Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3]C(Cl)=O.[CH3:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[NH:18][CH:19]1[CH2:24][O:23][C:21](=[O:22])[CH2:20]1.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][CH2:3][N:18]([CH:19]1[CH2:24][O:23][C:21](=[O:22])[CH2:20]1)[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH3:7]
Reactant: Cc1ccc2ccccc2c1NC1COC(=O)C1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCN(c1c(C)ccc2ccccc12)C1COC(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.4 g (0.022 mol) sample of methoxyacetyl chloride was added dropwise to a solution of 5.5 g (0.022 mol) 3-(N-2-methylnaphth-1-ylamino)-gamma-butyrolactone and 1.7 g (0.022 mol) pyridine in 100 ml dichloromethane. The reaction mixture was stirred one hour at about 25° C. and then heated under reflux for 6 hours. After cooling overnight, the reaction mixture was washed successively with water, saturated sodium bicarbonate solution, water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed through a silica gel column. Elution with 25% acetone/75% petroleum ether gave 4.3 g of the product, m.p. 42°-46° C. The product is tabulated in Table C as Compound No. C-2.
Reaction SMILES: [CH3:1][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[C:19](C=O)[CH:18]=[CH:17][C:16]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:11]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[BH4-].[Na+].O.[CH2:32]([OH:34])C>>[CH3:3][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:23]2[CH:28]=[CH:27][C:26]([CH2:32][OH:34])=[CH:25][CH:24]=2)=[N:11]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(C)(c1ccccc1)n1nnc(-c2cc(C=O)ccc2-c2ccccc2)n1
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-carbaldehyde (0.62 g, 1.7 mmol), prepared as in Example 8 or 9, and sodium borohydride in 30 mL of absolute ethanol was stirred at room temperature for 1 hour. The mixture poured into 150 mL of water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and then concentrated. The residue was dissolved in approximately 10 mL of absolute diethyl ether and the solution was cooled in an ice bath giving a precipitate. The precipitate was isolated by filtration and drying gave 2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-methanol (0.37 g, 1.0 mmol), m.p. 119°-120° C.
Reaction SMILES: [C:1]([O:13]C)(=O)[C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1.[CH3:15][C:16]([CH3:18])=[O:17].[H-].[Na+].Cl>C1(C)C=CC=CC=1.O>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([C:1](=[O:13])[CH2:15][C:16](=[O:17])[CH3:18])[CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Reactant: CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(C(=O)CC(C)=O)c1
Temperature: 100 °C
Yield: 13.1 %

Procedure:
A solution of dimethyl isophthalate (12 g, 61.85 mmole) and acetone (5 mL, 68 mmole) in a mixture of toluene/dimethoyethane (90 mL/30 mL) was added to a suspension of NaH 60% (2.97 g, 74.23 mmole) in dry toluene (30 mL) under argon. The mixture was heated at 100° C. for 4 hours. The reaction mixture was cooled to rt and 25 mL of water were added. The mixture was poured into water (250 mL) and the pH was adjusted to 3-4 with HCl 2N. The aqueous mixture was extracted with ethyl acetate (2×250 mL), washed with brine, dried over sodium sulphate and evaporated to afford a yellow solid which was purified by column cromatography (n-Hex/EtOAc 9:1 to 8:2) to afford the title compound (1.78 g, 11% yield) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][C:17]([NH2:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][C:17]([NH2:19])=[O:18])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)OB(c2cnn(CC(N)=O)c2)OC1(C)C
Temperature: 50 °C

