Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[C:7]([CH3:9])[N:8]=1)=[N+:2]=[N-:3].C(N(CC)C(C)C)(C)C.[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[C:30]#[CH:31]>O1CCCC1.[Cu]I>[CH2:13]([NH:12][C:10]([C:6]1[S:5][C:4]([N:1]2[CH:31]=[C:30]([C:29]([O:33][CH2:34][CH3:35])=[O:32])[N:3]=[N:2]2)=[N:8][C:7]=1[CH3:9])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: C#CC(=O)OCC
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn(-c2nc(C)c(C(=O)NCc3ccccc3)s2)nn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a solution of 2-azido-N-benzyl-4-methylthiazole-5-carboxamide (1.00 g, 3.67 mmol) in tetrahydrofuran (30 mL) was added copper(I) iodide (0.70 g, 3.67 mmol), N,N-diisopropylethylamine (1.28 mL, 7.32 mmol) and ethyl propiolate (0.45 g, 4.58 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:1) to afford the title compound as a white solid in 61% yield (0.83 g): 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 7.36-7.26 (m, 5H), 6.17 (br s, 1H), 4.63 (d, J=6.0 Hz, 2H), 4.47 (q, J=6.0 Hz, 2H), 2.70 (s, 3H), 1.42 (t, J=6.0 Hz, 3H); MS (ES+) m/z 372.3 (M+1).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]5[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N([O-])=O.[Na+].[N-:42]=[N+:43]=[N-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O.O.CCOCC>[N:29]([C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[NH:22][C:18]1[N:17]=[C:16]([C:15]2[C:14]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[N:13][N:12]3[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=[CH:10][C:11]=23)[CH:21]=[CH:20][N:19]=1)=[N+:42]=[N-:43]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(Nc3cccc(N)c3)n2)cc1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(Nc3cccc(N=[N+]=[N-])c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
The following transformation was performed in the dark. To a cold (0° C.) solution of N′-{4-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinyl}-1,3-benzenediamine (16.5 mg, 0.03 mmol) in acetic acid/water (80/20, 1 mL) was added aqueous sodium nitrite (0.32 mL of a stock solution prepared by dissolving 200 mg of sodium nitrite in 25 mL water, 0.04 mmol). The resultant dark solution was stirred at 0° C. for 15 minutes. Aqueous sodium azide (0.11 mL of a stock solution prepared by dissolving 200 mg of sodium azide in 10 mL of water, 0.04 mmol) was added and the resultant solution was stirred for 1.5 hours over which time it was allowed to warm to room temperature. Ether was added and the solution made basic by dropwise addition of saturated aqueous sodium bicarbonate. The organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate. Filtration and concentration gave a solid residue which was purified by flash chromatography (4:1 to 2:1 hexanes-ethyl acetate) to provide 3-[2-(3-azidoanilino)-4-pyrimidinyl]-N-cyclopentyl-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-7-amine (4 mg, 23%) as a tinted solid. 1H NMR (CDCl3): δ 8.12 (d, 1 H), 7.71 (d, 1 H), 7.60–7.56 (m, 3 H), 7.33–7.25 (m, 3 H), 6.98 (d, 2 H), 6.70 (d, 1 H), 6.54 (d, 1 H), 6.05–6.04 (m, 2 H), 4.00 (m, 1 H), 3.87 (s, 3 H), 2.13 (m, 2 H), 1.85–1.58 (m, 6 H); MS m/z 518 (M+1).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22]>>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:19]3[CH2:20][CH2:21][O:17][C:18]3=[O:22])=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCCO1
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Product: O=C1OCCN1Cc1ccc(C#Cc2ccccc2)cn1

Procedure:
The title compound, white solid, MS: m/e=279.2 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and oxazolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.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.[F:65][C:66]1[CH:67]=[C:68]([CH:70]=[CH:71][CH:72]=1)[NH2:69]>C(Cl)Cl>[F:65][C:66]1[CH:67]=[C:68]([NH:69][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH:70]=[CH:71][CH:72]=1
Reactant: Nc1cccc(F)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(F)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 3-fluoro-aniline (Aldrich, 38 mg, 0.32 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (20 g column, 0-10% EtOAc/methylene chloride) to give a white solid. 60 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=CC=C[CH:18]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([C:23]([C:25]2[CH:30]=CC=C[CH:26]=2)=[O:24])=[CH:5][CH:4]=1.ClCCl.BrBr>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:16])[CH:17]([CH3:22])[CH3:18])=[CH:11][CH:10]=2)=[CH:7][C:6]([C:23](=[O:24])[CH:25]([CH3:30])[CH3:26])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccccc2)cc1-c1ccc(C(=O)c2ccccc2)cc1
Agent: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(=O)C(C)C)cc1-c1ccc(C(=O)C(C)C)cc1
Reaction time: 8 h

