Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([CH2:12][C:13]([OH:15])=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][N:23]([CH3:26])[CH:24]=O>>[CH3:22][N:23]([CH3:26])[CH:24]=[C:12]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH:13]=[O:15]
Reactant: O=C(O)Cc1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)c1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Phosphorus oxychloride, 690 grams (4.5 moles), is warmed to about 30° C., and 478 mL of N,N-dimethylformamide is added dropwise during a two hour period. Upon completion of addition, a solution of 202 grams (1.5 moles) of phenylacetic acid in 158 mL of N,N-dimethylformamide is added dropwise during a one hour period. Upon completion of the addition, the reaction mixture is slowly warmed to about 70°-75° C. where it is stirred for about 16 hours. After this time the reaction mixture is poured into five kilograms of ice. Two kilograms of potassium carbonate are added, and the mixture is stirred until the ice melted. The mixture is separated into two five liter reaction vessels, and 500 mL of toluene is added to each of the vessels. The stirred mixtures are then warmed to about 70° C. where they stirred for about 16 hours. After this time, the mixtures in each vessel are extracted with three 500 mL portions of toluene. The combined extracts are then washed with two one liter portions of water and one one liter portion of an aqueous solution saturated with sodium chloride. The organic layer is dried with potassium carbonate and filtered. The filtrate is concentrated under reduced pressure, yielding 94.9 grams of crude product. The crude product is distilled under vacuum, yielding 78.3 grams of 3-dimethylamino-2-phenylpropenaldehyde, bp 154°-160° C./1 mm Hg. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]=[C:5]([CH3:28])[CH2:6][CH:7]([C:9]1[N:10]([CH:25]([CH3:27])[CH3:26])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)C.C(N(CC)CC)C.COC(=O)CC(=O)/C=C/C1N(C(C)C)C2C(C=1C1C=CC(F)=CC=1)=CC=CC=2>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[C:5](\[CH3:28])/[CH:6]=[CH:7][C:9]1[N:10]([CH:25]([CH3:26])[CH3:27])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: COC(=O)C=C(C)CC(C)c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: COC(=O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)/C=C(\C)C=Cc1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 2 h

Procedure:
2.0 g of crude 5-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-methylhex-2-enoic acid methyl ester in 50 ml of toluene are introduced into a 100 ml three-necked round-bottomed flask, equipped with a magnetic stirrer, thermometer, reflux condenser and nitrogen delivery line, 0.9 g (8.87 mmol) of triethylamine are added and the yellow solution is heated at reflux with stirring. After 2 hours, the reaction mixture is cooled, diluted with 50 ml of toluene, washed once with 100 ml of 1N hydrochloric acid and three times with 50 ml of water and concentrated by evaporation using a rotary evaporator. The crude product (orange oil) is purified by means of flash chromatography (hexane/ethyl acetate=10:1). An orange resin is obtained which, according to NMR, contains approximately 30% (E)-5-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-oxopent-4-enoic acid methyl ester (mixture of keto and enol forms).
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: CCN(CC)c1ccc([N+](=O)[O-])cc1C#N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCN(CC)c1ccc(N)cc1C#N
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Ammonium chloride (1.5 g) and iron powder (15.9 g) were added to a mixed solvent of water (50 ml) and ethanol (150 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-diethylaminobenzonitrile (15.6 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (12.1 g), melting point: 63–66° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:6][S:7]([N:10]([C:18]2[C:19]([F:28])=[C:20]([C:24]([F:27])=[CH:25][CH:26]=2)[C:21]([OH:23])=[O:22])S(CC2CC2)(=O)=O)(=[O:9])=[O:8])[CH2:5][CH2:4]1>C1COCC1.CO>[CH:3]1([CH2:6][S:7]([NH:10][C:18]2[C:19]([F:28])=[C:20]([C:24]([F:27])=[CH:25][CH:26]=2)[C:21]([OH:23])=[O:22])(=[O:8])=[O:9])[CH2:5][CH2:4]1
Reactant: O=C(O)c1c(F)ccc(N(S(=O)(=O)CC2CC2)S(=O)(=O)CC2CC2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(F)ccc(NS(=O)(=O)CC2CC2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
