Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:7](=[O:15])[C:6]3([CH3:20])[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.[CH3:21][NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)=[O:24].C(=O)(O)[O-].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:12]([N:8]1[C:7](=[O:15])[C:6]2([CH3:20])[CH2:16][O:17][CH2:18][CH2:19][N:5]2[C:4]2[N:3]=[C:2]([C:29]3[CH:28]=[CH:27][C:26]([NH:25][C:23]([NH:22][CH3:21])=[O:24])=[CH:31][CH:30]=3)[N:11]=[CH:10][C:9]1=2)([CH3:14])[CH3:13]
Reactant: CC(C)N1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCOCC2(C)C(=O)N3C(C)C)cc1
Temperature: 100 °C
Yield: 22.1 %

Procedure:
2-Chloro-5-isopropyl-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (98 mg, 0.330 mmol) was mixed with PdCl2(dppf) (48.3 mg), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (100 mg, 0.363 mmol) and saturated sodium bicarbonate solution (2 mL, sat.) in 1,4-dioxane (4 mL). The suspension was heated by microwave irradiation at 100° C. for 30 minutes. The suspension was filtered, the solids washed with methanol then DMSO and the filtrate evaporated in vacuo. The resulting solid was purified by mass-triggered preparative HPLC eluted with 20-35% of ACN (containing 0.035% TFA) in water (containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mm column) to give the title compound (30 mg 22% yield) as a pale yellow solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.55 (m, 6 H) 1.62 (s, 3 H) 2.80 (s, 3 H) 3.50 (td, J=12, 4 Hz, 1 H) 3.68 (td, J=12, 4 Hz, 1 H) 3.79 (d, J=12 Hz, 1 H) 4.14 (m, 1 H) 4.62 (dd, J=12, 4 Hz, 1 H) 4.66 (m, 1H) 7.62 (d, J=8 Hz, 2 H) 8.10 (d, J=8 Hz, 2H) 8.13 (s, 1H). MS [M+H] Found 411.
Reaction SMILES: [Cl:1][C@@:2]1([CH3:30])[C@H:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:29])[C@@H:17]([NH:18]C(=O)COC3C=CC=CC=3)[C@H:5]2[S:4][CH2:3]1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>C1C=CC=CC=1.O1CCCC1>[NH2:18][C@@H:17]1[C:16](=[O:29])[N:6]2[C@@H:7]([C:8]([O:10][CH2:11][C:12]([Cl:14])([Cl:13])[Cl:15])=[O:9])[C@@:2]([Cl:1])([CH3:30])[CH2:3][S:4][C@H:5]12
Reactant: C[C@@]1(Cl)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCC(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C[C@@]1(Cl)CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OCC(Cl)(Cl)Cl
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 2,2,2-trichloroethyl 3β-chloro-3α-methyl-7β-phenoxyacetamidocepham-4α-carboxylate (2.29 g) in benzene (130 ml) is added pyridine (10 ml) and the mixture is cooled at -60°C in the presence of phosphorous pentachloride (1.51 g) for 2 hours. The reaction mixture is evaporated in vacuo to remove benzene, methanol (250 ml) is added thereto, and the solution kept at room temperature overnight. The solution is concentrated to give a residue which is dissolved in 50% aqueous tetrahydrofuran (50 ml), and the tetrahydrofuran is evaporated after 15 minutes. The residual solution is neutralized with 1N sodium hydroxide, and evaporated to give 2,2,2-trichloroethyl 7β-amino-3β-chloro-3α-methylcepham-4α-carboxylate (1.53 g).
