Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:11]1[S:15][C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([Li])CCC.CN([CH:29]=[O:30])C.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH2:1]([C:11]1[S:15][C:14]([C:16]2[S:17][C:18]([CH:29]=[O:30])=[CH:19][CH:20]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCc1ccc(-c2cccs2)s1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCc1ccc(-c2ccc(C=O)s2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
5-Decyl-2,2′-bithiophene (39.0 g, 0.127 mol) prepared above and THF (300 ml) were placed in a 1000-ml three-necked flask equipped with a 200-ml dropping funnel and a reflux tube. The solution was cooled in an ice bath to 0° C., and a solution (80 ml) of n-butyllithium (1.6 M) in n-hexane was added dropwise to the cooled solution over a period of about one hr. After the completion of the dropwise addition, the mixture was stirred for about one hr. DMF (13.9 g, 0.191 mol) was added dropwise thereto at 0° C. over a period of about one hr. After the completion of the dropwise addition, the reaction temperature was raised to room temperature, and, at that temperature, the mixture was stirred overnight. After the completion of the reaction, a 1 N ammonium chloride solution (200 ml) was added, and the organic layer was extracted with diethyl ether, was dried over sodium sulfate, and was applied to column chromatography (CH2Cl2:hexane=1:1) to give an objective compound 5-decyl-5′-formyl-2,2′-bithiophene as a yellow solid (37.2 g, yield 87.60%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.26 (m, 14H), 1.69 (m, 2H), 2.81 (t, 2H, J=7.32 Hz), 6.74 (d, 1H, J=3.90 Hz), 7.16 (d, 1H, J=3.90 Hz), 7.18 (d, 1H, J=3.90 Hz), 7.64 (d, 1H, J=3.90 Hz), 9.84 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:29]([O:31]C)=[O:30])([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:33])[NH:12][CH:11]3[C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[CH3:41])[C:5]2=[CH:4][C:3]=1[F:43].O[Li].O.O.Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:29]([OH:31])=[O:30])([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:33])[NH:12][CH:11]3[C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[CH3:41])[C:5]2=[CH:4][C:3]=1[F:43]
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)c(F)cc12)C(=O)OC
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)c(F)cc12)C(=O)O
Temperature: 80 °C

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-ethyl-propoxy)-phenyl]-5-fluoro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.19 mmol), LiOH.H2O (140 mg, 3.3 mmol), H2O (1.25 mL) and methanol (3.75 mL) was heated at 80° C. for 1 h. After cooled to room temperature, the mixture was acidified by addition of 0.5 N HCl and partitioned between EtOAc and water. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product, which was used for the next step reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
4-Amino-benzoic acid (100 mmol) was dissolved in DMF (50 mL) and N-bromosuccinimide (100 mmol) was added. Stirred at ambient temperature for 18 h, the reaction mixture was then poured into water (100 mL). The product was removed by filtration, washed with water and dried in vacuo to give 4-amino-3-bromo-benzoic acid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[C:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H+].[B-](F)(F)(F)F.O(CC)CC>ClCCl>[O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C@@H:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC1=C(CC(=O)OC)CCC1=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC[C@@H]1C(=O)CC[C@@H]1CC(=O)OC
Yield: 99 %