A solution of 1N NaOH (2.78 mL, 2.78 mmol) was added to a solution of crude 3-(1-cyclopropyl-N-(cyclopropylmethylsulfonyl)methylsulfonamido)-2,6-difluorobenzoic acid (380 mg, 0.928 mmol) in 4:1 THF/MeOH (5 mL, 0.2M). The reaction mixture was stirred at room temperature for 1 hour, after which most of the organic solvents were removed. 1N HCl (3 mL) was slowly added to the mixture to acidify to a pH of 1. The acidified aqueous layer was extracted with ethyl acetate (75 mL). The ethyl acetate extract was washed with water (2×20 mL), brine (20 mL), dried (Na2SO4), filtered and concentrated. Trituration of the residue with Et2O afforded 3-(cyclopropylmethylsulfonamido)-2,6-difluorobenzoic acid as a solid (139 mg, 51%). 1H NMR (400 MHz, d6-DMSO) δ 9.76 (s, 1H), 7.60-7.54 (m, 1H), 7.22-7.16 (m, 1H), 3.10 (d, J=7.0 Hz, 2H), 1.10-0.99 (m, 1H), 0.58-0.53 (m, 2H), 0.36-0.31 (m, 2H); m/z (APCI-neg) M−1=289.9.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.Br[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.O>C1COCC1.C(OCC)(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([O:13][CH2:12][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:16][CH:17]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc(OCC2CCCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium t-butoxide (550.6 mg, WAKO) in dehydrated THF (10 ml) was added with cyclopentane methanol (450 μl), and then added with a solution of 2,5-dibromopyridine (982.8 mg, TCI) in dehydrated THF (15 ml) under ice cooling. The reaction mixture was stirred for 30 minutes, then warmed to room temperature, and stirred for 11 hours. The reaction mixture was added with water (100 ml) and ethyl acetate (60 ml) for extraction. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine sequentially, and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=15:1) to obtain the title compound (Intermediate 28, 896 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3](=[O:14])[C:4]([N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)=[CH:5]N(C)C.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O.Cl>CCOCC>[CH:17]1([CH:5]=[C:4]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)[C:3](=[O:14])[C:2]([CH3:1])([CH3:15])[CH3:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Br[Mg]C1CCCCC1
Reactant: CN(C)C=C(C(=O)C(C)(C)C)n1cncn1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)C(=O)C(=CC1CCCCC1)n1cncn1
Reaction time: 1 h
Yield: 82.6 %

Procedure:
11.1 g (0.05 mol) of 4,4-dimethyl-1-dimethylamino-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one were dissolved in 250 ml of ether. An ethereal solution of 13.1 g (0.07 mol) of cyclohexyl-magnesium bromide was added dropwise to this solution in the course of 30 minutes. The reaction mixture was subsequently stirred for one hour, 250 ml of water were added and the mixture was adjusted to a pH value of 6-7 with hydrochloric acid. The organic phase was separated off, dried and filtered and the filrate was concentrated. 10.8 g (83% of theory) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one of refractive index nD20 1.5003 were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:38])[C:6]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[CH2:18][N:19]1C(=O)C3C(=CC=CC=3)C1=O)[CH2:10]2.NN>CO.O1CCCC1>[NH2:19][CH2:18][C@@H:17]([N:11]1[CH2:10][C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[N:5]([CH3:38])[N:4]=[CH:3][C:2]=3[Br:1])[CH:8]=2)[C:12]1=[O:16])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1
Reactant: Cn1ncc(Br)c1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1ccc2c(c1)CN([C@H](CN)Cc1cccc(F)c1)C2=O
Yield: 33.6 %

Procedure:
A solution of 2-[(2S)-2-[5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (30.0 mg, 0.0523 mmol) and hydrazine (0.2 mL, 6 mmol) in methanol (1.0 mL) and tetrahydrofuran (1.0 mL) was stirred at room temperature overnight. Direct purification on prep.—HPLC (pH=10) gave 7.8 mg of the desired product as white solid. LC/MS found: 443.0 (M+1)+; 1H NMR (400 MHz, DMSO-d6) δ: 7.74 (d, J=7.60 Hz, 1H), 7.68 (m, 2H), 7.54 (dd, J1=8.00 Hz, J2=1.60 Hz, 1H), 7.24 (m, 1H), 7.05 (m, 2H), 6.95 (dt, J1=8.40 Hz, J2=2.00 Hz, 1H), 4.49 (d, J=2.80 Hz, 2H), 4.42 (m, 1H), 3.76 (s, 3H), 3.04 (dd, J1=14.00 Hz, J2=5.20 Hz, 1H), 2.90 (dd, J1=14.40 Hz, J2=9.60 Hz, 1H), 2.81 (d, J=6.80 Hz, 2H).