Reaction SMILES: [CH:1]1[C:14]2[C:5]([S:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.C(N(CC)CC)C.[CH2:23]([SH:27])[CH2:24][CH2:25][CH3:26].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CO>[CH2:23]([S:27][C:2]1[C:3](=[O:15])[CH:4]=[C:5]2[C:14](=[N:13][C:12]3[C:7]([S:6]2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:1]=1)[CH2:24][CH2:25][CH3:26]
Reactant: O=c1ccc2nc3ccccc3sc-2c1
Reactant: CCCCS
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCSc1cc2nc3ccccc3sc-2cc1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3H-phenothiazin-3-one (0.64 g) in 75 ml methanol was added triethylamine (1.0 ml) and n-butanethiol (0.58 ml). The mixture was stirred at room temperature for 48 hours. Then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.67 g) was added. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was chromatographed on neutral alumina (Act III) and eluted with 15% EtOAc/hexane to afford the title compound (0.4 g), m.p. 133° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:10]([O:13]C(=O)C)[CH:11]=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([Mg]Cl)[CH:25]([CH3:27])[CH3:26]>C1COCC1.CCOCC.CO.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:10]([OH:13])[C@@H:11]([OH:12])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)O[C@@H](C=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC(C)C[Mg]Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The oil prepared in Example 2 was dissolved under nitrogen in 100 mL of dry THF and cooled to -70°. To this solution was added 13 mL (26 mmol) of a 2.0M solution of isobutylmagnesium chloride in ether and the stirred mixture was allowed to warm to room temperature and stir for 2 hrs. After decomposition with MeOH/H2O the mixture was diluted with ether, washed with saturated NH4Cl solution twice, then dried and the solvents stripped off under vacuum. The residue was allowed to stand overnight in 80% MeOH-H2O containing excess ammonium hydroxide. The MeOH was stripped off and the mixture was extracted with ether. These extracts were combined, washed with water, dilute KHSO4, then dried and evaporated to give 2.36 g of a yellow glass which crystallized from 50 mL of pentane on standing overnight. The yellow-white powder obtained was recrystallized from ether-hexane and furnished the title compound (0.41 g) as white, hairy needles, mp 134°-136°, Rf (ether): single spot, 0.6. By chromatography of the mother liquors and crystallization of the appropriate fractions, an additional 0.22 g of product, mp 138°-139° was obtained.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16](B4OC(C)(C)C(C)(C)O4)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:29][C:30]1[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[I:29][C:30]1[CH:35]=[CH:34][C:33]([C:16]2[CH:17]=[CH:18][C:19]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:8]4[C:13]([C:14]=3[CH:15]=2)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:32][CH:31]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC1(C)OB(c2ccc3c(c2)c2ccccc2n3-c2ccccc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Ic1ccc(-c2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
90 g (244 mmol) 9-Phenyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9H-carbazole and 69 g (244 mmol) 1-Iodo-4-Brombenzene [589-87-7] are dissolved in 500 ml toluene treated with 200 ml of a 2 M solution of sodium carbonate. The reaction mixture is carefully degassed and 200 mg tetrakistriphenylphosphine palladiume are added. The reaction is heated to reflux for 20 h. The solution is then cooled to room temperature and the layers are separated. The water phase is extracted three times with toluene, and then the organic layers is washed twice with water dried over magnesium sulphate, filtrated and the solvent is removed in the vacuum. The residue is recrystallized from DMF, to yield 100 g (225 mmol) (92%) of a with powder with a purity of 98.7%.
Reaction SMILES: O.[NH2:2][NH2:3].Br[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8]>C(O)(C)C>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([CH:5]([NH:2][NH2:3])[CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: NN
Reactant: CCCC(Br)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CC(C)O
Product: CCCC(NN)c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Hydrazine monohydrate (8.9 g) was dissolved in isopropanol (25 ml) and 1-(1-bromobutyl)-4-(trifluoromethyl)benzene (as prepared in WO 2005013985, 2.0 g, 7.12 mmol) added. The mixture was heated to 70° C. and stirred for 16 h. After this time the solvent was removed and the residue taken up in ethyl acetate and washed three times (H2O). The combined organics were dried (sodium sulfate) and concentrated to give the mixture of products as a white solid suspended in a clear oil. The mixture was triturated with diethyl ether to give a white solid; 1H NMR δ (ppm)(DMSO): 9.20 (1 H, s), 7.76 (2 H, d, J=8.1 Hz), 7.64 (2 H, s), 4.16 (1 H, s), 1.85 (1 H, s), 1.59 (1 H, s), 1.20-0.96 (2 H, m), 0.82 (3 H, t, J=7.3 Hz).