Procedure:
The reaction was carried out analogously to that described in example 6, but using 100 g (446 mmole) of methyl 3-oxo-2-pentyl-1-cyclopentene-acetate, 427 mg (1.34 mmole) of [(COD)Ru(2-methylallyl)2 ], 410 mg (1.34 mmole) of (-)-Me-DuPHOS and 26.5 ml of HBF4.O(C2H5)2 in dichloromethane (0.1M, 2.68 mmole). This corresponds to a catalyst concentration of 0.3 mole %, relative to the substrate. 170 ml of dichloromethane were added, and the mixture was hydrogenated at a temperature of 7.5° C. and a pressure of 5×106Pa for 70 h to obtain methyl (+)-(1R)-cis-3-oxo-2-pentyl-1-cyclopentaneacetate in 99% yield, cis/trans ratio=99.2/0.8 and (+)-cis/(-)-cis ratio=84/16.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=O.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15].C(O)C.Cl>[OH-].[Na+]>[C:9]([CH2:8][CH2:7][C:6]1[CH:12]=[CH:13][C:3]([CH:1]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:4][CH:5]=1)([OH:11])=[O:10]
Reactant: O=Cc1ccc(CCC(=O)O)cc1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccc(C=CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 5.34 g of 4-formyldihydrocinnamic acid in 50 ml of 1N sodium hydroxide was added a solution of 3.6 g of acetophenone and 20 ml of ethanol. The reaction mixture was stirred at room temperature for 4 hrs. and then poured onto 300 g of crushed ice. 1N Hydrochloric acid was added and, after stirring at 0° C for 15 min., the precipitate was collected and washed with water. The precipitate was dissolved in 500 ml of ethyl acetate, dried over anhydrous sodium sulfate and the drying agent was collected on a filter. The filtrate was concentrated to about 100 ml and seeded with crystalline product. The solid was collected, washed with 1:4-ethyl acetate-ether followed by ether and dried at 70°-75° C under vacuum to give 8.4 g (72%) of 4-(2-carboxyethyl)benzalacetophenone, as yellow needles, m.p. 159°-160° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:19]([Cl:20])=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[Cl:21])=[CH:4][CH:3]=1.[Cl:22]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:14]([Cl:21])=[CH:15][C:16]([NH2:17])=[C:18]([Cl:22])[C:19]=2[Cl:20])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1
Solvent: c1ccccc1
Product: Nc1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1Cl
Yield: 56 %

Procedure:
Into a magnetically stirred solution of 4-(4-chloro-1-naphthoxy)-3,5-dichloroaniline (6.00 grams, 17.72 mmol) prepared in Part B in benzene (50 milliliters) was added solid N-chlorosuccinimide (2.84 grams, 21.20 mmol). The mixture was heated to reflux for 1 hour. cooled and filtered. The solvent was evaporated under reduced pressure and the crude product when subjected to flash column chromatography (3:1 hexane:ethyl acetate) afforded pure 4-(4-chloronaphthoxy)-2.3.5-trichloroaniline (3.70 grams. 9.92 mmol, 56%). Elemental analysis of the product indicated the following:
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].CC(C)([O-])C.[K+].F[C:11]1[C:12]2[C:16]([CH:17]=[CH:18][CH:19]=1)=[N:15][N:14]([CH3:20])[C:13]=2[S:21]([NH2:24])(=[O:23])=[O:22]>CS(C)=O>[CH2:1]([S:3][C:11]1[C:12]2[C:16]([CH:17]=[CH:18][CH:19]=1)=[N:15][N:14]([CH3:20])[C:13]=2[S:21]([NH2:24])(=[O:23])=[O:22])[CH3:2]
Reactant: CCS
Reactant: Cn1nc2cccc(F)c2c1S(N)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCSc1cccc2nn(C)c(S(N)(=O)=O)c12
Temperature: 120 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
4.8 g (77 mmol) of ethanethiol was added to a solution containing 8.6 g (77 mmol) of potassium t-butoxide in DMSO (70 ml), under cooling with ice, and 8 g (35 mmol) of 4-fluoro-2-methyl-2H-indazole-3-sulfonamide was further added thereto. This mixture was stirred at 120° C. for 2 hours. After confirming the disappearance of the starting material by TLC, treatment was conducted in the same manner as in Preparation Example 6 to obtain 6.8 g (yield: 72.5%) of the desired product. Melting: 145°-147° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10](I)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[F:16][C:17](I)([F:19])[F:18]>[Cu].N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([C:17]([F:19])([F:18])[F:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: FC(F)(F)I
Reactant: COC(=O)c1cccc2c(I)cccc12
Agent: [Cu]
Solvent: c1ccncc1
Product: COC(=O)c1cccc2c(C(F)(F)F)cccc12
Temperature: 130 °C
Yield: 60.4 %

