Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH3:9][N:10]([CH3:32])[CH:11]1[C:25]2=[CH:26][CH:22]([O:23][C:24]2=[O:27])[CH:21]2[CH:17]([O:18][C:19](=[O:29])[CH:20]2[CH3:28])[CH2:16][C:15]2([CH3:30])[CH:13]([O:14]2)[CH:12]1[OH:31].CC(C)=O>>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[OH:31][CH:12]1[CH:11]([NH+:10]([CH3:9])[CH3:32])[C:25]2=[CH:26][CH:22]([O:23][C:24]2=[O:27])[CH:21]2[CH:17]([O:18][C:19](=[O:29])[CH:20]2[CH3:28])[CH2:16][C:15]2([CH3:30])[CH:13]1[O:14]2.[OH:31][CH:12]1[CH:11]([NH+:10]([CH3:9])[CH3:32])[C:25]2=[CH:26][CH:22]([O:23][C:24]2=[O:27])[CH:21]2[CH:17]([O:18][C:19](=[O:29])[CH:20]2[CH3:28])[CH2:16][C:15]2([CH3:30])[CH:13]1[O:14]2
Reactant: CC1C(=O)OC2CC3(C)OC3C(O)C(N(C)C)C3=CC(OC3=O)C21
Reactant: O=C(O)/C=C\C(=O)O
Solvent: CC(C)=O
Product: CC1C(=O)OC2CC3(C)OC3C(O)C([NH+](C)C)C3=CC(OC3=O)C21
Product: O=C([O-])/C=C\C(=O)[O-]
Yield: 60.7 %

Procedure:
A solution of maleic acid (0.1 mmol; 11.6 mg) in acetone (0.5 ml) is added to a solution of the compound of Example 5 (0.1 mmol; 34 mg) in acetone (0.5 ml). The precipitate is filtered, washed with acetone and dried under reduced pressure. 24 mg of the expected product is obtained in the form of a white powder. Melting point: 178.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=1.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][C:26]=1[C:32]([F:34])([F:33])[F:35]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccc(F)cc1C(F)(F)F
Temperature: 100 °C
Yield: 39.7 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol), tetrabutylammonium iodide (120 mg, 0.32 mmol) and 4-fluoro-2-(trifluoromethyl)benzyl bromide (204 μL, 1.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. overnight. Dichloromethane (50 mL) was added and the solution was washed with 1:1 water/brine (2×25 mL), aqueous sodium thiosulfate, water, and brine. The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 50% ethyl acetate/petroleum ether, to give an orange oil. 1H NMR showed that this oil contained some dimethyl formamide. The oil was dissolved in ethyl acetate and the solution was washed with water (3×10 mL), dried (magnesium sulfate), filtered, evaporated, then co-evaporated with ethyl ether and dichlormethane, and held under high vacuum to give (4S,7R)-2-(2,4-difluoro-phenyl)-1-(4-fluoro-2-trifluoromethyl-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (63 mg, 40%) as a pale foam. APCI(+)-MS (M+H) 481.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:20]=2)[O:4]1.CCN(C(C)C)C(C)C.Cl[C:32]1[C:37]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[C:36]([CH3:46])[N:35]=[CH:34][N:33]=1>CN1C(=O)CCC1>[F:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][C:37]2[C:32]([N:16]3[CH2:15][C:14]4[CH:20]=[C:10]([B:5]5[O:4][C:3]([CH3:21])([CH3:2])[C:7]([CH3:8])([CH3:9])[O:6]5)[CH:11]=[CH:12][C:13]=4[O:19][CH2:18][CH2:17]3)=[N:33][CH:34]=[N:35][C:36]=2[CH3:46])=[CH:44][CH:43]=1
Reactant: Cc1ncnc(Cl)c1Cc1ccc(F)cc1
Reactant: CC1(C)OB(c2ccc3c(c2)CNCCO3)OC1(C)C
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncnc(N2CCOc3ccc(B4OC(C)(C)C(C)(C)O4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 120 °C
Yield: 79.5 %

