Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[C:11]([Br:20])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:22](O)([CH3:24])[CH3:23]>>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19][CH:22]([CH3:24])[CH3:23])=[O:18])[C:12]2=[C:11]([Br:20])[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cc(Br)c2n1CCC2C(=O)O
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)C1CCn2c(C(=O)c3ccccc3)cc(Br)c21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1.34 g. of 5-benzoyl-7-bromo-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 50 ml. of isopropanol, cooled in an ice bath is saturated with gaseous hydrogen chloride, maintaining the temperature of the reaction mixture below 50° C. The ice bath is then removed and the reaction mixture is stirred for 1.5 hours at room temperature, and evaporated to dryness under reduced pressure; 10 ml. of benzene is added to the residue and the solution is evaporated under vacuum once again, repeating this process a total of three times to completely remove the excess hydrogen chloride, thus obtaining of isopropyl 5-benzoyl-7-bromo-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate. The product is recrystallized from methanol-ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([C:9]([F:12])([F:11])[F:10])[C:5]([O:7][CH3:8])=[O:6].[CH:14]([C:16]([CH3:18])=[O:17])=[CH2:15].C(N(CC)CC)C.N1C=CC=CC=1>O>[F:10][C:9]([F:11])([F:12])[C:4]([C:5]([O:7][CH3:8])=[O:6])([C:3]([O:2][CH3:1])=[O:13])[CH2:15][CH2:14][C:16](=[O:17])[CH3:18]
Reactant: C=CC(C)=O
Reactant: COC(=O)C(C(=O)OC)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(CCC(C)=O)(C(=O)OC)C(F)(F)F
Temperature: 70 °C
Yield: 73.5 %

Procedure:
A mixture of dimethyl(trifluoromethyl)malonate (4.0 g, 20 mmol), methyl vinyl ketone (1.54 g, 22 mmol), triethylamine (0.30 g, 3 mmol), and pyridine (20 ml) was heated for 4 h at 70° C. The reaction mixture was poured into water and worked up as usual. The adduct, dimethyl 1,1,1-trifluoro-5-oxo-2,2-hexanedicarboxylate (3.97 g), b.p. 88°-89° C./0.2 mmHg, was obtained and identified in a similar way.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][N:18]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]1>CN(C=O)C>[CH3:24][C:20]1[CH:21]=[C:22]([CH3:23])[N:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)[N:19]=1
Reactant: Cc1cc(C)n(CBr)n1
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCn2nc(C)cc2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (1.2 g, 8.8 mmol) was dissolved in anhydrous DMF (50 mL), then potassium carbonate (3.6 g, 26.3 mmol) and 1-(bromomethyl)-3,5-dimethyl-1H-pyrazole (3.0 g, 15.8 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM in MeOH to afford 2-{[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]sulfanyl)-6-methylpyrimidin-4-ol (218 mg, 10% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6) δ 2.12 (s, 3H), 2.22 (s, 3H), 2.30 (s, 3H), 5.81 (s, 2H), 5.83 (s, 6.07 (bs, 1H); LRMS (ES+) m/z 251 (50%, M+1).
Reaction SMILES: CS(O[C@@H:6]1[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH:19]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=O)=O.[NH:35]1[CH:39]=[N:38][CH:37]=[N:36]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[N:9]1[CH2:10][C@H:11]([CH3:12])[C@H:6]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[C@H:7]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[CH2:8]1
Reactant: C[C@H]1CN(c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1cncn1
Yield: 8 %

Procedure:
A solution of (3R,4R,5S)-3-(tert-butoxycarbonylamino)-1-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-5-methylpiperidin-4-yl methanesulfonate (1.0 equiv.), 1H-1,2,4-triazole (3.0 equiv.) and Cs2CO3 (3.0 equiv.) in DMF (0.17 M) was stirred at 90° C. for 3 hrs. The mixture was diluted with DMF, filtered and purified by RP HPLC, followed by free basing by partitioning between an equal volume of EtOAc and Na2CO3, separating, washing with NaCl(sat.), drying over MgSO4, filtering, concentrating to yield tert-butyl (3R,4S,5S)-1-(3-aminopyridin-4-yl)-5-methyl-4-(1H-1,2,4-triazol-1-yl)piperidin-3-ylcarbamate in 8% yield. LC/MS (m/z)=374.3 (MH+), Rt=0.53 min.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([O:22][CH3:23])=[C:16](I)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:27]([OH:30])[C:28]#[CH:29]>C(NCC)C.C1COCC1.C(Cl)Cl.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([O:22][CH3:23])=[C:16]([C:29]#[C:28][CH2:27][OH:30])[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1nc2c(cc1I)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1nc2c(cc1C#CCO)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Temperature: 25 °C
Yield: 68 %

