Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22]O)[C:11](=[O:26])[C@H:10]([CH:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:33][NH:34][S:35]([CH:38]1[CH2:40][CH2:39]1)(=[O:37])=[O:36].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCOC(C)=O.[Na+].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][N:34]([CH3:33])[S:35]([CH:38]3[CH2:40][CH2:39]3)(=[O:37])=[O:36])[C:11](=[O:26])[C@H:10]([CH:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNS(=O)(=O)C1CC1
Reactant: CC[C@@H](CO)N1C(=O)[C@H](C(C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@H](C(C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
A flask, containing a solution of methyl 2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-2-oxopiperidin-3-yl)propanoate (195 mg, 0.408 mmol; Example 127, Step E) and N-methylcyclopropanesulfonamide (165 mg, 1.223 mmol) in toluene (2038 μL) was evacuated and backfilled with Ar (5×). Then cyanomethylenetributylphosphorane (321 μL, 1.223 mmol) was added. The light brownish orange mixture was heated to 70° C. for 2 h. More N-methylcyclopropanesulfonamide (134 mg, 0.991 mmol) was added and the mixture was heated to 70° C. for 2 h. The mixture was heated to reflux overnight and then cooled to room temperature. The mixture was diluted with EtOAc and sat. aq. NaCl solution. The layers were separated. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (4 g column eluent: 0 to 100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](=O)[NH:9][N:8]=1)[CH3:2].O=P(Cl)(Cl)[Cl:23]>C(#N)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([Cl:23])=[N:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1n[nH]c(=O)c2cc(OC)ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)CCc1nnc(Cl)c2cc(OC)ccc12
Yield: 84.8 %

Procedure:
Operating analogously to example 114 starting from 3-(6-methoxy-4-oxo-3,4-dihydro-phthalazin-1-yl)-propionic acid ethyl ester (552 mg, 2 mmoles), prepared as described in example 119, and POCl3 (1.12 ml, 12 mmoles) in acetonitrile (5 ml), 0.5 g of the title compound were obtained (yield: 84.8%).
Reaction SMILES: [C:1](C(C)(CCCC)C(O)=O)(OCC)=O.ClCCl.F.[F:19][C:20]([F:32])([F:31])[CH:21]([CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCCCC>[F:19][C:20]([F:31])([F:32])[C:21]([CH3:1])([CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCCCC(C(=O)OCC)C(F)(F)F
Reactant: CCCCC(C)(C(=O)O)C(=O)OCC
Agent: F
Solvent: ClCCl
Solvent: CCCCC
Product: CCCCC(C)(C(=O)OCC)C(F)(F)F
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a 90 ml. stainless steel bomb was added 6.6 g. of 2-carboethoxy-2-methylhexanoic acid, 5 ml. of dichloromethane, and 0.4 ml. of 48% hydrofluoric acid. The bomb was sealed with an assembly consisting of a rupture disk (2400-3600 psig) and a needle valve. The bomb was then cooled in a dry ice-acetone bath and evacuated to less than 10 mmHg pressure. Sulfur tetrafluoride (15 g.) was condensed into the bomb from an attached lecture bottle. The needle valve was closed and the bomb was stored in a hood at room temperature for 3 days. After this time, the bomb was immersed to 1/3 of its length in a 60° C. bath. After warming at 60° C. for 3 days, the bomb was cooled and vented. The residual materials were taken up in pentane (250 ml.). The pentane solution was dried (NaF/MgSO4), filtered and distilled to give 3.14 g. (42%) of ethyl 2-trifluoromethylhexanoate, b.p. 79°-81° /20 mmHg.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][NH:9][CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:26](Cl)([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].O>C(Cl)Cl>[C:14]([O:13][C:12]([NH:11][C@@H:7]([CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:8][N:9]([CH3:10])[C:26](=[O:27])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:18])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNC[C@H](CC1CCCC1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C[C@H](CC1CCCC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 40 %