Procedure:
To a solution of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (1.4 g, 4.5 mmol) and DIPEA (6.4 mL, 37 mmol) in NMP (24 mL) was added and 4-chloro-5-(4-fluorobenzyl)-6-methylpyrimidine (reagent preparation 5) (1.7 g, 7.3 mmol). The resulting mixture was heated (120° C.) for 12 h and then partitioned between ethyl acetate (100 mL) and 1N aqueous hydrochloric acid (50 mL). The organic layer was washed with additional 1N aqueous hydrochloric acid (50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. Column chromatography on silica (0-30% ethyl acetate/hexanes) provided 4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (1.7 g, 47% yield) as a white foam. MS (EI) for C27H31BFN3O3: 476 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].S(=O)(=O)(O)O.[S-:18][C:19]#[N:20].[Na+].C1OCCOCCOCCOCCOC1>ClC1C=CC=CC=1>[CH3:12][C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=1[NH:1][C:19]([NH2:20])=[S:18]
Reactant: N#C[S-]
Reactant: COC(=O)c1cccc(N)c1C
Agent: C1COCCOCCOCCOCCO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COC(=O)c1cccc(NC(N)=S)c1C
Temperature: 100 °C

Procedure:
90.7 g of methyl 3-amino-2-methylbenzoate (0.55 mol) were dissolved in 510 ml of chlorobenzene and, at −5° C., admixed with 14 ml of conc. sulfuric acid and 49 g of sodium thiocyanate (0.6 mol). 2 ml of 15-crown-5 were then added, and the reaction mixture was heated at 100° C. for 13 h. After cooling, the solid was filtered off with.suction, washed with water and dried. Yield: 104.8 g (85%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]1[O:24][C:23]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=2[O:14]1.Cl.[CH3:26][NH:27][O:28][CH3:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.C(N(CC)CC)C>[CH3:29][O:28][N:27]([CH3:26])[C:18]([C:17]1[CH:21]=[CH:22][C:23]2[O:24][CH2:13][O:14][C:15]=2[CH:16]=1)=[O:20]
Reactant: CNOC
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
1,1'-Carbonyl-diimidazole (48.8 g) was added portionwise within 30 minutes under argon and while stirring to a suspension of 50.0 g of 3,4-methylenedioxy-benzoic acid in 500 ml of methylene chloride. The resulting clear solution was stirred at room temperature for 2 hours and added dropwise within 30 minutes to 42 ml of triethylamine. Thereafter, 29.4 g of N,O-dimethylhydroxylamine hydrochloride were added and the mixture was stirred at room temperature overnight. After the addition of 800 ml of 30% citric acid solution the mixture was extracted twice with 300 ml of methylene chloride each time. The organic phases were washed in succession with 300 ml of 30% citric acid solution, 500 ml of saturated sodium hydrogen carbonate solution and 300 ml of saturated sodium hydrogen carbonate solution. The organic phases were combined, dried with MgSO4 and freed from solvent. 60.9 g (97%) of N-methoxy-N-methyl-1,3-benzodioxol-5-carboxamide were isolated as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[C:8]([OH:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+:19].[Cs+].CC(C)=O>O>[OH:1][C:2]1[CH:10]=[C:9]([C:11]([O-:13])=[O:12])[C:8]([OH:14])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Cs+:19].[Cs+:19]
Reactant: O=C(O)c1cc(O)c(C(=O)O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: O=C([O-])c1cc(O)c(C(=O)[O-])cc1O
Yield: 200 %

