Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[H][H]>CO.[Ni]>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[NH2:12])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCS(=O)(=O)c1cccc(N)c1

Procedure:
1-(Ethylsulfonyl)-3-nitro-benzene (1.9 g; 9 mmol) was dissolved in 80 mL of methanol then 1 g of Raney-Nickel is added and the mixture treated with hydrogen gas. The reaction mixture was subsequently filtered and concentrated to yield 1.5 g (8.1 mmol; yield=93%) of an yellow oil.
Reaction SMILES: CC(N(C[C@@H:10]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][N:12]([C:17]2[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([NH2:24])[N:18]=2)[CH2:11]1)C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O.C[CH2:33][N:34](C(C)C)C(C)C.[CH3:41][C:42]([CH3:48])([CH3:47])[CH2:43][C:44](Cl)=[O:45].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:24][C:19]1[N:18]=[C:17]([N:12]2[CH2:13][C@H:14]([CH3:16])[CH2:15][C@@H:10]([N:34]([CH3:33])[C:44](=[O:45])[CH2:43][C:42]([CH3:48])([CH3:47])[CH3:41])[CH2:11]2)[CH:22]=[C:21]([Cl:23])[N:20]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H]1C[C@@H](CN(C(=O)[O-])C(C)(C)C)CN(c2cc(Cl)nc(N)n2)C1
Reactant: CC(C)(C)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C[C@@H](N(C)C(=O)CC(C)(C)C)CN(c2cc(Cl)nc(N)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.6 %

Procedure:
To 1,1-dimethylethyl[(3R,5R)-1-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-3-piperidinyl]methylcarbamate (75 mg, 0.211 mmol) in CH2Cl2 (2 mL) was added TFA (2 mL) and the reaction was let sit at room temperature for 2 hours. Toluene (˜15 mL) was added, and the resulting mixture was evaporated under vacuum. To the resulting residue were added CH2Cl2 (2 mL) and Hunig's base (0.18 mL, 1.05 mmol) followed by 3,3-dimethylbutanoyl chloride (0.03 mL, 0.21 mmol), and the resulting mixture was stirred overnight at room temperature. Saturated aqueous NaHCO3 (20 mL) was added, and the resulting mixture was extracted with EtOAc (˜50 mL). The organic layer was separated, washed with brine, dried (MgSO4), filtered, and concentrated to afford the title compound (80 mg). LC-MS (ES) m/z=354 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.[C:11]([O-:14])(=[O:13])[CH3:12].[Na+]>C(O)(=O)C.[I-].[Na+]>[C:11]([O:14][CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)[O-]
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCc1cc(=O)[nH]c(=O)[nH]1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A mixture of 16.05 g (0.10 mol) of 6-chloromethyl-uracil, 9.85 g (0.12 mol) of sodium acetate and 0.3 g of sodium iodide in 50 ml of glacial acetic acid is heated at reflux for 20 minutes. The mixture is subsequently cooled to room temperature and filtered. The filtrate is treated with 250 ml of diethyl ether and the resulting crystals are filtered off. The combined crystallizate is added to 200 ml of water and thus liberated from the residual salts. 11.3 g of 6-acetoxymethyl-uracil are isolated by filtration.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:13][C:14]([F:26])([F:25])[S:15]([C:18]1[CH:23]=[CH:22][C:21](Cl)=[CH:20][CH:19]=1)(=[O:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([O:1][C:21]2[CH:22]=[CH:23][C:18]([S:15]([C:14]([F:26])([F:25])[F:13])(=[O:17])=[O:16])=[CH:19][CH:20]=2)[CH:11]=[C:10]([O:12][C:21]2[CH:20]=[CH:19][C:18]([S:15]([C:14]([F:25])([F:13])[F:26])(=[O:17])=[O:16])=[CH:23][CH:22]=2)[CH:9]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2)cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2)c1