Reaction SMILES: [Cl-].[Li+].C([Mg]Cl)(C)C.[S:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[C:13]([CH:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1)(=[O:15])[CH3:14]>O1CCCC1.[Cl-].[NH4+]>[OH:15][C:13]([CH:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17]1)([C:9]1[S:8][CH:12]=[CH:11][N:10]=1)[CH3:14]
Reactant: c1cscn1
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2nccs2)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Isopropylmagnesium chloride lithium chloride (1.3 M in tetrahydrofuran, 0.6 mL, 0.780 mmol) was added dropwise at room temperature to a flask containing a solution of thiazole (0.050 mL, 0.705 mmol) in tetrahydrofuran (5 mL) with a water bath around the flask. After 40 min, tert-butyl 3-acetylpyrrolidine-1-carboxylate (160 mg, 0.750 mmol) in tetrahydrofuran (5 mL) was added dropwise. After stirring at room temperature for 35 min, the mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-60% ethyl acetate/hexane) to afford tert-butyl 3-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]pyrrolidine-1-carboxylate as a 1:1 mix of diastereomers. 1H NMR (500 MHz, CDCl3) δ 7.69-7.55 (m, 1H, two sets of doublets overlap from two diastereomers), 7.23-7.14 (m, 1H, two sets of doublets overlap from two diastereomers), 3.59-2.98 (m, 4H), 2.80-2.60 (m, 1H), 1.98-1.70 (m, 2H), 1.59 (s, 3H), 1.45-1.30 (m, 9H, two sets of peaks overlap from two diastereomers).
Reaction SMILES: CC1(C)COB([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])OC1.Br[C:30]1[N:31]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:32]=[C:33]([C:35]([N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])=[O:36])[N:34]=1>>[CH2:38]([N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[C:35]([C:33]1[N:34]=[C:30]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[N:31]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:52])([CH3:51])[CH3:53])[CH:32]=1)=[O:36])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCN(CCCC)C(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Reactant: COC(=O)c1ccc(B2OCC(C)(C)CO2)c(C(=O)OCc2ccccc2)c1
Product: CCCCN(CCCC)C(=O)c1cn(COCC[Si](C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Yield: 62.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 264I, 3-benzyl 1-methyl 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)isophthalate (1.76 g, 4.62 mmol) and 2-bromo-N,N-dibutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide (1.0 g, 2.31 mmol) were converted to the title compound (900 mg, 62%). 1H NMR (CDCl3) δ 8.66 (d, J=1.6 Hz, 1H), 8.23 (dd, J=8.0, 1.6 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.36-7.32 (m, 3H), 7.25-7.23 (m, 2H), 5.14 (s, 2H), 4.87 (s, 2H), 3.97 (s, 3H), 3.89 (br s, 2H), 3.45 (br s, 2H), 3.34 (t, J=8.0 Hz, 2H), 1.60-1.54 (m, 2H), 1.39-1.21 (m, 6H), 0.95-0.78 (m, 6H), 0.76 (t, J=8.0 Hz, 2H), −0.06 (s, 9H); MS(ESI+) m/z 622.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2/[CH:28]=[CH:29]/OCC)[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:34])[C:19](=[O:33])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=O)(C)(C)C.[ClH:35]>>[ClH:35].[CH3:34][C@@H:18]1[C:19](=[O:33])[NH:20][N:21]=[C:22]2[N:17]1[C:16]1[CH:15]=[C:14]3[N:13]([C:10]4([CH3:12])[CH2:9][NH:8][CH2:11]4)[CH:29]=[CH:28][C:27]3=[CH:26][C:25]=1[O:24][CH2:23]2
Reactant: CCO/C=C/c1cc2c(cc1NC1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Agent: Cl
Product: C[C@@H]1C(=O)NN=C2COc3cc4ccn(C5(C)CNC5)c4cc3N21
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of HCl (4M in EtOAc, 160 mL) was added 3-[(R)-7-((E)-2-ethoxy-vinyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (16 g, 33.9 mmol) at 0° C. and the reaction mixture was stirred for 30 min. The reaction mixture was concentrated in vacuo to give crude (R)-1-methyl-10-(3-methyl-azetidin-3-yl)-3,5-dihydro-10H-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-2-one hydrochloride (10 g, 91%), which was used in the next step without further purification. LC/MS (Table 1, Method 25) Rt=0.627 min; MS m/z: 326 [M+H]+
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:40]1[CH2:45][CH2:44][CH:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:40]1[CH2:45][CH2:44][CH:43]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[CH2:42][CH2:41]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC(N4CCOCC4)CC3)ccc2[nH]1
Yield: 72 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-(piperidin-4-yl)-morpholine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow foam (72%).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20](=O)/[C:21](/[C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1)=[CH:22]/[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)C.CO>C1COCC1.O.C(OCC)(=O)C>[CH:23]1(/[CH:22]=[C:21](\[C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)/[CH2:20][OH:19])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)/C(=C/C1CCCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)CO)cc1
Temperature: -78 °C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