Procedure:
A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.00 g, 10.3 mmol), 2-bromoacetamide (2.14 g, 15.5 mmol), and potassium carbonate (2.14 g, 15.5 mmol) in acetone (60 mL) was heated at about 50° C. for about 3.5 days. The reaction mixture was then cooled to ambient temperature, filtered through diatomaceous earth, while washing with additional acetone, and then concentrated under reduced pressure. The crude material was then dissolved in a minimal amount of dichloromethane and purified via silica gel chromatography eluting with a gradient of 80-100% ethyl acetate in heptane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.88 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.24 (s, 1H), 4.77 (s, 2H), 1.26 (s, 12H). MS (ESI+) m/z 252.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)C=O.ClC1C=C(C=CC=1)C(OO)=[O:28].[OH-].[Na+].Cl>ClCCl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([OH:28])[CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Oc2c(C)cc(C=O)cc2C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Oc2c(C)cc(O)cc2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a solution of 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzaldehyde (0.18 g, 0.60 mmol, Example 28, step a) in dichloromethane (6.0 mL) at 0° C. was added m-chloroperoxybenzoic acid (0.22 g, 0.905-mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. The organic solution was washed with saturated sodium bicarbonate (2×10 mL) and water. The solvent was removed under reduced pressure and the residue was dissolved in methanol (5 mL). To the solution was added 1 N NaOH (1.81 mL, 1.81 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate, acidified with 2 N HCl and washed with brine. The solvent was evaporated and the residue was purified by preparatory TLC eluting with acetone-hexanes (1:4) to afford 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)phenol as an oil (0.08 g, 47%): 1H NMR (200 MHz, DMSO-d6): δ 9.17 (s, 1 H), 6.82 (m, 1 H), 6.70 (m, 1 H), 6.51 (s, 2 H), 6.32 (m, 1 H), 3.71 (s, 3 H), 3.18 (m, 1 H), 1.95 (s, 6 H), 1.12 (d, J=6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (4:1); Rf=0.44.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15](OS(C(F)(F)F)(=O)=O)[N:14]([C@H:25]([C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=2)[CH3:26])[N:13]=1.[CH3:38][O:39][C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[CH:46]=[C:45](B(O)O)[CH:44]=[CH:43]2.C(N(CC)CC)C.N#N>COCCOC.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15]([C:45]2[CH:44]=[CH:43][C:42]3[C:47](=[CH:48][CH:49]=[C:40]([O:39][CH3:38])[CH:41]=3)[CH:46]=2)[N:14]([C@H:25]([C:27]2[CH:28]=[CH:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:36][CH:37]=2)[CH3:26])[N:13]=1
Reactant: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(C(F)(F)F)ccc3F)cc2OS(=O)(=O)C(F)(F)F)cc1
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(C(F)(F)F)ccc3F)cc2-c2ccc3cc(OC)ccc3c2)cc1
Temperature: 100 °C

Procedure:
Ethyl 4-[(1S)-1-(3-[2-fluoro-5-(trifluoromethyl)phenyl]-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoate (1.05 g, 1.90 mmol), 6-methoxy-2-naphthylboronic acid (0.43 g, 2.1 mmol), and triethylamine (0.53 ml, 3.8 mmol) were dissolved in DME (20 ml). After deoxygenation (vacuum-N2 cycles) Pd(PPh3)4 (85 mg, 4% mol) was added. The mixture was deoxygenated again and heated in microwave reactor to 100° C. for 15 min. The reaction mixture was filtered through a Celite pad, concentrated and purified by flash column chromatography (SiO2, 5-20% ethyl acetate in hexane gradient) to give ethyl 4-{(1S)-1-[3-[2-fluoro-5-(trifluoromethyl)phenyl]-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoate as colorless gel. NMR (500 MHz, CDCl3) δ: 1.38 (t, J=7.1 Hz, 3H); 1.99 (d, J=7.1 Hz, 3H); 3.96 (s, 3H); 4.37 (q, J=7.1 Hz, 2H); 5.64 (q, J=7.1 Hz, 1H); 6.87 (d, JF-H=4.2 Hz, 1H); 7.17 (d, J=2.5 Hz, 1H); 7.20 (dd, J=2.5 Hz, 8.9 Hz, 1H); 7.25 (t, J=9.5 Hz, 1H); 7.30 (d, J=8.4 Hz, 2H); 7.32 (dd, J=1.5 Hz, 8.4 Hz, 1H); 7.56 (m, 1H); 7.66 (d, J=1.5 Hz, 1H); 7.68 (d, J=8.9 Hz, 1H); 7.77 (d, J=8.4 Hz, 1H); 8.00 (d, J=8.4 Hz, 2H); 8.48 (dd, J=2.7 Hz, 6.8 Hz, 1H). MS C32H26F4N2O3 Cald: 562.19; Obsd (M+1): 563.33.
Reaction SMILES: [ClH:1].Cl.Cl.C([C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH2:16][C:17]3[N:18]=[CH:19][NH:20][CH:21]=3)[CH2:14][C@@H:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:12][CH2:11][C:10]=2[CH:29]=1)#N.[CH:30](=O)[CH2:31][CH2:32][CH3:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[CH2:30]([N:12]1[CH2:11][C:10]2[CH:29]=[CH:6][CH:7]=[CH:8][C:9]=2[N:15]([CH2:16][C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[CH2:14][CH:13]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCC=O
Reactant: N#Cc1ccc2c(c1)CN[C@H](Cc1ccccc1)CN2Cc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCN1Cc2ccccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1
Reaction time: 14 h
Yield: 354.3 %

