0.2 mol) in THF (10 mL) was added a solution of 5-bromopyridin-2(1H)-one (8.6 g, 0.05 mol) in THF (120 mL) at 0° C. The resulting mixture was stirred for 1 h and CH3I (35.5 g, 0.25 mol) was added. The mixture was stirred for 3 h. The reaction was quenched with aqueous NH4Cl solution. The organic phase was concentrated to give the crude product, which was purified by column chromatography to give 5-bromo-1-methylpyridin-2(1H)-one (8.9 g, 96.78%). 1H NMR (CDCl3): δ=3.5 (S, 3H), 6.52 (m, 1H), 7.32 (m, 1H), 7.45 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([OH:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1ccc(-c2ccc(Br)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)Cc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
(4′-Bromobiphenyl-4-yl)acetone (7.6 g, 26 mmol) was dissolved in ethanol (250 mL), and sodium borohydride (1.2 g, 32 mmol) was added at 0° C., followed by stirring at the same temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and the organic layer was washed with water. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.45 (hexane/ethyl acetate=4/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (7.6 g, 26 mmol) as a white solid (yield 99%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[CH3:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([CH3:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4c(C)cccc4C)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C)cc(-c3c(C)cccc3C)c2O1

Procedure:
The title compound was prepared (0.035 g, 46%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,6-dimethylphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.10 g, 0.24 mmol) and methylamine (0.073 g, 2.4 mmol). mp 204-205° C.