Procedure:
0.5 mol of 2,5-dihydroxyterephthalic acid and 0.5 mol of cesium carbonate were added to 200 ml of acetone and 200 ml of water and dissolved therein by stirring. After completely dissolving, the resultant solution was concentrated to dryness to give 0.5 mol of cesium 2,5-dihydroxyterephthalate. 46.2 g (0.1 mol) of cesium 2,5-dihydroxyterephthalate, 38.62 g (0.2 mol) of bromooctane and 400 ml of DMF were introduced into a reactor and reacted under a nitrogen gas stream at 100° C. for 3 hours. The reaction solution was concentrated, washed with water and dried to give 40.1 g (0.95 mol) of 2,5-dihydroxybenzene-1,6-dicarboxylic octane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[CH:15]([OH:17])[CH3:16].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:19](=[O:21])[O:17][CH:15]([CH3:16])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(-c2cccc(Cl)c2)ccc1N
Solvent: C1CCOC1
Product: CC1OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.17 h
Yield: 283.1 %

Procedure:
A mixture of 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanol (0.03 g, 0.13 mmol) and triphosgene (0.01 g, 0.04 mmol) in dry THF (3 mL) was stirred under a blanket of nitrogen for 10 minutes. The solvent was removed to give 6-(3-chloro-phenyl)-4-methyl-1, 4-dihydro-benzo[d][1,3]oxazin-2-one as a white solid (0.031 g, 91%): mp 155-156° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.72 (m, 1H), 7.62 (m, 2H), 7.56 (m, 1H), 7.47 (t, 1H, J=8.00 Hz), 7.39 (d, 1H, J=8.0 Hz), 6.98 (d, 1H, J=8.0 Hz), 5.50 (q, 1H, J=6.82 Hz), 1.6 (d, 3H, J=6.82 Hz); MS (APCI) m/z 274 ([M+H]+, 100%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[C:17]([NH:21][OH:22])([CH3:20])([CH3:19])[CH3:18]>C(Cl)(Cl)Cl>[C:17]([N+:21]([O-:22])=[CH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=CCCc1ccccc1
Reactant: CC(C)(C)NO
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)[N+]([O-])=CCCc1ccccc1
Reaction time: 22 h
Yield: 45.1 %

Procedure:
To a mixture of 3-phenylpropionaldehyde (10.0 g, 74.5 mmol, 1.0 equiv) and benzene (150 ml) was added chloroform (25 ml) until a clear solution was obtained. To the clear solution was added N-tert-butylhydroxylamine (7.31 g, 82.0 mmol, 1.1 (equiv) and the resulting mixture was refluxed under nitrogen and Dean-Stark trap for 22 h. Upon cooling oil separated. Oil was separated and product purified by flash chromatography (hexanes: EtOAc=1:1) to give N-tert-butyl-C-(2-phenylethyl)nitrone (7.31 g, 45.1%) as a light color oil: 1H NMR (CD3OD) δ 7.30–7.27 (m, 2H, Ar—H), 7.23–7.19 (m, 3H, Ar—H), 6.80 (t, 1H, Ar—H), 2.77–2.62 (m, 4H, 2CH2), 1.46 (s, 9H, t-Bu).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([CH2:15][NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[C:34]([OH:44])=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[C:37]([Cl:39])[CH:38]=1>C(Cl)Cl>[Cl:32][C:33]1[C:34]([OH:44])=[C:35]([S:40]([N:16]([CH2:15][C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:13]([Cl:14])=[CH:12][CH:11]=2)[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)(=[O:42])=[O:41])[CH:36]=[C:37]([Cl:39])[CH:38]=1
Reactant: Fc1ccc(CNCc2ccc(Cl)c(-c3ccc(Cl)cc3)c2)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1ccc(Cl)c(-c2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
1-(4′,6-Dichlorobiphenyl-3-yl)-N-(4-fluorobenzyl)methanamine (200 mg, 0.555 mmol, 1.0 eq) was dissolved in dry DCM and the resulting solution was stirred for 10 minutes and cooled to 0° C. Triethylamine (168 mg, 1.6 mmol, 3 eq) was added to the above solution and the mixture was stirred for 10 minutes. 3,5-Dichloro-2-hydroxybenzene-1-sulfonyl chloride dissolved in DCM was added slowly over a period of 10 minutes and the mixture was stirred for 4 h at ambient temperature. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (60-120) eluting with 5-10% ethyl acetate/hexane to give the title compound (0.14 g, 46%). 1H NMR (400 MHz, CD3OD) δ 4.47 (s, 2H), 4.53 (s, 2H), 6.91-6.98 (m, 3H), 7.12-7.15 (m, 1H), 7.22-7.27 (m, 4H), 7.33-7.35 (d, 1H), 7.43-7.45 (d, 2H), 7.54 (d, 1H), 7.67 (d, 1H). MS (ESI): 583.8 (M−H)−.
Reaction SMILES: [N:1]1([C:7]([NH:9][C@@H:10]([CH2:14][S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])[C:11]([OH:13])=O)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:25][C:26]([F:40])([F:39])[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][CH2:35][C@@H:36]([NH2:38])[CH3:37])=[CH:30][CH:29]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH3:37][C@H:36]([NH:38][C:11]([C@@H:10]([NH:9][C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:8])[CH2:14][S:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])=[O:16])=[O:13])[CH2:35][NH:34][C:31]1[CH:30]=[CH:29][C:28]([O:27][C:26]([F:25])([F:39])[F:40])=[CH:33][CH:32]=1
Reactant: C[C@H](N)CNc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)[C@H](CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@H](CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Yield: 28.6 %