Procedure:
A mixture of 5-iodo-1-naphthalenecarboxylic acid methyl ester [8.8 g, 28 mmoles, described by C. Seer and R. School, Justus Leibigs Ann. Chem., 398, 82 (1913)], trifluoromethyl iodide (12 g, 61.2 mmoles) freshly prepared copper powder (5.7 g, prepared according to the procedure of R. Q. Brewster and T. Groening, "Organic Syntheses", Coll. Vol. II, John Wiley and Sons, New York, N.Y., U.S.A., 1948, p. 445) and pyridine (45 ml) was charged into a stainless steel autoclave. The vessel was shaken and heated at 130° C. for 24 hr and cooled to room temperature. The mixture was filtered to remove insoluble material. The filtrate was washed with 1 N aqueous HCl, water and brine, dried (MgSO4) and concentrated to dryness. The residue was crystallized from methanol to give 4.3 g of 5-(trifluoromethyl)-1-naphthalenecarboxylic acid methyl ester, NMR (CDCl3) δ4.0 (s, 3H), 8.0 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[CH2:27]([NH2:30])[CH2:28][NH2:29].C(N(CC)CC)C>C(#N)C>[NH2:29][CH2:28][CH2:27][NH:30][C:15]1[C:16]([Cl:18])=[C:17]2[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]2[C:6]2[CH:7]=[C:2]([NH2:1])[C:3]([F:26])=[CH:4][C:5]=2[F:25])=[CH:13][C:14]=1[F:20]
Reactant: NCCN
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NCCNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Yield: 65.2 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), ethylenediamine (16 mg) and triethylamine (70 mg) were added to acetonitrile (5 ml), and the mixture was heated under reflux for 2 hours. After the reaction mixture was allowed to cool, deposits were collected by filtration. The deposits were washed successively with ethanol and diethyl ether to obtain the title compound (72 mg) as a pale yellow powder.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1)#[N:2].[CH2:11]([N:17]=[C:18]=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>N1C=CC=CC=1>[C:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[N:7]([C:18]([NH:17][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:19])[CH:8]=1)#[N:2]
Reactant: CCCCCCN=C=O
Reactant: N#Cc1c[nH]c(=O)[nH]c1=O
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCNC(=O)n1cc(C#N)c(=O)[nH]c1=O
Temperature: 100 °C
Yield: 15.6 %

Procedure:
5-Cyanouracil (0.10 g, 0.73 mmol) was dissolved in dry pyridine (5.0 mL) and hexyl isocyanate (0.08 mL, 1.10 mmol) was added. The mixture was heated under microwave irradiation to 100° C. for 10 min and then was poured into water (50 mL). The product was extracted with dichloromethane (2×50 mL), the combined organic layers were dried over Na2SO2 and the solvent was concentrated under reduced pressure. The crude was purified by column chromatography using SI (2 g) cartridge (dichloromethane) and subsequently washed with warm heptane to afford the title compound (0.03 g, 16%) as white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.86-0.96 (m, 3H), 1.29-1.41 (m, 6H), 1.57-1.70 (m, 2H), 3.44 (q, J=6.4, 2H), 5.01 (s, 1H), 8.85 (br s, 1H), 9.05 (s, 1H). MS (ESI) m/z: 263 [M-H]−.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.[S:11]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]([NH:24][C:25](=[O:27])[CH3:26])[CH2:18]2)(=[O:14])(=[O:13])[NH2:12].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O.CN1C(=O)CCC1>[F:8][C:7]([F:10])([F:9])[C:4]1[S:3][C:2]([NH:12][S:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][CH:19]([NH:24][C:25](=[O:27])[CH3:26])[CH2:18]3)(=[O:13])=[O:14])=[N:6][N:5]=1
Reactant: CC(=O)NC1Cc2ccc(S(N)(=O)=O)cc2C1
Reactant: FC(F)(F)c1nnc(Cl)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)NC1Cc2ccc(S(=O)(=O)Nc3nnc(C(F)(F)F)s3)cc2C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The mixture of 300 mg of 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazol, 300 mg of N-(5-sulfamoyl-indan-2-yl)-acetamide, 1.8 g cesium carbonate und 10 ml of NMP was stirred at 70° C. for 3 hours. After cooling to room temperature 50 ml of water were added and with 2N hydrochloric acid a pH=3 was adjusted. The product was extracted twice with 30 ml of ethyl acetate, the organic layer was washed with 20 ml of water, dried over sodium sulfate and evaporated in vacuo. The resulting crude material was purified by column chromatography (silica gel, eluent: dichloromethane:methanol=90:10).
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]([OH:23])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]([NH2:3])=[O:23]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CCN(CC)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1cc2ccccc2[nH]1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 327 %