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[C:16]([N+:17]([O-])=O)=[C:15]2[C:10]([N:11]=[CH:12][C:13]([CH3:20])=[N:14]2)=[CH:9][CH:8]=1>CCOC(C)=O.C(O)C>[Cl:6][C:7]1[C:16]([NH2:17])=[C:15]2[C:10](=[CH:9][CH:8]=1)[N:11]=[CH:12][C:13]([CH3:20])=[N:14]2
Reactant: Cc1cnc2ccc(Cl)c([N+](=O)[O-])c2n1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1cnc2ccc(Cl)c(N)c2n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Tin(II)-chloride dihydrate (21.7 g, 96.12 mmol, 5.4 equiv) was added at room temperature to a solution of 7-chloro-2-methyl-8-nitro-quinoxaline (3.98 g, 17.80 mmol) in a mixture of EtOAc (56 ml) and ethanol (28 ml). After 40 minutes at 80° C., the reaction mixture was cooled to room temperature, diluted with ice water, filtered, and extracted with EtOAc. The combined organic layers were washed with concentrated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford 6-chloro-3-methyl-quinoxalin-5-ylamine, which was used in the next transformation without purification. MS (ES+): 194.2 (M+H)+.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[C:13]2[CH2:14][CH2:15][C@@H:16]3[C@H:21]([C:12]=2[CH:11]=[CH:10][C:9]=1[O:23][CH3:24])[CH2:20][NH:19][C:18](=O)[CH2:17]3.[ClH:25]>CCOCC.CCO>[ClH:25].[CH3:6][O:7][C:8]1[C:13]2[CH2:14][CH2:15][C@@H:16]3[C@H:21]([C:12]=2[CH:11]=[CH:10][C:9]=1[O:23][CH3:24])[CH2:20][NH:19][CH2:18][CH2:17]3
Reactant: COc1ccc2c(c1OC)CC[C@H]1CC(=O)NC[C@@H]21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc2c(c1OC)CC[C@H]1CCNC[C@@H]21
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.6 %

Procedure:
A flame-dried 1-neck flask was charged with 50 mL of distilled THF and 0.130 g (0.498 mmol) of the cis lactam 15a were added. A 1.0 M solution of BH3 in THF (2.49 mL, 2.49 mmol) was added dropwise to the flask and the reaction was heated at reflux overnight. The reaction was then cooled to room temperature, quenched carefully with H2O, and evaporated to about one-third the volume. Following the addition of 10 mL 2N HCl, the solution was stirred at ambient temperature for 4 h. The aqueous solution was washed once with Et2O, basified with NH4OH, and extracted with CH2Cl2 (3×25 mL). The organic layers were combined, dried over Na2SO4, filtered, and evaporated to yield a colorless residue, which was dissolved in Et2O and acidified with 6N HCl in EtOH. The solid that formed was collected by filtration to yield 0.084 g (0.297 mmol, 59.6%) of the isoquinoline HCl 17a as a white powder; mp 186° C. (dec). 1H NMR: (500 MHz, DMSO): δ 8.80 (bs, 2H, NH2); 6.87 (m, 2H, ArH); 3.75 (s, 3H, ArOCH3); 3.66 (s, 3H, ArOCH3); 3.18-3.15 (dd, 1H, J=4.2, 12.4 Hz, ArCHCH2NH2); 3.12-3.05 (m, 2H, CH2NH2CH2); 2.99-2.82 (m, 3H, ArCHCH2NH2CH2, ArCH2); 2.59-2.48 (m, 1H, ArCH2); 2.10-1.89 (m, 3H, ArCH2CH2CHCH2); 1.76-1.68 (bd, 1H, J=11.8 Hz, NH2CH2CH2); 1.62-1.54 (m, 1H, ArCH2CH2). ESIMS (M+H)=248.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[C:15]4[CH2:27][C:26]5[C:21](=[CH:22][CH:23]=[C:24]([NH2:28])[CH:25]=5)[C:16]=4[NH:17][C:18]=3[C:19]=2[F:20])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].CC(O)=O.O.[O:34]([C:36]#[N:37])[Na]>O.CCOC(C)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[C:15]4[CH2:27][C:26]5[C:21](=[CH:22][CH:23]=[C:24]([NH:28][C:36]([NH2:37])=[O:34])[CH:25]=5)[C:16]=4[NH:17][C:18]=3[C:19]=2[F:20])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2ccc3c4c([nH]c3c2F)-c2ccc(N)cc2C4)cc1
Reactant: N#CO[Na]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2F)-c2ccc(NC(N)=O)cc2C4)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.6 %

Procedure:
To a suspension of 7-(4-Butyl-phenyl)-6-fluoro-5,10-dihydro-indeno[1,2-b]indol-2-ylamine (25 mg, 0.068 mmol, 1 eq.) in a 1:1 v/v mixture of AcOH/H2O (1 mL) is added a solution of NaOCN (4.4 mg, 0.068 mmol, 1 eq.) in H2O (1 mL). The resulting mixture is stirred at 25° C. for 2 h, at which point an additional NaOCN (4.4 mg, 0.068 mmol, 1 eq.) is added to the reaction. The resulting mixture is stirred at 25° C. for an additional 12 h. The reaction is diluted with EtOAc and sequentially washed with H2O, saturated aqueous NaHCO3, and saturated aqueous NaCl. The resulting organic solution is dried over Na2SO4. After concentration, the crude product is purified by preparative RP LC-MS to give [7-(4-Butyl-phenyl)-6-fluoro-5,10-dihydro-indeno[1,2-b]indol-2-yl]-urea (10 mg, 36% yield): 1H NMR (Acetone-d6) δ 11.09 (s, 1H), 8.26 (s, 1H), 7.89 (s, 1H), 7.59 (d, 2H), 7.58 (s, 1H), 7.48 (d, 1H), 7.42 (d, 1H), 7.33 (d, 2H), 7.18 (dd, 1H), 5.53 (bs), 3.72 (s, 2H), 2.72 (t, 2H), 1.72-1.64 (m, 2H), 1.49-1.36 (m, 2H), 0.96 (t, 3H); LC/MS calculated for [M+H]+ C26H24FN3O: 414.2, found: 414.