Procedure:
To a mixture of tert-butyl (S)-3-cyclopentyl-1-(methylamino)propan-2-ylcarbamate (900 mg, 3.52 mmol) and Et3N (1.5 mL, 10.6 mmol) in CH2Cl2 (10 mL) was added dropwise a solution of CbzCl (720 mg, 4.22 mmol) in CH2Cl2 (5 mL) at 0° C. After stirring for an additional 2 h, water (30 mL) was added and the mixture was extracted with CH2Cl2 (2×10 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica chromatography to obtain benzyl (S)-2-(t-butoxycarbonylamino)-3-cyclopentylpropylmethylcarbamate (550 mg, 40%) as an oil. 1H NMR (CDCl3, 400 MHZ) δ 1.10 (m, 2 H), 1.43 (s, 9 H), 1.49 (m, 3 H), 1.60 (m, 3 H), 1.81 (m, 3 H), 2.96 (s, 3 H), 3.15 (m, 1 H), 3.40 (m, 1 H), 3.83 (brs, 1H), 4.57 (brs, 1 H), 5.16 (s, 2 H), 7.33 (m, 5H).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][CH:2]=1.CC(C)([O-])C.[K+].[C:16]([O:19][CH2:20][CH2:21][O:22][CH2:23]Br)(=[O:18])[CH3:17]>CN(C=O)C>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:23][O:22][CH2:21][CH2:20][O:19][C:16](=[O:18])[CH3:17])[CH:2]=1
Reactant: c1cnc2[nH]cnc2c1
Reactant: CC(=O)OCCOCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOCn1cnc2cccnc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 41 %

Procedure:
To a solution of 1.0 g (8.39 mmol) 3H-imidazo[4,5-b]pyridine in 20 ml DMF kept under argon at 0° C. 0.94 g (8.39 mmol) potassium tert-butoxide were added. The solution was warmed to room temperature and after 1 hour a solution of 1.74 g (8.8 mmol) (2-acetoxyethoxy)methyl bromide in 5 ml DMF was added dropwise over half an hour. The reaction was stirred at room temperature for 20 hours and then poured onto 75 ml of ice water. The mixture was extracted twice with 50 ml ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, gradient DCM, DCM/MeOH 95/5 and 9/1) to afford 0.81 g (41%) of the desired product. MS(ISP): 236.2 [MH]+.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([C:23]([O:25]C)=[O:24])[N:20]([CH3:22])[CH:21]=2)=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCOCC1>[C:3]([O:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[C:19]([C:23]([OH:25])=[O:24])[N:20]([CH3:22])[CH:21]=2)=[CH:15][CH:16]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 0.5 M solution of NaOH (2.0 eq) was added to a solution of 5 (1.0 g, 3.027 mmol) in dioxane (40 mL). The reaction mixture was allowed to stir at room temperature for 6 hours at which point TLC revealed completion of reaction. Excess 1,4-dioxane was evaporated under vacuum and the residue was diluted with water. The resulting solution was acidified with 0.5 M HCl. The product was extracted from water with 2× ethyl acetate (100 mL×2) and the organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo. The product was purified using flash chromatography (ethyl acetate/n-hexane 2:8). Yield—0.92 g, 96.8%. IR (FTIR, vmax/cm−1): 3371, 2979, 1698, 1671, 1522, 1445, 1367, 1285, 1161, 1112, 1047, 823, 803, 762, 714, 631; 1H-NMR (400 MHz, CDCl3): δ 8.33 (1H, s), 7.55 (d, 2H, J=8.8 Hz), 7.50 (d, 2H, J=8.8 Hz), 7.36 (d, 1H, J=2.0 Hz), 7.22 (d, 1H, J=2.0), 3.97 (s, 3H), 1.50 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ 162.3, 153.7, 138.6, 123.0, 127.1, 126.0, 124.4, 124.0, 119.5, 115.1, 79.9, 36.9, 28.6; EIMS m/z (+EI) calc. for C17H20N2O4 (M)+ 316.35. found 315.16 (M+H)+.