Procedure:
A mixture of methyl 3,5-dihydroxybenzoate (100 mg, 0.595 mmol), 4-(trifluoromethylsulfonyl)chlorobenzene (291 mg, 1.189 mmol) and potassium carbonate (330 mg, 2.379 mmol) was heated in DMF to give 3,5-bis-(4-trifluoromethanesulfonyl-phenoxy)-benzoic acid methyl ester. It was then hydrolysed with potassium hydroxide (25 mg) in THF (10 mL) and water (10 mL) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=9.2 Hz, 4H), 7.57 (d, J=2.11 Hz, 2H), 7.39 (d, J=9.2 Hz, 4H), 7.39 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:14]([O:16][CH3:17])=[O:15])=[O:2].CCN(CC)CC.[C:25]1([N:31](S(C(F)(F)F)(=O)=O)[S:32]([C:35]([F:38])([F:37])[F:36])(=[O:34])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl.CCOCC>[C:25]1([NH:31][S:32]([C:35]([F:38])([F:36])[F:37])(=[O:34])=[O:33])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1.[CH:1]([C:3]1[C:12]([O:13][S:32]([C:35]([F:38])([F:37])[F:36])(=[O:34])=[O:33])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:14]([O:16][CH3:17])=[O:15])=[O:2]
Reactant: COC(=O)c1cccc2c(C=O)c(O)ccc12
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)c1cccc2c(C=O)c(OS(=O)(=O)C(F)(F)F)ccc12
Product: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of methyl 5-formyl-6-hydroxy-1-naphthoate (500 mg, 2.17 mmol) in CH2Cl2 (10.2 mL) at rt was added Et3N (483 mg, 4.78 mmol, 0.664 mL) followed by PhNTf2 (928 mg, 2.6 mmol). The mixture was stirred for 18 h and then diluted with Et2O and washed with 1.0 M HCl. The extract was dried with MgSO4 and concentrated in vacuo. The crude material was chromatographed on silica gel (20:1 hexanes/EtOAc), and the material thus obtained was recrystallized from hexanes to give 1.0 g of a 3:2 mixture of the title compound and PhNHTf (˜90% yield).
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=O.Cl.[NH:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>S(Cl)(Cl)=O.ClCCl>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([O:23][CH3:24])=[O:22])=[O:6]
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 22 h
Yield: 83 %

Procedure:
A solution of 1.82 g (8.94 mmol) of 2,6-difluoro-3-nitrobenzoic acid in 36 ml of thionyl chloride was refluxed for three and a half hours. The reaction medium was concentrated and was co-evaporated twice with toluene. The residue obtained was dissolved in 50 ml of dichloromethane under nitrogen. 1.48 g (8.94 mmol) of methyl (S)-pyrrolidine-2-carboxylate hydrochloride were added and the reaction medium was cooled to 0° C. 2.75 ml (19.67 mmol, 2.2 eq) of triethylamine were then added dropwise. After 22 hours, a saturated aqueous sodium hydrogen carbonate solution was added. The organic phase was again washed with a saturated aqueous sodium hydrogen carbonate solution and then twice more with a 1 M aqueous hydrochloric acid solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. 2.52 g were obtained. Yield=83%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[N:11]#[C:12][NH2:13].[N+:14]([O-:17])([OH:16])=[O:15]>>[N+:14]([O-:17])([O-:16])=[O:15].[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:12]([NH2:13])=[NH2+:11])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: N#CN
Product: NC(=[NH2+])Nc1ccc2[nH]ncc2c1
Product: O=[N+]([O-])[O-]

Procedure:
Indazol-5-ylguanidinium nitrate was prepared from 5-aminoindazole (4.0 g, mmol), cyanamide (1.89 g, 45.1 mmol) and concentrated HNO3 (2.8 ml) to give the desired material as a solid m.p. 252-254°.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][NH2:37])[CH2:30]2)[CH2:24][CH2:23][CH2:22][CH2:21]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:50].Cl.N>ClCCl.C(O)C>[ClH:1].[ClH:50].[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][NH:37][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCCC(CCCCN2CCCC2)C1
Agent: Cl
Agent: N
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Solvent: ClCCl
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCC(CCCCN3CCCC3)C2)c2ccccc21
Yield: 35 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[4-(pyrrolidin-l-yl)butyl]-piperidin-l-yl]ethanamine in a yield of 35% of theory. The colourless dihydrochloride melted at 170°-172° C.; RF 0.69 (HPTLC ready-made silica gel plates 60 F254 for Nano-TLC, Messrs Merck; eluant: dichloromethane/ethanol/conc. ammonia 65/30/5 v/v/v).
Reaction SMILES: C(SCC1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](C3C=CC=CC=3OC)[CH:18]=2)[NH:13]C(C)(C)C=1)C1C=CC=CC=1.Br[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][CH3:49])[CH:40]=2)[NH:35][C:34]([CH3:51])([CH3:50])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].C(S)C1C=CC=CC=1>>[CH3:49][O:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([CH3:51])([CH3:50])[CH:33]=[C:32]2[CH2:31][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSCc1ccccc1)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: SCc1ccccc1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-Benzylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 80 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 69 mg of potassium carbonate, and 52 μL of benzyl mercaptan reacted to give 12 mg of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7]1.[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28])(=[O:23])=[O:22].C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][NH:15][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH:25]=2)[CH2:10][CH2:11]1
Reactant: NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(C(=O)NCCCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1
Product: Cl
Yield: 112.3 %