Procedure:
N-(4-chlorobenzyl)-6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide (250 mg), copper iodide (40 mg) and dichlorobis(triphenylphosphine)palladium (30 mg) are dissolved in a mixture of diethylamine (15 mL) and THF (15 mL). To this is added propargyl alcohol (452 μL). The mixture is heated at reflux for 1 h, cooled to room temperature, diluted with CH2Cl2, washed with 1N HCl, brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography (CH2Cl2/MeOH 1/0, 45/1, 19/1, 9/1) and the resulting product is recrystalized from MeOH to afford 144 mg (68%) of N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide. Physical characteristics are as follows: 1H NMR (CDCl3) δ 8.80, 8.60, 7.32, 4.65, 4.57, 4.13, 3.98; IR (diffuse reflectance) 2425, 2350, 2318, 2233, 1921, 1662, 1607, 1551, 1512, 1492, 1465, 1397, 1380, 1292, 809, cm−1; MS (EI) m/z 411 (M+), 244, 86, 84, 80, 79, 78, 65, 63, 61, 51; HRMS (FAB) calcd for C21H18ClN3O4+H1 412.1064, found 412.1067.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>O1CCCC1>[F:23][C:24]1[CH:25]=[C:26]([CH2:27][CH2:13][C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])[CH:29]=[CH:30][CH:31]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1ncccc1C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cccnc1CCc1cccc(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Dissolve diisopropylamine (3.8 mL, 27.3 mmol) in dry tetrahydrofuran (75 mL). Chill the resulting mixture to −78° C. and add butyl lithium (1.6M solution in hexanes, 17.1 mL, 27.3 mmol). Warm the reaction mixture to 0° C. and add a fine slurry of 2-methyl-nicotinic acid (1.5 g, 10.9 mmol) in THF (25 mL) portionwise during 10 min. Stir the resulting slurry for 1 h, then add 3-fluorobenzyl bromide (2.0 mL, 16.4 mmol) and stir 5 min. Quench the reaction with water (100 mL). Extract the reaction mixture with diethyl ether (100 mL). Adjust the pH of the aqueous layer to 3.1 with concentrated aqueous hydrochloric acid solution. Treat the resulting slurry with ethyl acetate and stir to dissolve all solids. Separate the layers and extract the aqueous layer with ethyl acetate. Concentrate the combined extracts to dryness. LCMS (APCI-pos): 244.1 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:24])[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=2)[C:5]1=[O:23].[I:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]I.[NH4+].[Cl-]>CN(C=O)C>[I:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:8]1[C:4]([CH3:24])([CH3:3])[C:5](=[O:23])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=2)[C:7]1=[O:9]
Reactant: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Reactant: ICCCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCI
Temperature: 23 °C
Yield: 47 %

Procedure:
NaH (to 60%) (65 mg, 1.6 mmole) is added under argon to a solution of 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-imidazolidine-2,4-dione (500 mg, 1.6 mmole) in anhydrous DMF (20 ml). A gaseous release accompanies the change of colour of the reaction medium which becomes orange. The stirring is maintained for 1 hour at 23° C. before adding, without dilution, the 1,5-diiodopentane (350 μl, 2.4 mmoles). After reaction for 15 hours, the reaction medium is poured into a saturated aqueous solution of NH4Cl (25 ml) and extracted with AcOEt (2×25 ml). The organic phases are combined and washed successively with water (25 ml) and salt water (25 ml). After drying over Na2SO4, the organic solution is filtered and concentrated under vacuum. The evaporation residue is purified on a silica column (eluent: Heptane/AcOEt:7/3 to 6/4). The expected compound is obtained in the form of a colourless oil with a yield of 47% (380 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]=[C:5]([CH3:18])[C:3]=1[NH2:4].CCN(C(C)C)C(C)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>ClCCl>[Cl:28][CH2:29][C:30]([NH:4][C:3]1[C:2]([CH3:1])=[CH:8][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][C:5]=1[CH3:18])=[O:31]
Reactant: O=C(Cl)CCl
Reactant: CCCCCCCCOc1cc(C)c(N)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCOc1cc(C)c(NC(=O)CCl)c(C)c1