Procedure:
Under nitrogen atmosphere 4.3 grams of 1,1′-(6-methoxy-[1,1′-biphenyl]-3,4′-diyl)bis(2-methylpropan-1-one), which was prepared by following a procedure described in the below Example 4 for the synthesis of (6-methoxy-[1,1′-biphenyl]-3,4′-diyl)bis(phenylmethanone), was mixed with 80 mL of dry dichloromethane and 10 mL of CCl4 at room temperature. 4.2 grams of bromine was added and the resultant solution was continuously stirred at this temperature until the reaction completion was detected by TLC monitoring. The mixture was then concentrated and the residue was mixed with 100 mL of 2N NaOH solution. After stirring overnight the mixture was poured into 200 mL of water, and the aqueous layer was extracted by 100 mL of dichloromethane. The combined organic layer was washed by brine and dried over MgSO4. The filtered solution was then concentrated and the residue was loaded onto silica gel column and eluted by mixtures of hexane/ethyl acetate to give 3.6 grams of the light-yellow product (77% yield). 1H NMR (CDCl3, ppm): 8.13-8.09 (m, 4H), 7.63 (d, 2H, J=8.4 Hz), 7.05 (d, 1H, J=9.0 Hz), 4.17 (s, 1H), 4.16 (s, 1H), 1.68 (s, 6H), 1.65 (s, 6H); 13C NMR (CDCl3, ppm): 204.0, 202.4, 160.2, 142.2, 133.0, 132.3, 129.6, 129.5, 129.2, 126.1, 110.6, 77.4, 76.0, 55.8, 28.6, 28.1.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[C:41]([O:45][CH3:46])(=[O:44])[CH:42]=[CH2:43].C(N(CC)CC)C>C(O)C>[CH3:46][O:45][C:41](=[O:44])[CH2:42][CH2:43][NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C=CC(=O)OC
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=C(C)[C@@H]1CC[C@]2(NCCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Yield: 64.4 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (20 mg, 0.037 mmol), methyl acrylate (0.013 mL, 0.147 mmol) and triethylamine (0.026 mL, 0.184 mmol) in ethanol (1 mL) was refluxed for 5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to provide the desired product as a yellow oil (15 mg 65%). LCMS: m/e 630.43 (M+H)+, 3.81 min (method 10).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C([O-])([O-])=O.[K+].[K+].[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][C:17]=1[CH3:26].Cl>O1CCOCC1.O.O1CCOCC1.C(OC(=O)C)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])(=[O:24])=[O:23])=[CH:18][C:17]=1[CH3:26]
Reactant: CC(C)[C@@H](N)C(=O)O
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
D-Valine (1.39 g, 11.9 mmol) was dissolved in 80 ml of dioxane/water (1:1) containing K2CO3 (3.3 g, 24 mmol). A solution of 4-fluro-3-methylphenyl-sulfonylchloride (10 mmol) in dioxane (4 ml) was dropped in with good stirring. The reaction mixture was stirred at room temperature for 30 min. Ethylacetate (80 ml), 1N HCl (50 ml) was added. The organic layer was washed with 1N HCl 2 times, and extracted with 5% K2CO3 (3×25 ml). The combined base extracts was acidified and extracted with ethylaceate (80 ml). The organic layer was washed with brine (2×), dried over Na2SO4. The solvent was removed on rotavap, and residue tritrated with hexane. The resulting solid was dried to give 2(R)-[(4-fluoro-3-methylphenyl-sulfonyl)]amino-3-methylbutyric acid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH:25]([C:29]([OH:31])=[O:30])[CH2:24]1>>[NH:2]1[CH:3]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:23]5[CH2:28][CH2:27][CH2:26][CH:25]([C:29]([OH:31])=[O:30])[CH2:24]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:5]=[N:1]1
Reactant: O=C(O)C1CCCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(O)C1CCCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and piperidine-3-carboxylic acid to give 263. MS: (ESI+)=396.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.I[CH:28]1[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH:30]1[CH2:31][CH:28]([N:10]2[CH:11]=[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:25][CH3:26])=[N:9]2)[CH2:29]1
Reactant: COc1ccc(Cl)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(C2CNC2)cc1NC(=O)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
A suspension of N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (50.0 mg, 0.136 mmol, 1 equiv), tert-butyl 3-iodoazetidine-1-carboxylate (230.3 mg, 0.813 mmol, 6.00 equiv), and cesium carbonate (177 mg, 0.542 mmol, 4.00 equiv) in N,N-dimethylformamide (1 mL) was heated at 50° C. After 5 h, the reaction mixture was partitioned between saturated aqueous sodium chloride solution (5 mL) and ethyl acetate (5 mL). The aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) at 24° C. After 5 h, the reaction mixture was concentrated in vacuo and purified by preparative HPLC to afford product (12.7 mg, 22% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.75 (s, 1H), 9.36 (m, 1H), 8.79 (m, 1H), 8.67 (s, 1H), 8.46 (s, 1H), 7.53-7.56 (m, 2H), 7.29-7.34 (m, 2H), 5.45 (m, 1H), 4.33 (m, 2H), 4.23 (m, 2H), 3.86 (s, 3H). LCMS (ESI): M+H=424.1.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:60][CH:61]=[CH:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:60][CH:61]=[CH:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: N=C(OCC=Cc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OCC=Cc4ccccc4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg in 3 ml 33% methylene chloride in cyclohexane), cinnamyl trichloroacetimidate (52 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 15 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (17 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=[C:18]([CH3:20])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=[C:18]([CH3:20])[C:19]=1[O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Cc1cc(Cl)c(C)c([N+](=O)[O-])c1
Reactant: Oc1ccc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Temperature: 130 °C
Yield: 47.5 %