Procedure:
A solution of Example 391 (0.23 g, 0.7 mmol) and butyraldehyde (1 g, 14 mmol) in 1:4 AcOH/CH2Cl2 (25 mL) was stirred at rt for 1 hr. NaBH(OAc)3 (3.0 g, 14 mmol) was added and stirring was continued for 14 hrs. The reaction was quenched with conc. NH4OH and diluted with 10% iPrOH in CH2Cl2 (50 mL). The organic phase was washed with 1 N NaOH (2×20 mL), dried over Na2SO4 and evaporated to give a yellow solid (0.4 g) which was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and converted to the HCl salt by lyophilizing with 1N HCl to give Example 392 as a yellow solid (45 mg, 12%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:9])[CH2:4][C:5](=O)[CH2:6][CH3:7].[NH3:10]>C1(C)C(C)=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3](=[O:9])[CH:4]=[C:5]([NH2:10])[CH2:6][CH3:7]
Reactant: N
Reactant: CCC(=O)CC(=O)NC
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: CCC(N)=CC(=O)NC
Temperature: 25 °C

Procedure:
A solution of N-methyl propionylacetamide (4.25 g, 32.9 mmol) in 30 ml xylene was bubbled with ammonia gas at 110° C. for 2 hrs. After cooling to room temperature, the mixture was diluted with 30 ml of CHCl3 and dried (Na2SO4). After evaporation of solvent, N-methyl 3-amino-2-pentenamide was obtained as light-gray oil (4.15 g, 98).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[C:7]([O:10][CH3:11])[CH:6]=[C:5]([CH:12]=[O:13])[CH:4]=1.S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(=O)=O>C1C=CC=CC=1.O>[CH3:11][O:10][C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:18])[CH:12]=[O:13]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(C=O)cc(OC)c1OC
Temperature: 75 °C
Reaction time: 1 h

Procedure:
25.0g syringealdehyde (0.137 mol), 26.6g of dimethyl sulfate (0.211 mol), and 27.7 g. of potassium carbonate (0.201 mol) were heated with stirring as in Example 1. When the temperature reached 45° C the mixture became fluid and carbon dioxide was given off. The temperature was slowly increased to 75° C and held at this value for 1 hour. Addition of water, acidification, and benzene extraction gave a quantitative yield of 3,4,5-trimethoxybenzaldehyde which contained no detectable syringealdehyde or other impurities as determined by g.l.c. analysis.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:19]O>[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([O:10][CH3:19])=[O:9])=[CH:13][CH:14]=1
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)O
Reactant: CO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)(C)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2-(4-Bromophenoxy)-2-methylpropionic acid (1 g) was dissolved in methanol (5 mL), a catalytic amount of thionyl chloride was added, and the mixture was stirred at room temperature for 7 hrs. Saturated brine was added to the reaction mixture, and the mixture was extracted with a mixed solvent of chloroform-methanol. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (920 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][C:9]#N)=[C:6]([N+:11]([O-])=O)[CH:5]=[CH:4][CH:3]=1.C[OH:15].O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:11]2
Reactant: N#CCc1c(F)cccc1[N+](=O)[O-]
Reactant: CO
Solvent: O
Product: O=C1Cc2c(F)cccc2N1
Temperature: 25 °C