Procedure:
Under a nitrogen atmosphere, 2,6-dimethyl-4-(octyloxy)-aniline (7.2 mmols) was dissolved in 50 mL dichloromethane. To this was added DIPEA (9.4 mmols). The reaction mixture was cooled in an ice bath, and chloroacetyl chloride (7.95 mmoles) dissolved in 50 mL dichloromethane was added by dropping funnel. After the addition was complete, the reaction was stirred at room until reaction was complete by TLC (approximately 0.5 hours). The reaction mixture was concentrated, and partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3 (×2), brine, dried over MgSO4, and filtered (rinsing with ethyl acetate). The filtrate was concentrated to yield 2-chloro-N-(2,6-dimethyl-4-octyloxyphenyl)-acetamide as a white solid (1.21 grams; 51%). The product was characterized by NMR (DMSO).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN1C=CN=C1CC1N(C)C=CN=1.Cl>C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni].CN(C)C(=O)C>[CH2:13]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCCCCCCCBr
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Agent: Cl
Solvent: C1=CCCC=CCC1
Solvent: CC(=O)N(C)C
Product: CCCCCCCCc1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
In an argon atmosphere, 0.4 mmol (61 mg) of p-methoxyphenylboronic acid, 0.3 mmol (57 mg) of 1-bromooctane, 0.45 mmol (95 mg) of potassium phosphate, 0.015 mmol (2.6 mg) of bis(N-methylimidazole-2-yl)methane, and 0.015 mmol (4.1 mg) of bis(1,5-cyclooctadiene)nickel were mixed with 1 ml of N,N-dimethylacetamide. The resulting mixture was heated to 80° C. and then held at the same temperature for 2 hours under stirring. After the reaction was completed, the reaction mixture was allowed to stand at room temperature. After 10 ml of 1 N hydrochloric acid was added to dissolve potassium phosphate, the reaction mixture was transferred to a separating funnel and extracted with ethyl acetate. The extracted organic layer was washed with a saturated sodium chloride solution. The 4-octylanisole was obtained in a yield of 87% as shown in Table 1.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:70])/[C:13](=[N:27]\[O:28][C@@H:29]([CH2:46][O:47][C:48]3[CH:53]=[CH:52][C:51]([C:54](=[NH:69])[NH:55][CH:56]4[CH2:61][CH2:60][N:59](C(OC(C)(C)C)=O)[CH2:58][CH2:57]4)=[CH:50][CH:49]=3)[C:30]([O:32]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:31])/[C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[S:17][CH:18]=3)[C:9](=[O:71])[N:8]2[S:72]([OH:75])(=[O:74])=[O:73])[CH:5]=[N:4][CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:70])/[C:13](=[N:27]\[O:28][C@@H:29]([CH2:46][O:47][C:48]3[CH:49]=[CH:50][C:51]([C:54](=[NH:69])[NH:55][CH:56]4[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]4)=[CH:52][CH:53]=3)[C:30]([OH:32])=[O:31])/[C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)[C:9](=[O:71])[N:8]2[S:72]([OH:75])(=[O:74])=[O:73])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/O[C@@H](COc2ccc(C(=N)NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cncn2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(NC1CCNCC1)c1ccc(OC[C@H](O/N=C(\C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cncn2)c2csc(N)n2)C(=O)O)cc1