Procedure:
Into a solution containing 9.10 grams (51.1 mmol) of 4-chloro-1-naphthol and 10.12 grams (46.0 mmol) of 3-chloro-2,5-dimethyl-1-nitrobenzene in 22 milliliters of dimethylsulfoxide at room temperature and under a nitrogen atmosphere was added 8.89 grams (64.4 mmol) of anhydrous potassium carbonate. The resulting mixture was heated to a temperature of 130° C. and maintained at that temperature for a period of 6 hours. The reaction mixture was then filtered and the filtrate was diluted with 20 milliliters of methanol and allowed to cool to room temperature. Crystallization occurred during this cooling period. The filtrate was further cooled in an ice bath, filtered and the collected crystals washed with cold methanol. Recrystallization from a hexane-ethyl acetate mixture afforded 7.92 grams of 3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethyl-1-nitrobenzene as a white solid having a melting point of 135° C.-137° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([C:19](O)=[O:20])[CH:13]=[CH:12][C:11]=2[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:20])[CH:15]=2)[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2cc(C(=O)O)ccc2C1
Product: CC(C)(C)OC(=O)N[C@H]1CCc2cc(C(=O)N3CCCC3)ccc2C1

Procedure:
According to method G, (S)-6-tert-butoxycarbonylamino-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid was reacted with pyrrolidine. The product was thus obtained with the molecular weight of 344.46 (C20H28N2O3); MS (ESI): 345 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[Si]([C:16]#[N:17])(C)(C)C.Cl.[F:19][C:20]1([F:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[Na])(C)=O>CC(O)=O>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([CH:10]([N:23]3[CH2:24][CH2:25][C:20]([F:26])([F:19])[CH2:21][CH2:22]3)[C:16]#[N:17])=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cnc(C2CC2)nc1
Reactant: C[Si](C)(C)C#N
Reactant: FC1(F)CCNCC1
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: CC(=O)O
Product: N#CC(c1cnc(C2CC2)nc1)N1CCC(F)(F)CC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of 2-cyclopropylpyrimidine-5-carbaldehyde (2 g, 13.5 mmol) and TMSCN (2.68 g, 27 mmol) in AcOH (30 mL) was added 4,4-difluoropiperidine hydrochloride (3.1 g, 13.5 mmol), followed by AcONa (2.66 g, 32.4 mg). The mixture was stirred at 30° C. for overnight. The solvent was removed under reduced pressure and saturated NaHCO3 (aq) was added to the mixture to pH=8. The resulting mixture was extracted with EtOAc (3×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give the 2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)acetonitrile as a light red solid (3.5 g, 93%), which was used directly for next step without further purification. 1H NMR (CDCl3 400 MHz): δ 8.69 (s, 2H), 4.88 (s, 1H), 2.73-2.70 (t, J=5.5 Hz, 4H), 2.34-2.27 (m, 1H), 2.11-2.00 (m, 4H), 1.19-1.13 (m, 4H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C@@H:14]1[C@@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C@H:19]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[C@@H:18]([CH2:35][O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)[O:17][C:15]1([CH:43]1[S:48][CH2:47][CH2:46][CH2:45][S:44]1)[OH:16].CO>O1CCCC1.C(OCC)C>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C@H:14]([C@H:20]([C@@H:19]([C@@H:18]([CH2:35][O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1)[OH:17])[O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH:15]([CH:43]1[S:44][CH2:45][CH2:46][CH2:47][S:48]1)[OH:16]
Reactant: OC1(C2SCCCS2)O[C@H](COC2CCCCO2)[C@@H](OC2CCCCO2)[C@H](OC2CCCCO2)[C@H]1OC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: OC(C1SCCCS1)[C@H](OC1CCCCO1)[C@@H](OC1CCCCO1)[C@H](OC1CCCCO1)[C@H](O)COC1CCCCO1
Yield: 49.8 %