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([OH:35])(=[O:34])=O)=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].S(Cl)(Cl)=O.[CH3:43][O:44][C:45](=[O:49])[C@@H:46]([CH3:48])[NH2:47].C([O-])([O-])=O.[Na+].[Na+].S(Cl)(Cl)(=O)=O>C(Cl)Cl.CN(C=O)C.CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([NH:47][C@H:46]([CH3:48])[C:45]([O:44][CH3:43])=[O:49])(=[O:35])=[O:34])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: COC(=O)[C@@H](C)N
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)[C@@H](C)NS(=O)(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(F)c1
Temperature: 0 °C
Yield: 0.1 %

Procedure:
To a solution of 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzenesulfonic acid (650 mg, 1.11 mol) in DCM (7 mL) and DMF (cat.) was added thionyl chloride (1.32 g, 11.1 mol, 10 eq.) and heated to reflux for 1.5 h with stirring. The reaction mixture was concentrated to dryness and the residue was diluted with 1,2-dichloroethane, co-evaporated (3×2 mL) and dried under high vacuum. Meanwhile a mixture of D-alanine methyl ester (622 mg, 4.44 mol, 4.0 eq.), MeCN (1.2 mL) and 2M Na2CO3 (6 mL) was stirred for 30 min and then cooled to 0° C. with an ice-water bath. A solution of the above sulfonyl chloride in MeCN (6 mL) then was added dropwise to the chilled aqueous mixture over 15 min with vigorously stirring. After complete addition, the ice-water bath was removed and the reaction slurry was stirred vigorously another 15 min. The reaction mixture was transferred into a separatory funnel with MeCN and the organic layer was collected. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were washed with water/brine (1:1), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting product was purified by chromatography (silica, Hex/EtOAc, 1:1) to afford (R)-methyl 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylsulfonamido)propanoate (709 mg, 95%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, 2H), 7.18 (s, 1H), 7.13-7.15 (d, 1H), 6.76-6.80 (t, 2H), 6.46-6.48 (m, 2H), 6.36-6.39 (m, 2H), 5.37 (d, 1H), 4.06 (s, 2H), 3.93-4.03 (m, 1H), 3.73 (s, 3H), 3.60 (s, 3H), 1.46 (s, 6H), 1.39-1.41 (d, 3H).
Reaction SMILES: CS([O:5][CH:6]([C:8]([F:11])([F:10])[F:9])[CH3:7])(=O)=O.[N+]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O-])=O>>[F:9][C:8]([F:11])([F:10])[CH:6]([O:5][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[CH3:7]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(OS(C)(=O)=O)C(F)(F)F
Product: CC(Oc1ccc(O)cc1)C(F)(F)F

Procedure:
Following the above procedures, 1-trifluoromethylethyl methanesulfonate is reacted with 4-nitrophenol to give 4-(1-trifluoromethylethoxy)phenol, which is then reacted with ethyl N-(2-chloroethyl)carbamate to give ethyl N-{2-[4-(1-trifluoromethylethoxy)phenoxy]ethyl}carbamate (compound 29, Table A).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([O:9][C:10]([C:12]1[C:13](OS(C(F)(F)F)(=O)=O)=[N:14][C:15]2[C:20]([C:21]=1[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[O:11])[CH3:8].[CH:35](/B(O)O)=[CH:36]\[CH3:37].C(O)C.C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(=O)OCC.CCCCCC>[CH2:7]([O:9][C:10]([C:12]1[C:13](/[CH:35]=[CH:36]/[CH3:37])=[N:14][C:15]2[C:20]([C:21]=1[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[O:11])[CH3:8]
Reactant: C/C=C/B(O)O
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C/C=C/c1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)OCC
Temperature: 110 °C
Yield: 73.7 %

Procedure:
1.8 g (5.6 mmol) Cs2CO3 and 210 mg (0.2 mmol) Pd(PPh3)4 were added to a solution of 800 mg (1.9 mmol) 4-methyl-7-(trifluoromethyl)-2-(trifluoromethyl-sulfonyloxy)-quinoline-3-carboxylic acid ethyl ester and 320 mg (3.7 mmol) (E)-propene-1-yl-boronic acid in an ethanol/toluene mixture (1:9 vv, 20 ml) and the mixture was heated to 110° C. for 1 h. The mixture was thereafter concentrated in a vacuum and the residue was taken up with EtOAc (20 ml) and water (20 ml). The organic phase was separated, washed with water and brine, dried over Na2SO4 and concentrated in a vacuum. After CC (EA/hexane 1:9) of the residue, 450 mg (1.4 mmol, 75%) (E)-4-methyl-2-(prop-1-enyl)-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH:9]=1)(=O)[CH3:2].Cl.[NH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[NH:31][C:30]2=[O:35])=[CH:26][CH:25]=1>>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[N:19][O:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:28][CH:29]3[S:33][C:32](=[O:34])[NH:31][C:30]3=[O:35])=[CH:36][CH:37]=2)[CH3:2])=[CH:9][N:8]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)nc1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(OCc2ccccc2)nc1
Yield: 78 %

Procedure:
Following a procedure similar to that described in Example 40(f), 130 mg of 5-acetyl-2-benzyloxypyridine were reacted with 182 mg of 5-[4-(2-aminooxyethoxy)-benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure, to give 219 mg of the title compound, melting at 160-161° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:3]=1[C:4]([OH:6])=O.[C:16]([O:20][C:21]([N:23]1[CH2:30][CH:29]2[CH:25]([CH2:26][NH:27][CH2:28]2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].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>CN(C=O)C.CCOC(C)=O>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH:25]2[CH:29]([CH2:28][N:27]([C:4](=[O:6])[C:3]3[C:7]([N:11]4[N:15]=[CH:14][CH:13]=[N:12]4)=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[CH2:26]2)[CH2:30]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3c(F)cccc3-n3nccn3)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
2-Fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (0.97 g, 4.71 mmol), hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (Intermediate 15, 1.0 g, 4.71 mmol), HATU (2.68 g, 7.06 mmol), in DMF (18.8 mL) was added DIEA (2.43 mL, 14.13 mmol). The mixture was stirred at rt for 1 hr. The mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, the organic layers were combined, dried (Na2SO4), filtered and concentrated to provide the crude product. Purification (FCC) (5-50% of a solution 10% MeOH, 0.1% NH4OH in DCM/EtOAc over 25 minutes, and 50-100% from 25-35 minutes) provided 5-(2-fluoro-6-[1,2,3]triazol-2-yl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (0.376 g, 19.5%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([F:16])([C:13]([OH:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+:18].O1CCCC1>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([F:16])([C:13]([O-:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[Li+:18]
Reactant: CC(C)(C)OC(=O)N1CC[C@@](F)(C(=O)O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@](F)(C(=O)[O-])C1
Temperature: 45 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
To a solution of #169 (75 mg, 0.32 mmol, 1 eq.) in methanol (0.3 mL) was added a solution of lithium hydroxide (13.8 mg, 0.572 mmol, 1.8 eq.) in water (0.4 mL). Next, tetrahydrofuran (0.45 mL) was added and the reaction was stirred at 45° C. for 18 hours. The reaction was concentrated in vacuo and the material was azeotroped (3×) with toluene (4 mL) to obtain #171 (77 mg, 100%) as a white solid, which was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(OCC)(=O)C>[CH2:5]([C:11]1[S:15][C:14]([N:16]=[C:1]=[O:2])=[N:13][N:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCc1nnc(N)s1
Solvent: CCOC(C)=O
Product: CCCCCCc1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-hexyl-2-amino-1,3,4-thiadiazole (40 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-hexyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [CH2:1]([O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3].C(N([C:26](C)(C)[C:27](NC(C)(C)C)=[O:28])O)(C)(C)C.ClC1CCCCO1>>[O:28]1[CH2:27][CH2:26][CH2:3][CH2:2][CH:1]1[O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: C=CCON(C(C)(C)C)C(C)(C)C(=O)NC(C)(C)C
Reactant: CC(C)(C)NC(=O)C(C)(C)N(O)C(C)(C)C
Agent: ClC1CCCCO1
Product: CC(C)(C)NC(=O)C(C)(C)N(OC1CCCCO1)C(C)(C)C
Yield: 33 %

Procedure:
The compound is prepared in analogy to compound (204) from tert-butyl-(dimethyl-tert-butylaminocarbonyl-methyl)-hydroxylamine and 2-chlor-tetrahydropyrane in 33% yield as colorless oil.