Yield: 20 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-3-((Z)-2-((((S)-1-(benzhydryloxy)-3-(4-(N-(1-(tert-butoxycarbonyl)piperidin-4-yl)carbamimidoyl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (0.085 mmol), DCM (850 μL) and TFA (327 μL, 4.25 mmol). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (12 mg, 17%) as a white powder. LCMS: Rt=0.41 min, m/z=706.2 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, DMSO-d6) δ 9.55 (d, J=7.4 Hz, 1H) 9.40 (br s, 1H) 9.01 (br s, 1H) 8.53-8.71 (m, 1H) 8.41 (s, 1H) 7.92 (s, 1H) 7.67 (d, J=9.0 Hz, 2H) 7.21 (br s, 2H) 7.03 (d, J=7.8 Hz, 1H) 6.76 (s, 1H) 5.17-5.24 (m, 1H) 4.94 (d, J=3.9 Hz, 1H) 4.46-4.53 (m, 2H) 4.37-4.45 (m, 1H) 4.25-4.32 (m, 1H) 3.88 (br s, 1H) 3.39 (br s, 4H) 2.92 (t, J=11.5 Hz, 2H) 2.05-2.14 (m, 2H) 1.79 (d, J=11.0 Hz, 2H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[O:9]=[C:10]1[NH:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:15][O:16][CH2:17][CH:18]=[CH2:19])[C:12](=[O:27])[N:11]1[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=1>CN(C=O)C>[O:9]=[C:10]1[N:14]([CH3:1])[C:13]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)([CH2:15][O:16][CH2:17][CH:18]=[CH2:19])[C:12](=[O:27])[N:11]1[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:38])([F:39])[F:37])[CH:29]=1
Reactant: C=CCOCC1(c2ccc(F)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCOCC1(c2ccc(F)cc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
325 mg of potassium carbonate and 0.25 mL of iodomethane are added to a solution of 0.85 g of 4-[2,5-dioxo-4-(4-fluorophenyl)-4-[(2-prop enyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile obtained in step 4, dissolved in 3 mL of DMF. The mixture is stirred at rt for 4 hours under argon atmosphere, evaporated to dryness, diluted with water and brine and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and evaporated to provide the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=S(=O)(Nc1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
3-Bromobenzenesulfonyl chloride (51a) (110 g, 3.9 mmol) was added to a mixture of aniline (0.47 g, 5.1 mmol) in acetonitrile (10 ml) and sodium carbonate (1.3 g, 12.3 mmol) in water (10 ml). The mixture was stirred at ambient temperature for 1 hour and the reaction product was extracted with ethyl acetate (30 ml). The extract was dried (Na2SO4) and solvents were removed under reduced pressure to give the title compound (1.15 g, 94%) as an oil witch solidified upon standing. M.p. 98-100° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.94-7.48 (5H, m, C6H5); 7.50-7.96 (4H, m, C6H4); 10.36 (1H, s, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5](I)[N:4]=1.[Cu](C#N)[C:13]#[N:14]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([C:13]#[N:14])[N:4]=1
Reactant: COc1ccc(I)nc1OC
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: COc1ccc(C#N)nc1OC
Temperature: 150 °C