Procedure:
6-Fluoro-2-nitrobenzyl cyanide (23.10 g, 0.12 mole) (prepared according to A. Kalir, Synthesis (1987) 514-515) was dissolved in 10:1 MeOH/H2O (250 mL) and the solution was chilled in an ice water bath. HBr gas was bubbled into the cold mixture for 75 min. The solution was allowed to warm up to r.t. and then concentrated to half its volume under reduced pressure. THF (100 mL), water (100 mL) and conc. HCl (6 mL) were successively added at r.t. and stirring was maintained for 75 min. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, sat. aq. NaHCO3 and brine, then dried over sodium sulfate and concentrated under educed pressure. This material (20.9 g) was dissolved in acetic acid (200 mL) and hydrogenated for 2 h in a Parr apparatus at 50 Psi, in the presence of 10% Pd/C (4.33 g). The reaction mixture was filtered through a cake of Celite®, and the cake was washed with acetic acid. The solution was concentrated under reduced pressure and dissolved in MeOH (300 mL) containing 1N NaOH (15 mL). This mixture was poured into 2:1 sat aq. NaCl/H2O (600 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude residue was triturated with ether to afford 5.8 g (first crop) of pure 1,3-dihydro-4-fluoro-2H-indol-2-one. The mother liquor was chromatographed on Silica Gel (230-400 mesh, eluted with 40% ethyl acetate in hexanes) to yield 16 g of product (overall yield from cyanide: 41%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[N:18][NH2:19])[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: NN=C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
A mixture of 50 g of 4,4'-difluorobenzophenone, 35.5 ml of hydrazine hydrate and 200 ml of ethanol is refluxed for 8 h. It is concentrated to dryness, taken up with water and extracted with ether. The organic phase is washed with water, dried over MgSO4 and then concentrated. The yellow oil obtained crystallizes slowly to give 50.6 g of 4,4'-difluorobenzophenone hydrazone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.CN(C)C=O.S(Cl)([Cl:20])=O>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([Cl:20])=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2ccccc2[nH]1

Procedure:
A mixture of indole-2-carboxylic acid (2.18 g), N,N-dimethylformamide (52 mg) and thionyl chloride (1.0 ml) in dry dichloromethane (22 ml) was refluxed for 1 hour to give a solution of 2-indolylcarbonyl chloride.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3](=O)[CH2:4][C:5]([C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)=O.[NH2:25][NH2:26]>C1(C)C=CC=CC=1>[CH3:21][S:18]([C:14]1[CH:13]=[C:12]([C:9]2[S:8][C:7]([C:5]3[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[NH:26][N:25]=3)=[CH:11][CH:10]=2)[CH:17]=[CH:16][CH:15]=1)(=[O:20])=[O:19]
Reactant: NN
Reactant: CS(=O)(=O)c1cccc(-c2ccc(C(=O)CC(=O)C(F)(F)F)s2)c1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)[nH]n3)s2)c1
Temperature: 100 °C