Procedure:
2-(R)-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (73 mg, 0.21 mmol, 1.0 eq.), N1-(4-Trifluoromethoxy-phenyl)-(S)-propane-1,2-diamine from Scheme 1a (48 mg, 0.21 mmol, 1.0 eq.), EDC (59 mg, 0.31 mmol, 1.5 eq.), and HOBT (38 mg, 0.25 mmol, 1.2 eq.) were dissolved in CH2Cl2 at room temperature. N-methylmorpholine (225 μL, 2.05 mmol, 10 eq.) was added via syringe and the reaction was monitored to completion by LC/MS. The solvent was evaporated and the reaction was purified by mass-directed HPLC and provided 44 mg (0.06 mmol, 31%) of a off-white solid as a mono-TFA salt: HPLC-MS calcd. for C25H31F3N4O6S (M+H+) 573.2, found 573.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7](Cl)(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+]>O.CCOCC>[C:7]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NCCC(=O)O
Reactant: CCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCC(=O)NCCC(=O)O

Procedure:
β-Alanine (20 mmol) was reacted with valeryl chloride (22 mmol) in the presence of NaOH (40 mmol) in a mixture of H2O and ether using the method described in Example 5. The crude crystalline product (2.75 g, 79%) was recrystallized from a mixture of isopropyl ether (150 ml) and ethyl acetate (10 ml) to give title acid (1.51 g, 44%), m.p. 73°-76° C.
Reaction SMILES: C[C@@H:2]([OH:34])[C@H:3]1[O:8][C@H:7]([O:9][C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H:6](N)[C@@H:5]([OH:32])[C@@H:4]1[OH:33].C([OH:39])C(C)C>>[O:9]=[CH:7][C@@H:6]([C@H:5]([C@@H:4]([C@@H:3]([CH2:2][OH:34])[OH:8])[OH:33])[OH:32])[OH:39]
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H]([C@@H](C)O)[C@@H](O)[C@H](O)[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Reactant: CC(C)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.17 h