Procedure:
To a solution of 2,3-dimethoxy-6-iodopyridine (4-4, 24.0 g, 91 mmol) in DMF (181 mL) was added copper cyanide (9.73 g, 109 mmol) and heated to 150° C. for 20 minutes in a microwave reactor. The mixture was partitioned between saturated sodium carbonate and EtOAc three times. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 40% EtOAc in hexanes) to yield the desired product (4-5) as an off-white crystalline powder. ESI+MS [M+H]+ C8H8N2O2: 165.0 found, 165.1 required.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14](SC)=[N:15][CH2:16][Si](C)(C)C)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:2].[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[C:25]=1[Cl:37].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[N:9]1([C:8]2[CH:7]=[CH:6][C:5]([C:14]3[CH2:31][C:30]([C:28]4[CH:27]=[C:26]([Cl:36])[C:25]([Cl:37])=[C:24]([Cl:23])[CH:29]=4)([C:32]([F:35])([F:34])[F:33])[CH2:16][N:15]=3)=[CH:4][C:3]=2[C:1]#[N:2])[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(-n2cncn2)c(C#N)c1
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1-n1cncn1
Temperature: -5 °C
Yield: 85 %

Procedure:
methyl 3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzenecarbimidothioate (0.2 g) and 1,2,3-trichloro-5-[1-(trifluoromethyl)ethenyl]benzene (0.17 g) were dissolved in THF and cooled to −5° C. to be stirring. Additionally a solution of tetrabutylammonium fluoride (0.099 mL of 1.0 M in THF) in THF was added over 10 minutes under argon atmosphere. The reaction mixture was stirred for 30 minutes at the same temperature and returned to room temperature gradually, and then stirred 4 hours. Water was added to the reaction liquor, and aqueous layer was extracted with ethyl acetate. The combined organic layers, were washed with a saturated aqueous brine, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 2-(1H-1,2,4-triazol-1-yl)-5-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]benzonitrile (0.25 g) at a yield of 85%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[CH2:17][C@H:16]([CH2:18][F:19])[O:15][CH2:14][C@:12]2([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[N:13]=1)(C)(C)C.FC(F)(F)C(O)=O.FC1C=CC=CC=1[C@]12CO[C@@H](COC(C)C)C[C@H]1CSC(N)=N2>>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[C@:12]12[CH2:14][O:15][C@@H:16]([CH2:18][F:19])[CH2:17][C@H:11]1[CH2:10][S:9][C:8]([NH2:7])=[N:13]2
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@H]2CS1
Agent: CC(C)OC[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2ccccc2F)CO1
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@H]2CS1

Procedure:
tert-Butyl[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]carbamate (C25) was converted to the product according to the general procedure for the synthesis of (4aR,6R,8aS)-8a-(2-fluorophenyl)-6-[(propan-2-yloxy)methyl]-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine, trifluoroacetate salt (2) in Example 2. In this case, the reversed-phase HPLC purification was carried out using a different system (Column: Waters XBridge C18, 5 μm; Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v); Gradient: 5% to 100% B), affording the product as an oil. Yield: 17 mg, 0.054 mmol, quantitative. LCMS m/z 317.2 (M+1). 1H NMR (600 MHz, DMSO-d6) δ 1.56-1.64 (m, 1H), 1.66-1.72 (m, 1H), 2.88 (dd, J=13.2, 3.5 Hz, 1H), 3.02 (br d, J=13 Hz, 1H), 3.14-3.21 (m, 1H), 3.88 (d, half of AB quartet, J=12.3 Hz, 1H), 3.92-4.01 (m, 2H), 4.38-4.57 (m, 2H), 7.21-7.26 (m, 1H), 7.28-7.34 (m, 1H), 7.36-7.41 (m, 1H).
Reaction SMILES: CN(C)[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.NC(N)=O.Cl.[C:17]1(=O)[CH:22]=[CH:21][C:20](=O)[CH:19]=[CH:18]1>>[C:6]1([CH:7]([C:3]2[CH:10]=[CH:9][CH:6]=[CH:5][CH:4]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=[CH:10][CH:3]=[CH:4][CH:5]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: O=C1C=CC(=O)C=C1
Agent: Cl
Agent: NC(N)=O
Product: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
1000 parts of the intermediate from Example 1 was charged to a flask containing 66 parts of p-dimethylaminobenzaldehyde and 14 parts of urea. To this mixture was charged 90 parts of muriatic acid over a 5 minute period. This mixture was allowed to heat up to 95-105° C., and maintained at this temperature overnight. At the end of the hold period, the reaction mixture was allowed to cool to 75° C., and 120 parts of p-benzoquinone was added. The mixture was allowed to stir for 1.5 hrs maintaining a temperature of 75-85° C. The acid is neutralized with a caustic solution, the product washed with water, and dried. A UV/VIS spectrum of the bright mid range blue product shows a lambda max absorbances at 548 nm and 607 nm in toluene.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[C:6]([I:13])[CH:7]=[C:8]([F:12])[C:9]=2[Cl:11])[C:4](=[O:14])[N:3]1C(C)(C1C=CC=CC=1)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[Cl:11][C:9]1[C:8]([F:12])=[CH:7][C:6]([I:13])=[C:5]2[C:10]=1[CH2:2][NH:3][C:4]2=[O:14]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(I)cc(F)c(Cl)c2C1O
Agent: CC[SiH](CC)CC
Solvent: C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2c(Cl)c(F)cc(I)c21
Yield: 84.6 %

Procedure:
In a similar manner to Step 4 of Example 16, 3-hydroxy-4-chloro-5-fluoro-7-iodo-2(1-methyl-1-phenylethyl)isoindolinone (806 mg, 1.81 mmol) was dissolved in nitromethane (32 mL), and the solution was treated with trifluoroacetic acid (1.40 mL, 18.1 mmol) and triethylsilane (0.578 mL, 3.62 mmol), followed by purification by slurry using diisopropylether to obtain 4-chloro-5-fluoro-7-iodoisoindolinone (477 mg, yield 85%).