Procedure:
The product of Step (b) (0.15 g) was dissolved in DMF (4 ml). 3-Methylsulphonyl-benzoic acid (0.110 g), triethylamine (0.250 ml) and PyBrop® (0.350 g) were added. After 8 hours at room temperature the solvents were evaporated and the residue redissolved in ethyl acetate. The organics were washed with H2O, dried with MgSO4 and concentrated. Purification by reverse phase HPLC (with a gradient eluent system (25% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)) and formation of the hydrochloride salt by addition of HCl dissolved in ether and evaporation of solvent gave the title compound (0.145 g).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[C@@H:30]3[CH2:31][C@@H:27]([CH:28]=[CH:29]3)[C@@H:26]2[C:32]([NH2:34])=[O:33])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C@@H:25]2[C@@H:30]3[CH2:31][C@@H:27]([CH:28]=[CH:29]3)[C@@H:26]2[C:32]([NH2:34])=[O:33])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Product: CN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)ccc21

Procedure:
The title compound was prepared in an analogous manner to the preparation of example 381 by combining 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide to yield an off-white solid, (64%). mp 233° C.; LCMS: m/z=481.06 (M+H+), 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.97 (m, 2H), 7.79 (m, 2H), 7.51 (s, 1H), 7.24 (m, 2H), 6.33 (m, 2H), 4.15 (m, 1H), 3.16 (s, 3H), 2.89 (s, 1H), 2.78 (s, 1H), 2.54 (s, 1H), 2.12 (m, 3H), 1.94 (m, 2H), 1.41 (m, 1H), 1.25 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[CH:14][C:15]1[CH:16]=[N:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])=[CH:19][CH:20]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[Pd].CO>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])=[CH:19][CH:20]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=Cc1ccc(-c2cccc(F)c2F)nc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(Cc1ccc(-c2cccc(F)c2F)nc1)NC(=O)OC(C)(C)C
Yield: 89.2 %

