Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>[Cu](I)I.C(N(CC)CC)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:18][C:19]2[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Reactant: Cc1ccc(O)cn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2cccc([C@H](C)NC(=O)OC(C)(C)C)c2)cn1
Temperature: 145 °C
Yield: 0 %

Procedure:
A mixture of (S)-[1-(3-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (10 g, 33.3 mol), 5-hydroxy-2-methylpyridine (4 g, 36.7 mol), copper iodide (6.3 g, 33.3 mol), potassium carbonate (9.2 g, 66.7 mol) and pyridine (33 mL) in sealed tube was heated at 145° C. for six days. The reaction was cooled down to room temperature and filtered, the filtrate was washed with H2O and extracted with CH2Cl2 three times, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 30:20:1/Hexane:EtOAc:triethylamine to give the title product (3.8 g, 33% yield) as sticky yellow oil.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:27])[O:5][C:6]1[C:7]([CH3:26])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=1[F:25])[CH3:2].[NH4+].[Cl-]>C(O)C.[Zn]>[CH2:1]([NH:3][C:4](=[O:27])[O:5][C:6]1[C:7]([CH3:26])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:25])[CH3:2]
Reactant: CCNC(=O)Oc1cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: CCNC(=O)Oc1cn2ncnc(Oc3ccc(N)cc3F)c2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl ethylcarbamate (12.5 mg, 0.033 mmol) in ethanol (2 mL) was added Zn (20 mg, 0.3 mmol) and NH4Cl (20 mg, 0.37 mmol). The reaction was stirred at room temperature for 1 h, filtered through Celite® and concentrated in vacuo to give the title compound (8 mg, 70%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:5]([O:7]CC)=O.[Cl:15][C:16]1[N:21]=[C:20]([CH3:22])[CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:22][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:15])[N:21]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: Cc1cccc(Cl)n1
Reactant: CCOC(=O)c1ccc(OC)c(Br)c1
Product: COc1ccc(C(=O)Cc2cccc(Cl)n2)cc1Br
Yield: 88.4 %

Procedure:
In a similar manner as described in Example 1 from ethyl 3-bromo-4-methoxybenzoate (13.6 g, 52.5 mmol) and 6-chloro-2-picoline (5.7 mL, 52.5 mmol), 1-(3-bromo-4-methoxyphenyl)-2-(6-chloro-2-pyridinyl)ethanone (15.8 g, 88%) was obtained as a yellow solid (existing as a mixture of ketone and enol tautomers). 1H NMR (CDCl3) of the ketone: δ 8.27 (s, 1H), 8.02 (dd, 1H), 7.63 (t, 1H), 7.23 (m, 2H), 6.94 (d, 1H), 4.41 (s, 2H), 3.97 (s, 3H); MS m/z340 (M+1).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:31]2[C:32](=[O:38])[C:33](=[O:37])[C:34]=2OC)[CH2:4]1)[CH3:2].Cl.[F:40][C:41]([F:46])([F:45])[CH2:42][CH2:43][NH2:44].CCN(C(C)C)C(C)C>CO>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:21])=[O:22])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:31]2[C:32](=[O:38])[C:33](=[O:37])[C:34]=2[NH:44][CH2:43][CH2:42][C:41]([F:46])([F:45])[F:40])[CH2:4]1)[CH3:2]
Reactant: NCCC(F)(F)F
Reactant: CC[C@@H]1C[C@H](Nc2c(OC)c(=O)c2=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC[C@@H]1C[C@H](Nc2c(NCCC(F)(F)F)c(=O)c2=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 50 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
A mixture of 3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-4-methoxycyclobut-3-ene-1,2-dione (0.090 g, 0.17 mmol, Preparation #29), 3,3,3-trifluoropropan-1-amine hydrochloride (0.050 g, 0.337 mmol, Fluorochem Limited), DIEA (0.18 mL, 1.0 mmol) and MeOH (1.2 mL) was heated at about 50° C. After about 18 h, the reaction was cooled to rt. The solid was collected via vacuum filtration, while washing with MeOH (about 3-5 mL), and then dried in a vacuum oven at about 60° C. to give 3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-4-(3,3,3-trifluoropropylamino)cyclobut-3-ene-1,2-dione (0.083 g, 79%) as an off-white solid: LC/MS (Table 1, Method a) Rt=2.27 min; MS m/z: 616 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](I)[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:12]