Reaction SMILES: OCC1C=CC([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=CC=1.[OH:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1>>[OH:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[CH:47][CH:46]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(CO)cc5)cc4)cc23)c1
Reactant: OCCCc1ccc(B(O)O)cc1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(CCCO)cc5)cc4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 65, using 4-(3-hydroxypropyl)phenylboronic acid in place of 4-(hydroxymethyl)phenylboronic acid. ES/MS calcd. for C33H32N3O5S+ 582.2. Found m/z=582.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]2[N:11]([CH3:14])[CH:12]=[N:13][C:8]2=[C:7]([F:15])[C:6]=1Br)=[O:4].[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]2[N:11]([CH3:14])[CH:12]=[N:13][C:8]2=[C:7]([F:15])[C:6]=1[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[F:17])=[O:4]
Reactant: Nc1ccccc1F
Reactant: COC(=O)c1nc2c(ncn2C)c(F)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1nc2c(ncn2C)c(F)c1Nc1ccccc1F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 6-bromo-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (1.00 equivalent), 2-fluoroaniline (1.00 equivalent), Pd(OAc)2 (0.10 equivalents), rac-BINAP (0.15 equivalents), and Cs2CO3 (1.50 equivalents) in toluene in a sealed tube is stirred at 80° C. for 16 hours. The reaction mixture is cooled to room temperature and diluted with EtOAc. The resulting precipitate is filtered off and washed with EtOAc. The filtrate is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product.
Reaction SMILES: [OH:1][CH:2]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:3]1[NH:12][C:13]([CH3:15])=[O:14].C([O:18][C:19](=O)[CH:20]([CH3:22])[OH:21])C>P([O-])([O-])([O-])=O>[C:19]([O:11][CH2:10][C@H:8]1[O:9][CH:2]([OH:1])[C@@H:3]([NH:12][C:13](=[O:14])[CH3:15])[C@@H:4]([OH:5])[C@@H:6]1[OH:7])(=[O:18])[CH:20]([CH3:22])[OH:21]
Reactant: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCOC(=O)C(C)O
Agent: O=P([O-])([O-])[O-]
Product: CC(=O)N[C@@H]1C(O)O[C@H](COC(=O)C(C)O)[C@@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
ManNAc (200 mg) and 50 mg of subtilisin mutant 8399 were added to a mixture of lactic acid ethyl ester (4 mL) and 400 mL of 0.5 N phosphate buffer (pH 7.5). The reaction mixture was shaken under 50° C. for three days. The solvent was then evaporated and methanol was added to the residue. After the insoluble materials were filtered off, the filtrate was concentrated. The residue was chromatographed on silica gel with ethyl acetate/methanol (5/1) to give 6-O-Lactyl N-acetylmannosamine in 50 percent yield.
Reaction SMILES: [C:1]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:20])[C:2]1[C:3](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:5].[H][H]>>[CH:3]1([C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:5])[CH2:16][CH2:17][CH2:18][CH2:19][CH:2]1[C:1]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:20]
Reactant: CC(C)CCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCC(C)C
Reactant: [H][H]
Product: CC(C)CCCCCCOC(=O)C1CCCCC1C(=O)OCCCCCCC(C)C

Procedure:
2 g of catalyst A (3% Ru/SiO2) were placed in a 300 ml pressure reactor. The reactor was subsequently charged with 100 g of diisononyl phthalate (DINP). The hydrogenation was carried out at 120° C. and a pressure of 200 bar using pure hydrogen. The hydrogenation was continued until no more hydrogen was taken up and the reactor was subsequently vented. The conversion of the diisononyl phthalate was 100%. Diisononyl cyclohexane-1,2-dicarboxylate was obtained with a selectivity of over 99%.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([O:24]C)=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CO.Cl>O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Yield: 83 %

Procedure:
A mixture of 1-benzyl-3-(5-methoxycarbonyl-2-furyl)-1H-indazole (1.46 g, 4.39 mmol), 15% aqueous KOH solution (100 mL) and methanol (100 mL) was heated to reflux for 4 h. The resultant solution was allowed to cool and then diluted with H2O (300 mL). The solution was acidified to pH 2 by the addition of conc. HCl and the precipitate collected by vacuum filtration. The off-white solid was washed with H2O and air dried. Recrystallisation of the crude solid (EtOH) gave the product as fine off-white needles (1.16 g, 83%): mp 205-206.5° C. (lit mp 200-202° C.); 1H-NMR (DMSO) 5.34 (s, 2H), 6.67 (d, 1H, J 3.6 Hz), 6.89-7.00 (m, 7H), 7.08 (m, 2H), 7.89 (d, 1H, J 8.0 Hz); 13C-NMR (CDCl3) 52.55, 109.06, 110.91, 119.84, 120.91, 121.22, 122.57, 127.49, 127.69 (2C), 128.02, 128.99(2C), 134.69, 137.40, 140.72, 144.41, 151.75, 159.67; MS (EI) M+; Anal. (C19H14N2O3) C, calcd 73.19; found 73.18, H, calcd 7.17; found 7.16, N, calcd 14.23; found 14.13.