Procedure:
10% Palladium on carbon (10 mg) was added to a mixture of methyl 2-[(tert-butoxycarbonyl)amino]-3-[6-(2,3-difluorophenyl)pyridin-3-yl]acrylate (70 mg, 0.2 mmol) in methanol (3 mL) and acetic acid (0.5 mL, 9 mmol). The reaction was shaken in parr shaker under H2 at 60 Psi for 5 h. The reaction was complete by LC-MS, this was filtered and concentrated under reduced pressure to give crude methyl 2-(tert-butoxycarbonylamino)-3-(6-(2,3-difluorophenyl)pyridin-3-yl)propanoate (0.07 g, 100%) as an oil. Analytical LCMS (M+H)+: m/z=393.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)OC(C)(C)C)=[C:4]([CH3:16])[CH:3]=1.[CH:17]([Li])([CH2:19][CH3:20])[CH3:18].CON(C)C(=O)C(C)CC.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:9]([CH:17]([CH3:18])[CH2:19][CH3:20])=[CH:16]2
Reactant: [Li]C(C)CC
Reactant: Cc1cc(Cl)ccc1NC(=O)OC(C)(C)C
Agent: CCC(C)C(=O)N(C)OC
Agent: Cl
Solvent: C1CCOC1
Product: CCC(C)c1cc2cc(Cl)ccc2[nH]1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (4-chloro-2-methylphenyl)carbamate (338 mg) in tetrahydrofuran (6 mL) was added dropwise sec-butyllithium (1.04 mol/L hexane-cyclohexane solution, 2.69 mL) at −70° C. under an argon atmosphere. The mixture was warmed to −40° C. and then stirred for 10 minutes. Then a solution of N-methoxy-N,2-dimethylbutanamide (203 mg) in tetrahydrofuran (0.5 mL) was added dropwise, and the mixture was stirred at −40° C. for 40 minutes. The mixture was stirred at room temperature for additional 2 hours. 1 mol/L Hydrochloric acid (2.8 mL) was added to the reaction mixture under cooling with ice, and this resulting mixture was extracted with diethyl ether. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue (446 mg) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (0.8 mL) was added and this resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with dichloromethane, washed successively with water and a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (173 mg).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8]([C@@:10]1([F:26])[C@@H:12]2[CH2:13][C@@H:14]3[C@:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([C@H:11]12)OS(=O)(=O)[O:15]3)=[O:9])[CH3:6]>CN(C)C=O.O>[CH2:22]([O:21][C:19]([C@:18]1([N:1]=[N+:2]=[N-:3])[C@H:14]([OH:15])[CH2:13][C@@H:12]2[C@H:11]1[C@@:10]2([F:26])[C:8]([O:7][CH2:5][CH3:6])=[O:9])=[O:20])[CH3:23]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H]3OS(=O)(=O)O[C@@]3(C(=O)OCC)[C@@H]21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 34 h
Yield: 91.2 %

Procedure:
37.7 g of sodium azide was added to 109 g of (1R,1aR,1bS,4aR,5aR)-1-fluoro-3,3-dioxotetrahydro-2,4-dioxa-3λ6-thiacyclopropa[a]pentalene-1,1b-dicarboxylic acid diethyl ester dissolved in 1.10 L of N,N-dimethylformamide and 110 mL of water, and the mixture was stirred for 14 hours at 50° C. The solvent was distilled off under reduced pressure, and after the residue was dissolved in 6.48 L of diethyl ether and 177 mL of water, 516 mL of 20% (V/V) sulfuric acid was added thereto, and the mixture was stirred for 34 hours at room temperature. After the reaction solution was separated, the organic layers were twice washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=4:1), thereby yielding 88.5 g of (1R,2R,3R,5R,6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[CH3:17][C:18]1[CH:19]=[C:20]([C:29](=[O:31])[CH3:30])[S:21][C:22]=1[C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26].CC(OC)(C)C>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]([OH:16])([C:12]([F:13])([F:14])[F:15])[CH2:30][C:29]([C:20]2[S:21][C:22]([C:23]#[C:24][Si:25]([CH3:28])([CH3:26])[CH3:27])=[C:18]([CH3:17])[CH:19]=2)=[O:31])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1cc(C)c(C#C[Si](C)(C)C)s1
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)sc1C#C[Si](C)(C)C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
LiH (1.72 g) is added to a solution of 3′,5′-dichloro-2,2,2-trifluoroacetophenone (26.6 g) and 1-(4-methyl-5-trimethylsilanylethynyl-thiophen-2-yl)-ethanone (18.2 g) in THF (100 ml). After 30 minutes at 60° C. MTBE is added (200 ml) and the reaction mixture is poured onto water (30 ml) at 5° C. The organic phase is extracted with water and a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo to yield 3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-1-(4-methyl-5-trimethylsilanylethynyl-thiophen-2-yl)-butan-1-one (20.7 g). The crude product is used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:31][C@H:32]1[O:34][CH2:33]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[O:34]1[CH2:33][C@H:32]1[CH2:31][N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2[nH]ncc2c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@@H]2CO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 1-(1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (1.1 g, 3.1 mmol), (S)-(+)-glycidyl nosylate (0.96 g, 3.7 mmol) and cesium carbonate (1.5 g, 4.6 mmol) in methyl sulfoxide (10 mL) was stirred at ambient temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by column chromatography (silica gel, ethyl acetate) gave the title compound (510 mg, 40%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.76-7.73 (m, 5H), 7.64 (d, J=9.0 Hz, 1H), 7.51 (d, J=7.0 Hz, 1H), 7.47 (dd, J=9.0, 2.0 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.52 (dd, J=7.5, 2.0 Hz, 1H), 4.78 (dd, J=15.5, 3.5 Hz, 1H), 4.48 (dd, J=15.0, 5.5 Hz, 1H), 3.41-3.38 (m, 1H), 2.88 (app t, J=4.5 Hz, 1H), 2.60 (dd, J=5.0, 3.0 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[N:16][C:17]#[N:18])OC2C=CC=CC=2)[CH:2]=1.[CH3:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(C)C>CO>[C:17]([N:16]=[C:8]([NH:27][C@@H:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:19])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)#[N:18]
Reactant: C[C@@H](N)c1ccccc1
Reactant: N#CN=C(Nc1cccnc1)Oc1ccccc1
Solvent: CO
Solvent: CC(C)O
Product: C[C@@H](NC(=NC#N)Nc1cccnc1)c1ccccc1
Yield: 7403.7 %