Reactant: CCI
Reactant: O=Cc1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(O)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
A mixture of 2,5-dihydroxybenzaldehyde (9.81 g), ethyl iodide (13.29 g), anhydrous potassium carbonate (14.72 g) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column a chromatography to give crystals (4.20 g, 36%) of 2-ethoxy-5-hydroxybenzaldehyde from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 108-109° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]1=[O:13].[C:14](Cl)(=[O:16])[CH3:15]>C(Cl)Cl>[C:14]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]1=[O:13])(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CN1CCC(O)C1=O
Solvent: ClCCl
Product: CCOC(=O)CN1CCC(OC(C)=O)C1=O

Procedure:
1.70 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate are boiled at reflux for 2.5 hours while stirring in 30 ml of methylene chloride and 0.53 ml of acetyl chloride. The mixture is then evaporated. The residue is distilled in a bulb-tube. There is obtained ethyl (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetate of boiling point 225°/0.01 mmHg.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19](O)=[O:20])[CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:24]1([C@H:30]2[CH2:34][O:33][C:32](=[O:35])[NH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1(C)C=CC=CC=1.Cl>[O:35]=[C:32]1[N:31]([C:19]([C@H:16]2[CH2:17][CH2:18][C@H:13]([NH:12][S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:1])[F:22])=[CH:8][CH:7]=3)(=[O:11])=[O:10])[CH2:14][CH2:15]2)=[O:20])[C@@H:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:34][O:33]1
Reactant: O=C(O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1OC[C@H](c2ccccc2)N1C(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a mixture of trans-4-(4-(trifluoromethyl)phenylsulfonamido)cyclohexanecarboxylic acid (Intermediate 18, 110 mg, 0.313 mmol,), (S)-4-phenyloxazolidin-2-one (25.5 mg, 0.157 mmol) in toluene (2 ml) was added triethylamine (0.087 ml, 0.626 mmol). The mixture was heated to 80° C. to obtain a solution. Pivaloyl chloride (0.039 ml, 0.313 mmol) in toluene (1 ml) was added to the reaction mixture, and it was heated to 110° C. with stirring for 18 hr. The reaction mixture was then diluted with 1M HCl and extracted with DCM. The DCM layer was dried (MgSO4), then filtered and concentrated in vacuo to a tanned solid. The crude material was purified via normal phase chromatography on biotage SP1, using 25+M column and a calculated gradient from 50% EtOAc in heptane, to yield the title compound as a white solid (8 mg, 10%). MS MH+ 497.2
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH:22]=[N:21]2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[O:5].CO.[CH3:30][Si](C=[N+]=[N-])(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N:20]2[C:25](=[O:26])[N:24]([CH3:30])[C:23](=[O:27])[CH:22]=[N:21]2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(NCCc1ccccc1Cl)c1cc(-n2ncc(=O)[nH]c2=O)ccc1Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1c(=O)cnn(-c2ccc(Cl)c(C(=O)NCCc3ccccc3Cl)c2)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide (70 mg, 0.173 mmol) in dioxane (1.5 ml) was added methanol (0.36 ml) followed by a 2.0 M solution of (trimethylsilyl)diazomethane (0.35 ml). After stirring for 16 hours at ambient temperature the mixture was concentrated under reduced pressure to give 75 mg of a white amorphous solid. Purification by silica gel chromatography eluting with 2:1 hexaned/ethyl acetate provided 39 mg of the title compound as a white amorphous solid. Melting Point 157–161° C.;