Add a solution of DIBAL in toluene (36.5 mL, 1.5 M, 54.6 mmol) dropwise over one h to a solution of (E)-3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-acrylic acid ethyl ester (7.35 g, 21.8 mmol) in THF (200 mL) cooled to −78° C. Then allow the reaction mixture to slowly warm to r.t., and stir it for 18 h. Add methanol (50 mL), and then remove volatiles under vacuum. Partion the residue between ethly acetate (200 mL) and water (200 mL). Then extract the aqueous layer with ethyl acetate (2×300 mL). Combine the organic layers, wash them with saturated aqueous sodium chloride solution (200 mL), dry them over magnesium sulfate, and then filter them through celite®. Concentrate the filtrate to afford the title compound as an oil (6.0 g). MS (m/e): 295 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:16]([F:27])([F:26])[F:15])=[CH:18][CH:19]=2)[N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Clc1cncc(Cl)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)c1ccc(-c2cncc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a mixture of 2,6-dichloropyrazine (0.5 g, 3.36 mmol), sodium carbonate (0.925 g, 8.73 mmol) and 4-trifluoromethylphenylboronic acid (0.638 g, 3.36 mmol) in dimethoxyethane (15 mL) and water (7.5 mL) under nitrogen was added tetrakis(triphenylphosphine) palladium (0) (0.078 g). The resulting mixture was heated at reflux for 5 h under nitrogen, before stirring at room temperature overnight. The reaction was diluted with water (50 mL) and extracted with chloroform (2×75 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) 10:1–6:1 cyclohexane:EtOAc afforded the title compound as a white solid (0.317 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[Cu][C:11]#[N:12].CN(C)C=O.O>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[N:12])=[N:4][C:3]=1[CH3:9]
Reactant: Cc1nc(Br)ccc1Br
Reactant: N#C[Cu]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(C#N)ccc1Br
Temperature: 110 °C
Yield: 48.8 %

Procedure:
3,6-Dibromo-2-methylpyridine (4.9 g, 19.53 mmol), copper(I)cyanide (1.75 g, 19.53 mmol) and N,N-dimethylformamide (20 mL) were combined in a sealable vessel with a stirbar. The resulting mixture was sealed, stirred vigorously and heated at 110° C. for 4 h. The resulting mixture was diluted with ethyl acetate, poured into a separatory funnel containing water and the layers were separated. The water layer was extracted with ethyl acetate twice. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by silica gel chromatography (10% ethyl acetate in hexanes) to give the title compound as a white solid (1.88 g, 9.54 mmol, 49% yield). MS (ESI) m/z 197.3 [M]+.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[CH2:10][CH2:9]2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:12][CH2:13]1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCN1CCC(c2c[nH]c3ccccc23)CC1
Yield: 91.1 %

Procedure:
A mixture of 1-(2-phthalimidoethyl)-4-(3-indolyl)piperidine (6.3 g) and hydrazine monohydrate (2.2 g) in ethanol (250 ml) was refluxed for 70 minutes. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was treated with 5% sodium hydroxide solution (300 ml) and extracted with ethyl acetate (300 ml). The organic layer was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The evaporation of solvent gave 1-(2-aminoethyl)-4-(3-indolyl)piperidine (3.74 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH3:11].[Br:13]N1C(=O)CCC1=O>C(#N)C.S(=O)(O)[O-].[Na+].CCOCC.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11][Br:13]
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)c1ccc(Br)cc1CBr
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid methyl ester (115 g, 500 mmol), N-bromosuccinimide (90 g, 500 mmol) and AIBN (3.1 g) in acetonitrile (700 mL) was warmed over 45 minutes to a gentle reflux, and held at reflux for 21 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bisulfite, and concentrated in vacuo. The residue was partitioned between water and 1:1 hexanes:ethyl acetate. The organic phase was washed with water, brine, and filtered through a pad of silica gel. The solvent was removed under vacuum to give an oil/solid mixture, which was digested in ether and filtered. The filtrate was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting the product at 4:1 hexanes-ethyl acetate and providing 102 g of 4-bromo-2-bromomethyl-benzoic acid methyl ester, in 66% yield; 1H NMR (DMSO-d6) δ 3.87 (s, 3H), 4.99 (s, 2H), 7.67-7.97 (m, 3H).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5](=[O:25])[CH2:6][N:7]([C:9]([C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])=[O:10])[CH3:8].OS([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:3][O:4][C:5](=[O:25])[CH2:6][N:7]([C:9]([C:11]1[C:20]2[C:15](=[C:16]([Br:1])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])=[O:10])[CH3:8]
Reactant: BrBr
Reactant: COC(=O)CN(C)C(=O)c1c(OC)ccc2cc(OC)ccc12
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CN(C)C(=O)c1c(OC)ccc2c(Br)c(OC)ccc12
Yield: 66.8 %

Procedure:
A solution of bromine (1.75 mL, 34.05 mmol) in acetic acid (40 mL) was added over 25 minutes to a stirred solution of N-[(2,6-dimethoxy-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester (10.70 g, 33.72 mmol, described in Example 2) in acetic acid (120 mL). After an additional 10 minutes the reaction was diluted with water (900 mL) and NaHSO3 (2.0 g) was added. The resulting precipitate was collected by filtration, washed with water and dried to give 8.93 g (67% yield) of the title compound, m.p. 142°-144° C.