Procedure:
A stirred mixture of N-(3-pyridyl)-N'-cyano-O-phenylisourea (see, Example 5 for procedure) (8.00 g, 0.336 mmol), (R)-α-methylbenzylamine (10.8 mL, 0.0835 mol) and isopropanol (53.3 mL) was refluxed, under nitrogen, for 4 hours. The reaction was complete by TLC with 10% MeOH-1% NH4OH-CHCl3. The mixture was concentrated in vacuo. The residue was mixed with EtOAc several times with concentration after each addition; the resulting solid was triturated with hot EtOAc, collected by filtration and recrystallized from MeOH-CH2Cl2 -EtOAc to give 6.6 g of product: mp 185°-187° C.
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][NH2:4].CN(C)C1C=CC=CC=1.[Br:19][CH2:20][C:21](Br)=[O:22]>C(OCC)(=O)C>[Br:19][CH2:20][C:21]([NH:4][CH2:3][C:2]([F:9])([F:1])[C:5]([F:8])([F:7])[F:6])=[O:22]
Reactant: O=C(Br)CBr
Reactant: NCC(F)(F)C(F)(F)F
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(CBr)NCC(F)(F)C(F)(F)F
Temperature: -10 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
2,2,3,3,3-Pentafluoropropylamine (produced by Synquest) (389 g) was dissolved in ethyl acetate (1.56 l), and N,N-dimethylaniline (316 g) was added thereto. The resulting mixture was cooled to −10° C., and bromoacetyl bromide (500 g) was added dropwise thereto, followed by stirring the resulting mixture at a temperature between 10° C. and 0° C. for 2 hours. After completion of the reaction, the organic layer was sequentially washed with hydrochloric acid, aqueous sodium bicarbonate and with brine, and dried over magnesium sulfate, followed by evaporation under reduced pressure to obtain 678 g of 2-bromo-N-(2,2,3,3,3-pentafluoropropyl)acetamide as white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=O)[NH:6][CH:7]=1.C(=O)([O-])[O-:10].[K+].[K+].I[CH:16]([CH3:18])[CH3:17]>CN(C=O)C.C(OCC)(=O)C.O>[CH:16]([O:10][C:2]1[CH:3]=[CH:4][CH:5]=[N:6][CH:7]=1)([CH3:18])[CH3:17]
Reactant: O=C([O-])[O-]
Reactant: CC(C)I
Reactant: O=c1ccc(Br)c[nH]1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1cccnc1

Procedure:
5-bromo-1H-pyridone 1BI (100 g, 0.58 mol), potassium carbonate (238 g, 1.73 mol) and 2-iodopropane (86 ml, 0.86 mol) were stirred in DMF (1 L) at r.t. for 1 day. The mixture were diluted with ethyl acetate and water, layers were separated. The separated organic layer was washed with water (×2), dried (Mg SO4) and filtered. Solvents were removed in vacuum and column purification [5% ethyl acetate in hexanes] gave first the less polar 5-isopropoxypyridine 2BIa (73 g, 59%) as colourless liquid. Continuous elution with [50% ethyl acetate in hexanes] gave the more polar 5-bromo-1-isopropylpyridone 2BIb as white solid (22 g, 18%).