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:14]=[C:13]([S:15]C(=O)N(C)C)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:21])[CH:11]=2)[CH:6]=1.[OH-].[K+].Cl>CO.O>[F:21][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:22])=[O:2])[CH:14]=[C:13]2[SH:15]
Reactant: COC(=O)Cc1cc(SC(=O)N(C)C)c2cc(F)ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cc(S)c2cc(F)ccc2c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A solution of (4-dimethylcarbamoylsulfanyl-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (40 mg, 0.13 mmol) and potassium hydroxide (72 mg, 1.3 mmol) in methanol (10 mL) was heated at reflux for 3 hours. The resulting mixture was cooled to room temperature, diluted with water (10 mL), acidified with 2 N hydrochloric acid, and extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with water and brine, then dried over sodium sulfate and concentrated in vacuo to afford crude (6-fluoro-4-mercapto-naphthalen-2-yl)-acetic acid (30 mg) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.C1(CCCNC(C2N=NC(Cl)=CC=2)=O)CC1.[F:32][C:33]1([F:49])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[C:34]1=[O:48]>>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:45]3[CH2:46][CH2:47][CH:42]([N:35]4[C:36]5[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:33]([F:32])([F:49])[C:34]4=[O:48])[CH2:43][CH2:44]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: O=C1N(C2CCNCC2)c2ccccc2C1(F)F
Agent: O=C(NCCCC1CC1)c1ccc(Cl)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(N3C(=O)C(F)(F)c4ccccc43)CC2)nn1
Yield: 77 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide to replace 6-chloropyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide to react with 3,3-difluoro-1-piperidin-4-yl-1,3-dihydroindol-2-one, the title compound was obtained as a white powder in 77% yield (0.075 g). 1H NMR (300 MHz, CDCl3) δ 8.06 (m, 2H), 7.56-7.53 (m, 1H), 7.42 (t, J=9.0 Hz, 1H), 7.21-7.04 (m, 2H), 6.88 (d, J=6.9 Hz, 1H), 4.73-4.69 (m, 2H), 4.46-4.35 (m, 1H), 3.61-3.52 (m, 2H), 3.17-3.09 (m, 2H), 2.50-2.37 (m, 2H), 1.97-1.93 (m, 2H), 1.59-1.43 (m, 2H), 0.81-0.68 (m, 1H), 0.51-40 (m, 2H), 0.11-0.06 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 165.2, 163.0, 159.6, 145.0, 142.4, 142.3, 133.5, 127.2, 125.2, 123.8, 120.4, 112.6, 110.8, 110.3, 50.9, 44.7, 39.7, 34.5, 27.6, 8.7, 4.2. MS (ES+) m/z 442.2 (M+1).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:36])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:36][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)cc1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (see J. Med. Chem. 45, 2994-3008 (2002)). Title compound: ES-MS: 465.5 [M+H]+; 1H NMR (CDCl3) 8.55 (d, J=3.9 Hz, 1H), 8.38 (s, 1H), 8.24 (d, J=8.2 Hz), 7.83 (d, J=8.2 Hz, 2H), 7.52-7.48 (m, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.42-7.40 (m, 1H), 7.39 (s, 1H, NH), 7.16 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.2 Hz, 2H), 6.66 (s, 1H), 3.81 (s, 2H), 2.13 (s, 3H), 1.36 (s, 9H).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C@H:7]1[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@H:11]([CH3:22])[O:10][CH:8]1[OH:9])(=[O:5])[CH3:4].[Cl:23][C:24]([Cl:28])([Cl:27])[C:25]#[N:26]>ClCCl>[Cl:23][C:24]([Cl:28])([Cl:27])[C:25](=[NH:26])[O:9][C@@H:8]1[O:10][C@@H:11]([CH3:22])[C@@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:7]1[O:6][C:3](=[O:5])[CH3:4]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)OC(O)[C@H]1OC(C)=O
Reactant: N#CC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](OC(=N)C(Cl)(Cl)Cl)O[C@@H](C)[C@H]1OC(C)=O
Reaction time: 12 h
Yield: 71 %

Procedure:
Sodium hydride (0.25 g, 10.9 mmol) is added under nitrogen and at room temperature to a mixture of 2,3,4-tri-O-acetyl-L-fucopyranose (anomer mixture) (2.00 g, 6.89 mmol) and trichloroacetonitrile (7.0 ml, 70 mmol) in 20 ml of dry dichloromethane. The mixture is stirred for about 12 h and then filtered through kieselguhr and concentrated. After chromatographic purification (petroleum ether/ethyl acetate 3:1), O-(2,3,4-tri-O-acetyl-α-L-fucopyranosyl) trichloroacetimidate (3) is obtained in a yield of 71% (2.13 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][NH:14][CH3:15]>C(OCC)(=O)C>[Cl:11][C:6]1[N:5]=[C:4]([CH3:12])[N:3]=[C:2]([N:14]([CH3:15])[CH3:13])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CNC
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(N(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. To a solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (2.65 g, 12.5 mmol) in ethyl acetate (200 ml), a 50% aqueous dimethylamine solution (1.10 ml) was dripped in at −15 degrees Celsius, this was further agitated for 1 hour, then agitated for 1 hour at 0 degrees Celsius, then at room temperature for 16 hours. The reaction liquid was poured into ice water and extraction was carried out 2 times with ethyl acetate. After washing together with the ethyl acetate layer with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. Purification was done by silica gel chromatography (hexane:ethyl acetate=1:1), and 827.4 mg of 6-chlor-4-dimethylamino 2-methyl-5-nitropyrimidine (yield 31%) was obtained. The MS measurement result, and the NMR data for the obtained 6-chlor-4-dimethylamino-2-methyl-5-nitropyrimidine are shown below.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[OH-].[K+].C(O)C.Cl>O>[CH2:1]([NH:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1ccc(CCC(=O)OCC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCNc1ccc(CCC(=O)O)cc1

Procedure:
A 4 g. sample of ethyl 4-(allylamino)hydrocinnamate is hydrolyzed with 1.6 g. 85% potassium hydroxide in 60 ml. 95% ethanol by refluxing the solution for 5 hours. The solution is cooled, diluted with 100 ml. water and acidified to pH 4.5 with 37% hydrochloric acid. The precipitate is collected, dried in vacuo and crystallized from acetone to yield the title compound as white powder.
Reaction SMILES: [CH:1]1([NH:5][S:6]([N:9]2[C:14]3([CH2:16][CH2:15]3)[CH2:13][N:12]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:11][CH2:10]2)(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[O:32](C(OC(C)(C)C)=O)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=O.O>CN(C=O)C>[CH:1]1([NH:5][S:6]([N:9]2[C:14]3([CH2:15][CH2:16]3)[CH2:13][N:12]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:32])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:11][CH2:10]2)(=[O:7])=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=S(=O)(NC1CCC1)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)NC4CCC4)C4(CC4)C3)ncnc21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
N-cyclobutyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8-diazaspiro[2.5]octane-8-sulfonamide (intermediate 30) (4.4 mmol) was dissolved in dry DMF (15 ml), added K2CO3 (5.28 mmol) and cooled to 0° C. A solution of BOC2O (1.06 g, 4.86 mmol) in dry DMF (5 mL) was added and the reaction mixture was allowed to warm up freely to rt and stirred at rt for 16 h. The crude mixture was treated with water (150 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C.[NH4+].[Cl-].C(OCC)(=O)C>C1COCC1.[Li]CCCC.CCCCCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:10]([OH:15])[OH:11])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-iodoanisole (26) (5 g) in THF (45 ml), n-BuLi in n-hexane solution (1.6 M) (16.02 ml) was added at -78° C. under the inert atmosphere. The reaction mixture was stirred at -78° C. for 1 hr, then a tri (i-propyl) borate (5.9 ml) was added. The reaction mixture was stiffed at room temperature for 2 hrs. The reaction mixture was cooled to room temperature and poured into satd. NH4Cl aq. The resulting solution was added with ethyl acetate and was stirred at room temperature for 1.5 hrs. The reaction mixture was extracted with ethyl acetate and then the organic layer was washed with satd. NH4Cl aq, water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The concentrate was crystallized with n-hexane-ether (4:1). The resulting precipitate was collected by filtration. 