Procedure:
Lithium aluminum hydride (1.74 g) was added in small portions under ice-cooling to a solution of 2,3,4,6-tetra-O-(tetrahydropyranyl)-1-C-(1,3-dithian-2-yl)-D-glucopyranose (6.9 g) in tetrahydrofuran-ethyl ether (3:1, 100 mL), and stirred at the same temperature for 5 hours Methanol (10 mL) was added to the mixture to work up the reaction, and then evaporated under reduced pressure. To the residue were added ethyl acetate (100 mL) and 2N hydrochloric acid (80 mL), the insoluble substances were filtrated off. The organic layer was separated, washed with water and saturated sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was chromatographed on a column of silica gel (400 mL). The column was washed with toluene (500 mL) and eluted with toluene-ethyl acetate (3:2) and then with toluene-ethyl acetate (1:2). The compounds supposed to be the two stereoisomers ((1R)- and (1S)-isomers) of 2,3,4,6-tetra-O-(tetrahydropyranyl)-1-C-(1,3-dithian-2-yl)-D-glucitol were eluted separately. The fraction eluted with toluene-ethyl acetate (3:2) was evaporated to dryness under reduced pressure to give a colorless syrup (3.45 g), and the fraction eluted with toluene-ethyl acetate (1:2) was evaporated to dryness under reduced pressure to give a colorless syrup (1.52 g). The isomer eluted with toluene-ethyl acetate (3:2):
Reaction SMILES: [OH-].[K+].C(O)C.[F:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][C:8]=1[NH:20]C(=O)OC>O>[F:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][C:8]=1[NH2:20]
Reactant: COC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 97.1 %

Procedure:
4N potassium hydroxide aqueous solution (4.75 liters) was added to an ethanol solution (3 liters) of methyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate (2.25 kg, 7.85 mol) and the mixture was heated under reflux for 5 hours. After reaction, the reaction liquid was cooled to room temperature, water (5 liters) was added thereto, and this was extracted with toluene (5 liters×2). The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The drying agent was taken out by filtration, and the solvent was removed by distillation under reduced pressure to obtain an oily product of 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.75 kg, 7.62 mol). Yield: 98.3%. Spectral data and other data of the product are those as shown in Example 21.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:8]1=[N:9][NH:10][C:11](=[O:13])[CH:12]=[C:7]1[CH2:6]2.O1[CH:22]=[CH:21][C:20](=[O:23])[CH:19]=[CH:18]1.N>O>[O:23]=[C:20]1[CH:21]=[CH:22][N:2]([C:3]2[CH:4]=[C:5]3[C:14](=[CH:15][CH:16]=2)[C:8]2=[N:9][NH:10][C:11](=[O:13])[CH:12]=[C:7]2[CH2:6]3)[CH:18]=[CH:19]1
Reactant: Nc1ccc2c(c1)Cc1cc(=O)[nH]nc1-2
Reactant: O=c1ccocc1
Agent: Cl
Agent: N
Solvent: O
Product: O=c1ccn(-c2ccc3c(c2)Cc2cc(=O)[nH]nc2-3)cc1

Procedure:
A stirred mixture of 7-amino-[5H]indeno[1,2-c]pyridazin-3(2H)-one hydrochloride (1.0 g) and 4H-pyran-4-one (0.48 g) in water (10 ml) was heated under reflux for 1 hour in a nitrogen atmosphere. The warm mixture was neutralised with aqueous ammonia to give a solid, 0.9 g, m.p. >300° C. This solid was triturated with warm dilute hydrochloric acid and washed with water to give the title compound, 0.42 g, m.p. >300° C.