Procedure:
Diethylaniline (0.33 μL, 2.1 μmol, 1.1 equiv) was added in one portion to a stirred solution of the amine (1.0 mg, 1.9 μmol, 1 equiv) in THF (0.15 mL) at 0° C. under an argon atmosphere and the solution was stirred for 5 min. Indole-2-carboxylic acid (0.40 mg, 2.5 μmol, 1.3 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.48 mg, 2.5 μmol, 1.3 equiv) and 1-hydroxybenzotriazole (0.31 mg, 2.3 μmol, 1.2 equiv) were then added separately, each in one portion, to the above solution at 0° C. The reaction mixture was warmed to 23° C. over 15 h 30 min, then was quenched with saturated aqueous ammonium chloride solution (3 mL). The mixture was diluted with ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layer was dried over sodium sulfate. Concentration in vacuo left a white solid, which was purified by flash column chromatography (60% ethyl acetate-hexanes) to give the indole-2-carboxylic acid amide derivative (1.1 mg, 87%) as a white solid.
Reaction SMILES: CNC[C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[CH:9]1[C:8]2[CH2:7][C:6]3[C:14](=[CH:15][CH:16]=[CH:4][CH:5]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CNCc1ccc2c(c1)Cc1ccccc1-2
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: c1ccc2c(c1)Cc1ccccc1-2

Procedure:
A solution of fluorene-2-carbonyl chloride (prepared from fluorene-2-carboxylic acid and oxalyl chloride) in THF is added to aqueous methylamine (2 molar equivalents) to prepare N-methyl fluorene-2-carboxamide. Reduction of the amide using LiAlH4 in ether provides 2-((methylamino)methyl)fluorene. The amine is protected by reaction with di-tert-butyl dicarbonate to provide 24N-tBOC—N-methylamino)methyl)fluorene.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[C:5]([C:11]([F:12])([F:13])[F:14])[CH:4]=1
Reactant: CSc1ccc(C=O)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CSc1ccc(CO)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methylsulfanyl-2-trifluoromethyl-benzaldehyde (4.87 mmol) was dissolved in mL of MeOH and the resulting solution was treated with NaBH4 (221.1 mg, 5.84 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue was partitioned between CH2Cl2 and 1N HCl solution. The combined extracts were washed with brine, dried over Na2SO4. A small portion of extracts was evaporated to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:7]=1.[F:23][C:24]([F:36])([F:35])[C:25]1[NH:29][C:28]2[CH:30]=[C:31]([NH2:34])[CH:32]=[CH:33][C:27]=2[N:26]=1>>[Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([NH:34][C:31]2[CH:32]=[CH:33][C:27]3[N:26]=[C:25]([C:24]([F:36])([F:35])[F:23])[NH:29][C:28]=3[CH:30]=2)=[O:11])[CH:7]=1
Reactant: Nc1ccc2nc(C(F)(F)F)[nH]c2c1
Reactant: CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc2nc(C(F)(F)F)[nH]c2c1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
68 mg (purity 94%, 0.20 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 12.1D) and 44 mg (0.22 mmol) of 2-(trifluoromethyl)-1H-benzimidazole-6-amine were reacted according to General Method 1. Yield: 63 mg (60% of theory)
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[NH2:18].C[Al](C)C.O.Cl>C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]2[S:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3](=[O:2])[NH:18][C:12]=2[CH:13]=1
Reactant: COC(=O)c1ccccc1Sc1ccc(Cl)cc1N
Agent: C[Al](C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C1Nc2cc(Cl)ccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 144 h
Yield: 28.5 %