4-methoxyphenylboronic acid (27) was obtained as a white crystal (1.98 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:24])[NH:17][C:16]([CH3:25])=[C:15]1[C:26]([O:28][CH3:29])=[O:27].[CH2:30]1[O:38][CH:31]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[OH:38][CH:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:24])[NH:17][C:16]([CH3:25])=[C:15]1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCN
Reactant: c1ccc(C2CO2)cc1
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCNCC(O)c1ccccc1
Reaction time: 48 h
Yield: 19.3 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 2 g of dimethyl 4-[2-(2-aminoethoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 0.6 g of styrene oxide, and the solution thus formed was allowed to stand for 2 days at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The product was eluted with chloroform-methanol (95:5 v/v). Crude crystals were recrystallized from ethyl acetate to give 500 mg of dimethyl 4-[2-[2-(β-hydroxyphenethylamino)ethoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:9]3[CH:10]=[C:11]([I:15])[CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:33][Si:34]([CH3:41])([CH3:40])[CH2:35][CH2:36][O:37][CH2:38]Cl.O>CN(C=O)C>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:16]3[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=3[F:22])[C:9]3[CH:10]=[C:11]([I:15])[CH:12]=[CH:13][C:14]=3[C:5]=2[N:4]([CH2:38][O:37][CH2:36][CH2:35][Si:34]([CH3:41])([CH3:40])[CH3:33])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Fc1cccc(F)c1-c1nc2c(Br)n[nH]c2c2ccc(I)cc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(Br)c2nc(-c3c(F)cccc3F)c3cc(I)ccc3c21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 150 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 1.2 g of 3-bromo-5-(2,6-difluorophenyl)-7-iodo-1H-pyrazolo[4,3-c]isoquinoline, prepared in step 1 of example 6, in 24 ml of DMF, 3 ml of diisopropylethylamine and 0.92 ml of 2-(trimethylsilyl)ethoxymethyl chloride. The mixture is stirred at RT for 24 h and then poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. This gives 1.52 g of crude product, which is purified by chromatography on silica gel (20-45 μm), eluting with a DCM/methanol mixture (99.5/0.5 by vol.), to give on one hand 832 mg of 3-bromo-5-(2,6-difluorophenyl)-1-(2-trimethylsilanyl ethoxymethyl)-7-iodo-1H-pyrazolo[4,3-c]isoquinoline in the form of a white solid. MS (E/I): m/z=616 (M+), and on the other hand 526 mg of 3-bromo-5-(2,6-difluorophenyl)-2-(2-trimethylsilanyl-ethoxymethyl)-7-iodo-2H-pyrazolo[4,3-c]isoquinoline (ochre oil), which is used as it is in the following step. MS (E/I): m/z=616 (M+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][CH2:8][NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)#[N:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:32]2)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][CH2:8][NH:9][C:10](=[S:32])[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#Cc1ccc(C(=O)NCCOc2cccc(C#N)c2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(=S)NCCOc2cccc(C#N)c2)cc1

Procedure:
1.46 g (5.00 mmol)) of N-[2-(3-cyanophenoxy)ethyl]-4-cyanobenzamide was dissolved in 50 ml of toluene. 3.03 g (7.5 mmol) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide was added to the solution, and the obtained mixture was heated under reflux for 4 hours. The precipitate was removed by the filtration, and the solvent was evaporated under reduced pressure. The residue was purified by the silica gel column chromatography, and the title compound was obtained.