Procedure:
Strains with integrated ALS genes expressed from the CUP1 promoter were transformed with pGV2082 (which carries the other 4 isobutanol pathway genes Ec_ilvC_coScQ110V (SEQ ID NO: 61), Ll_ilvD (SEQ ID NO: 65), Ll_kivd2_coEc (SEQ ID NO: 59), and Dm_ADH (SEQ ID NO: 60)). Strains were patched onto YPD plates containing 0.2 mg/mL G418. The following morning cells were removed from the plate with a sterile toothpick and resuspended in 4 mL of YPD with 0.2 mg/mL G418. The OD600 was determined for each culture. Cells were added to 50 mL YP with 5% dextrose and 0.2 mg/mL G418 such that a final OD600 of 0.1 was obtained. 1 mL of media was removed and the OD600 for this undiluted sample determined, leftover media was stored at 4° C. to act as media blank for the analytics submission, and to act as the t=0 sample for the fermentation. At t=24 h, 2 mL of media was removed and 25 μL used at a 1:40 dilution to determine OD600. The remaining culture was centrifuged in a microcentrifuge at maximum speed for 10 min and a 1:10 dilution read on the YSI. 50% glucose containing 0.2 mg/mL G418 was added to a final concentration of 100 g/L glucose. 1 mL of supernatant was analyzed by gas chromatography as described above. At t=48 h, 2 mL of media was removed and 25 μL used at a 1:40 dilution to determine OD600. The remaining culture was centrifuged in a microcentrifuge at maximum speed for 10 min and a 1:10 dilution read on the YSI. 50% glucose plus water (with 0.2 mg/mL G418) were added to give a final concentration of glucose of 100 g/L. 1 mL of supernatant was analyzed by gas chromatography. At t=72 h, 2 mL of media was removed and 25 μL used at a 1:40 dilution to determine OD600). The remaining culture was centrifuged in a microcentrifuge at maximum speed for 10 min and a 1:10 dilution read on the YSI. 1 mL of supernatant was analyzed by gas chromatography and high performance liquid chromatography.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:33][CH:32]2[NH:34][CH2:35][CH:27]1[CH2:28][CH:29]=[CH:30][CH2:31]2.CCN(C(C)C)C(C)C>C(O)C>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:33][CH:32]2[N:34]([CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]3[CH:15]=[CH:14][CH:13]=[C:12]4[C:7]=3[CH:8]=[CH:9][CH:10]=[N:11]4)[CH2:35][CH:27]1[CH2:28][CH:29]=[CH:30][CH2:31]2
Reactant: c1cc(OCC2CO2)c2cccnc2c1
Reactant: C1=CCC2CNC(C1)CN2c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: OC(COc1cccc2ncccc12)CN1CC2CC=CCC1CN2c1ccc2ccccc2c1

Procedure:
5-Oxiranylmethoxy-quinoline (13 mg, 0.065 mmol), 7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (20 mg, 0.042 mmol), DIPEA (0.1 mL, 0.55 mmol) and ethanol (2 mL) were μW for 900 sec at 130° C. in a μW reaction tube. The solvent was evaporated in vacuo to yield a crude solid that was purified with flash chromatography gradient [30% EtOAc/heptane to 100% EtOAc] to yield the title compound as its free base, as a residue.
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.COCCOC.C(=O)([O-])O.[Na+].[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[CH:24][N:23]=1>Br.O>[F:31][C:28]([F:29])([F:30])[C:26]1[N:25]=[CH:24][N:23]2[CH:8]=[CH:9][N:21]=[C:22]2[CH:27]=1
Reactant: Nc1cc(C(F)(F)F)ncn1
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)c1cc2nccn2cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.4 %