Reaction SMILES: N(C(C)C)[CH:2](C)C.[Li]CCCC.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[CH:17]=[C:16]([Cl:26])[N:15]=1.CI>C1COCC1>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[C:17]([CH3:2])=[C:16]([Cl:26])[N:15]=1
Reactant: CC(C)NC(C)C
Reactant: COc1ccc2cc(Cl)nc(Cl)c2c1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(C)c(Cl)nc(Cl)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
To a solution of i-Pr2NH (1.95 g, 19.3 mmol) in anhydrous THF (40 mL) was added dropwise n-BuLi (7.72 mL, 19.3 mmol, 2.50 M in hexane) at −78° C. under N2 atmosphere. After 30 minutes, 1,3-dichloro-7-methoxyisoquinoline (described in step 2 of Intermediate 12) (4.00 g, 17.5 mmol) in anhydrous THF (20 mL) was added to the reaction. After 15 minutes, MeI (4.97 g, 35.0 mmol) was added dropwise. The resulting mixture was warmed to 25° C. and allowed to stir for 16 hours. The reaction was quenched with H2O (150 mL) followed by an ethyl acetate extraction/workup to give the crude product, which was purified by prep-HPLC (0.1% TFA as additive). Most of CH3CN was removed under reduced pressure and extracted with EtOAc (50 mL×3). The combined organic layers were washed with H2O (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 1,3-dichloro-7-methoxy-4-methylisoquinoline (2.0 g, yield 47%) as an off-white solid.
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][C:23](=[NH:6])[NH2:24])[CH2:18][CH2:19]2)=[CH:12][CH:13]=1
Reactant: [NH4+]
Reactant: N#CCCCN1CCN(c2ccc(Cl)cc2)CC1
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: N=C(N)CCCN1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
Trimethylaluminium (2M solution in toluene, 12.32 ml, 24.64 mmol) was added dropwise to a suspension of ammonium chloride (1.32 g, 24.64 mmol) in dry toluene (20 ml) over a period of 20 min at 0° C. under nitrogen atmosphere. The resulting mixture was allowed to stir for 15 min at room temperature. To this was added dropwise a solution of 4-(4-(4-chlorophenyl) piperazin-1-yl)butanenitrile (1.3 g, 4.93 mmol) in dry toluene (10 ml) over a period of 10 min and the reaction mixture was heated at about 90° C. - about 100° C. for 15 h under stirring. The reaction mixture was cooled to 25° C., slowly poured into a slurry of silica gel (100-200 mesh, 30 g) in chloroform (100 ml) and was stirred for 10 min. The silica was filtered through celite and washed with methanol (3 ×50 ml). Combined filtrate was evaporated to obtain a crude solid which was dissolved in 10% hydrochloric acid (100 ml) and washed with diethyl ether (2 x 25 ml). To the resulting aqueous layer was added saturated aqueous solution of sodium hydroxide (30 ml) to bring the pH between 13 and 14. The aqueous layer was extracted with chloroform (3 ×100 ml). The combined organic layer was dried over anhydrous sodium sulphate. The solvent in the organic was evaporated under reduced pressure to obtain the title compound (1.1 g, 79% yield).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:14]1([CH:20]([CH3:25])[CH2:21][C:22](Cl)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:14]1([CH:20]([CH3:25])[CH2:21][C:22]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: CC(CC(=O)Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(CC(=O)Oc1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 24 h
Yield: 83.8 %

Procedure:
To the solution of phenol (8.62 g, 92 mmol) and 4-dimethylaminopyridine (400 mg) in toluene (110 ml) was added pyridine (18.1 g, 229 mmol) and the resulting solution was cooled to 10° C. Then a solution of 3-phenylbutanoyl chloride (20.1 g, 110 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 24 h, and then cooled to 5° C. before the careful addition of 2N aq. HCl-solution (225 ml). The mixture was stirred intensely for 15 min, then diluted with toluene and transferred into a separatory funnel. The aqueous layer was separated and the organic layer washed 4 times with water, then brine and dried over MgSO4. The solvent was removed in a rotary evaporator and the residue short-path distilled at 125-128° C./0.07 mbar to yield 18.52 g (70%) of colourless oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]1[O:37][C:10]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)([CH2:11][CH2:12][CH:13]([N+:25]([O-])=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[O:9][CH2:8]1.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:8]1[O:9][C:10]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)([CH2:11][CH2:12][CH:13]([NH2:25])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[O:37][CH2:7]1
Reactant: COc1ccc(CC(CCC2(CCc3ccc(F)cc3)OCCO2)[N+](=O)[O-])cc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CC(N)CCC2(CCc3ccc(F)cc3)OCCO2)cc1OC

Procedure:
To a suspension of 22.0 g (0.58 mole) of LiAlH4 in 400 ml of dry tetrahydrofuran was added dropwise a solution of 84.8 g (0.2 mole) of 1-(3',4'-dimethoxyphenyl)-7-(4'-fluorophenyl)-2-nitro-5-heptanone ethylene ketal in a minimum amount of dry tetrahydrofuran. After the addition the reaction mixture was refluxed gently for 2 hours. The excess LiAlH4 was decomposed with saturated Na2SO4 solution. The inorganic salts were filtered off and washed with ether. The organic layer was extracted twice with water, dried over anh MgSO4, filtered and concentrated under reduced pressure to 250 ml. This was used in the next step.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([C:11]([OH:13])=[O:12])[S:8][C:9]=1[CH3:10])[CH:2]([CH3:4])[CH3:3].[CH3:14]C#N>>[CH2:1]([C:5]1[C:6]([CH3:14])=[C:7]([C:11]([OH:13])=[O:12])[S:8][C:9]=1[CH3:10])[CH:2]([CH3:4])[CH3:3]
Reactant: CC#N
Reactant: Cc1sc(C(=O)O)cc1CC(C)C
Product: Cc1sc(C(=O)O)c(C)c1CC(C)C

Procedure:
4-Isobutyl-3,5-dimethyl-thiophene-2-carboxylic acid is prepared from 4-isobutyl-5-methyl-thiophene-2-carboxylic acid in analogy to Intermediate A2; LC-MS: tR=0.97 min, [M+1+CH3CN]=254.26; 1H NMR (CDCl3): δ 2.46 (s, 3H), 2.39 (s, 3H), 2.36 (d, J=7.0 Hz, 2H), 1.78 (hept, J=7.0 Hz, 1H), 0.91 (d, J=7.0 Hz, 6H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[N:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[Cl:14][O-].[Na+]>O>[Cl:14][C:10]1[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]([OH:3])=[N:12][C:11]=1[CH3:13]
Reactant: Cc1ccc(C(=O)O)c(O)n1
Reactant: [O-]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(O)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 15.7 g of 50% sodium hydroxide and 18.2 ml of water was added 10 g (0.065 mole) of 2-hydroxy-6-methylnicotinic acid. When the acid had dissolved, 200 ml of 5.25% aqueous sodium hypochlorite was added rapidly through a dropping funnel. The temperature was not moderated (slight exotherm did occur). The entire mixture was stirred at room temperature for 18 hr. The reaction mixture was then filtered and acidified with concentrated hydrochloric acid. The precipitate was recrystallized from isopropyl alcohol/ethereal to give ~6 g of analytically pure crystals, m.p. 291°-94° C.