Procedure:
A mixture of 2-(2-amino-4-chlorophenylsulfanyl)-benzoic acid methyl ester (189JO11) (149 mg, 0.51 mmol) and AlMe3 (355 μL, 0.71 mmol, 2 M in toluene) in CH2Cl2 (3 mL) was stirred at ambient temperature for six days, and then water was added carefully. The mixture was diluted with CH2Cl2, and was acidified with 2 M aqueous HCl. The organic phase was separated, dried (Na2SO4), concentrated and flash chromatographed (heptane:EtOAc, 5:1-3:1) to give 38 mg (29%) of the title compound (189JO13). MS (ESI) 262 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([NH:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=1)[C:31](O)=[O:32])(=[O:26])[CH3:25]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:31]([C:30]3[CH:34]=[CH:35][N:36]=[C:28]([NH:27][C:24](=[O:26])[CH3:25])[CH:29]=3)=[O:32])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccnc(NC(C)=O)c1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 2-acetylamino-isonicotinic acid to yield (3aR,4S,7aR)-4-(2-acetylamino-pyridine-4-carbonyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 476; RT=7.443 min HPLC Method I
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][OH:16])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].[H][H]>CO.[Pd]>[CH3:14][C:11]1([CH2:15][OH:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC1(CO)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC1(CO)CCNCC1

Procedure:
To a solution of (1-benzyl-4-methylpiperidin-4-yl)methanol (2.7 g, 12 mmol) in methanol (34 mL) was added ammonium formate (8.6 g, 135 mmol) followed by palladium on carbon (10% w/w, 3.6 g, 1.7 mmol). The reaction mixture was stirred for 18 hours under a balloon of hydrogen, then degassed, flushed with nitrogen, and filtered over a pad of celite. The solvent was removed in vacuo and the resulting residue was purified by flash chromatography (silica, 40 g, ISCO, 0-20% methanol in methylene chloride) to afford the title compound as a colorless oil, which was used in the next step without any further purification (1.2 g, 76%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.[Li]CCCC.[CH3:18][C:19]([CH3:21])=[O:20]>C1COCC1.[NH4+].[Cl-]>[Br:12][C:4]1[CH:3]=[C:2]([C:19]([OH:20])([CH3:21])[CH3:18])[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=1
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Br)cc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1,3-dibromo-5-tert-butylbenzene (404 mg) in dry THF (10 mL) was added n-BuLi (0.84 mL) at −78° C. and after 20 min, acetone was added dropwise to the above solution at −78° C. and the mixture was stirred at this temperature for 30 min and at rt for 1 h, diluted with sat. NH4Cl and extracted with EA (3×30 mL). The organic layer was dried over Na2SO4, evaporated and purified by CC to give compound P23a (380 mg, 70%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N:14]([O-])=O.[Na+].Cl>O>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[NH2:14]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(N)ccc1OC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(NN)ccc1OC
Yield: 78411.6 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-7 by using methyl 5-amino-2-methoxybenzoate (15.0 g, 0.082 mol), stannous chloride (37.25 g, 0.16 mmol), sodium nitrite (6.28 g, 0.091 mmol), conc. HCl (400 mL) and water (100 mL) to afford 14.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.75 (s, 6H), 7.09 (m, 1H), 7.20-7.23 (m, 1H), 7.34 (s, 1H), 10.20 (br s, 2H); MS (m/z): 197.27 (M+H)+.