Procedure:
A stirred mixture of bromoacetaldehyde diethyl acetal (2.09 ml, 13.5 mmol) in concentrated hydrobromic acid (0.68 ml) and water (0.68 ml) was heated at reflux under nitrogen for 20 min. The solution was allowed to cool to room temperature, ethylene glycol dimethyl ether (5 ml) was added and the solution was neutralised to pH 7 with solid sodium hydrogen carbonate. The mixture was filtered and the solid was washed with more ethylene glycol dimethyl ether (7 ml). To the combined filtrates was added 4-amino-6-trifluoromethylpyrimidine (2.00 g, 12.3 mmol) and the mixture was stirred at 65° C. for 18 h. After allowing to cool, the solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) to give 2.426 g of 7-trifluoromethylimidazo[1,2-c]pyrimidine: 1H NMR (360 MHz, CDCl3) δ 7.81 (1H, s), 7.86 (1H, s), 7.96 (1H, s), 9.13 (1H, s).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:7][CH:8]=[CH2:9])[CH2:4][CH:5]=O.S(O)(O)(=O)=O.[NH2:15][OH:16].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][O:2][CH:3]([CH2:7][CH:8]=[CH2:9])[CH2:4][CH:5]=[N:15][OH:16]
Reactant: NO
Reactant: C=CCC(CC=O)OC
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCC(CC=NO)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
A mixture of 3-methoxy-5-hexenal (3.0 g, contaminated with dichloromethane and triethylamine), hydroxylamine sulfate (990 mg) and sodium acetate (624 mg) in ethanol (6.5 mL)-water (0.65 mL) was stirred at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain the title compound (500 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[N:15])[CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[N:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CCCC(N)C1
Reaction time: 1 h

Procedure:
(3-Cyano-cyclohexyl)-carbamic acid tert-butyl ester (0.74 g, 3.30 mmol) was dissolved in TFA/DCM and stirred for 1 hr. The solvent was evaporated to give 3-amino-cyclohexanecarbonitrile as a brown solid. The crude material was used without further purification. LCMS (Method H, ESI): RT=0.35 min, m+H=125.0.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]=C.O1[CH2:11][CH2:10]O[CH2:8][CH2:7]1>>[CH3:1][N:2]([CH3:3])[CH2:10][CH3:11].[CH2:1]([N:2]([CH2:7][CH3:8])[CH3:3])[CH3:4]
Reactant: C=C
Reactant: CNC
Reactant: C1COCCO1
Product: CCN(C)C
Product: CCN(C)CC

Procedure:
A mixture of 104 parts of 1,4-dioxane (inert solvent), 5.6 parts of dimethylamine and 0.363 parts (0.11 mol/mol C2H4) of [Ru(NH3)4 (OH)Cl]Cl.2H2O were placed in a 300 ml stainless steel autoclave. The autoclave was pressured with 200 psig of ethylene. A total of 0.12 parts of dimethylethylamine and 2.1 parts of diethylmethylamine were obtained corresponding to a conversion of 21% and a combined yield of 99% (based on dimethylamine).
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[CH3:7].[Cl:9][C:10]1[CH:15]=[C:14](C2C=NN(C3CCCCO3)C=2)[CH:13]=[CH:12][N:11]=1>>[Cl:9][C:10]1[CH:15]=[C:14]([C:2]2[C:3]([CH3:8])=[N:4][O:5][C:6]=2[CH3:7])[CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(-c2cnn(C3CCCCO3)c2)ccn1
Reactant: Cc1noc(C)c1Br
Product: Cc1noc(C)c1-c1ccnc(Cl)c1

Procedure:
The title compound was prepared from 4-bromo-3,5-dimethylisoxazole generally according to the synthetic procedure described for 2-Chloro-4-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-pyridine. HPLC (Rt)=0.81 min (method N)
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[C:26]([F:29])([F:28])[F:27])[N:19]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:18]1=[O:37])[CH3:16].[H-].[Na+].O>CN(C=O)C>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[C:26]([F:27])([F:29])[F:28])[N:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:32][CH:31]=2)[C:18]1=[O:37])[CH3:16]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C(F)(F)F)c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccc(C(F)(F)F)c21
Temperature: 100 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (81 mg) and 1-ethyl-3-(4-hydroxyphenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (103 mg) in DMF (dry) (1.5 mL) was added NaH (19.12 mg), and the mixture was stirred at 100° C. for 1 h. The mixture was heated at 180° C. for 30 min under microwave irradiation. The mixture was poured into water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound as white crystals (62.2 mg).