Procedure:
Into a 100 mL flask was weighed 5.18 g (13.8 mmol) of 4,4,4-Trifluoro-1-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-butane-1,3-dione, 50 mL of toluene, and 450 μL (14.3 mmol) of hydrazine. The resulting solution was heated at 100° C. for 21 h. The reaction was then concentrated in vacuo and was partially purified by silica gel flash chromatography (Jones Flashmaster, 70 g SiO2, gradient elution from 100% hexanes to 20% ethyl acetate over 30 minutes. Appropriate fractions were combined, concentrated in vacuo, and were precipitated from ethyl acetate with hexanes to afford the intermediate 3-[5-(3-Methanesulfonyl-phenyl)-thiophen-2-yl]-5-trifluoromethyl-1H-pyrazole as a faintly yellow, semi-crystalline solid, yield: 1.24 g (24%). 1H NMR (400 MHz, CDCl3): δ 8.15 (s, 1H), 7.86 (d, J=8 Hz, 2H), 7.62 (t, J=8 Hz, 1H), 7.45 (d, J=4 Hz, 1H), 7.39 (d, J=4 Hz, 1H), 6.70 (s, 1H), 3.12 (s, 3H); MS (ES): 373 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[OH:9][C:10]([CH3:43])([CH3:42])[CH2:11][C@:12]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:17][CH2:16][N:15]([C@H:18]([C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=2)[CH3:19])[C:14](=[O:35])[CH2:13]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.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>[OH:9][C:10]([CH3:43])([CH3:42])[CH2:11][C@:12]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:17][CH2:16][N:15]([C@H:18]([C:20]2[CH:21]=[CH:22][C:23]([C:2]3[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=3)=[CH:24][CH:25]=2)[CH3:19])[C:14](=[O:35])[CH2:13]1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)CC1=O
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)CC1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
To a solution of 5-bromopyridin-2(1H)-one (30 mg, 0.17 mmol) in DME (6 mL) was added Pd(PPh3)4 (10 mg, 0.01 mmol) under N2. The mixture was stirred at rt for 1 h. (R)-4-(2-hydroxy-2-methylpropyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)piperidin-2-one (25 mg, 0.05 mmol) in EtOH (2 mL) was added, followed by satd aq NaHCO3 (2 mL). The mixture was stirred at 100° C. for another 2 h under N2. The reaction was quenched with H2O, and extracted with EtOAc (3×). The combined organic phase was dried and concentrated to give the crude final product, which was purified by preparative TLC to give 5-(4-((S)-1-((R)-4-(2-hydroxy-2-methylpropyl)-2-oxo-4-phenylpiperidinyl)ethyl)phenyl)pyridin-2(1H)-one (4.5 mg, 20%). LC-MS Method 2 tR=1.034 min, m/z=445.2; 1H NMR (CDCl3): δ 0.86 (s, 3H), 1.02 (s, 3H), 1.41 (d, 3H), 1.82 (d, 2H), 2.00 (m, 2H), 2.11 (m, 2H), 2.62 (d, 1H), 2.85 (m, 1H), 3.42 (d, 1H), 6.0 (m, 1H), 6.69 (m, 1H), 6.88 (m, 2H), 7.09 (m, 2H), 7.17 (m, 1H), 7.25 (m, 4H), 7.51 (m, 1H), 7.78 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:14]2[CH:13]=[C:12]3[NH:15][C:16]4[C:21]([C:11]3=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:20][N:19]=[CH:18][CH:17]=4.[H-].[Na+].Cl[C:26]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]=[C:28]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:27]=1>CN(C)C=O.C1COCC1>[C:38]1([C:28]2[N:29]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:31]=[C:26]([N:15]3[C:12]4=[CH:13][C:14]5[C:2]([CH3:22])([CH3:1])[C:3]6[C:8]([C:9]=5[CH:10]=[C:11]4[C:21]4[C:16]3=[CH:17][CH:18]=[N:19][CH:20]=4)=[CH:7][CH:6]=[CH:5][CH:4]=6)[N:27]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccncc13
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)c2ccccc2-c2cc3c4cnccc4n(-c4nc(-c5ccccc5)nc(-c5ccccc5)n4)c3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g (35.17 mmol) of 10,10-dimethyl-10,12-dihydro-3,12-diazaindeno-[2,1-b]fluorene are dissolved in 150 ml of dimethylformamide under a protective-gas atmosphere, and 1.7 g of 60% NaH in mineral oil (42.2 mmol) are added. After 1 h at room temperature, a solution of 2-chloro-4,6-diphenyl-1,3,5-triazine (10.7 g, 38.68 mmol) in 100 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum, the purity is 99.9%. The yield is 14.4 g (80%).
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]\Br)[CH3:2].C([Li])(C)(C)C.Cl[Sn:13]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17].C([O-])(O)=O.[Na+]>C(OCC)C.CCCCC>[CH2:1]([O:3]/[CH:4]=[CH:5]\[Sn:13]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH3:17])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCO/C=C\Br
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCCCC
Solvent: CCOCC
Product: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
(Ref. Wollenberg, R. H.; Albizati, K. F.; Peries, R. J. Am. Chem. Soc. 1977, 99, 22, 7365-7367.) To a −78° C. solution of (Z)-2-ethoxy-1-bromoethene (5.0 mL, 46.8 mmol) in diethyl ether (160 mL) was added a 1.7 M solution of tert-butyl lithium in pentane (55 mL), dropwise over 20 min. This pale yellow solution was stirred at −78° C. for 40 min, and then chloro-tri-n-butylstannane (13.3 mL, 49.0 mmol) was added, dropwise over 7 minutes. The resulting reaction mixture was allowed to warm slowly. Once the cooling bath had reached −30° C., saturated aq. NaHCO3 (150 mL) was added, and the cooling bath was removed. This mixture was stirred for 15 minutes, and then the layers were separated. The aq. layer was extracted with diethyl ether (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford (Z)-2-ethoxy-1-tri-n-butylstannanylethene.