Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.C1C(=O)N([I:19])C(=O)C1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]2[N:4]([C:9]([I:19])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1cc(Br)c2nccn2n1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc(Br)c2ncc(I)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.2 g, 5.16 mmol) in chloroform (30 mL) were added NIS (1.161 g, 5.16 mmol) and TFA (0.795 mL, 10.32 mmol). The reaction mixture was stirred at room temperature for 2 h and quenched with NaHCO3. The organic layers were washed with brine and dried over Na2SO4. The crude product was purified by BIOTAGE® (100% CH2Cl2) to give the product (1.4 g, 76%). 1H NMR (400 MHz, CDCl3) δ ppm 7.91 (1H, s), 7.46 (1H, s); LC/MS: Rt=2.44 min. LC/MS (Condition A): 357.80/359.80/361.80.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:14][C@H:15]1[CH2:20][NH:19][CH2:18][C@@H:17]([CH3:21])[NH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:14][C@H:15]1[NH:16][C@@H:17]([CH3:21])[CH2:18][N:19]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([O:3][C:2]([F:13])([F:12])[F:1])=[CH:5][CH:6]=2)[CH2:20]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(OC(F)(F)F)cc2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of 4-(trifluoromethoxy)-benzaldehyde (776 uL, 4.38 mmol) in methylene chloride (30 mL) was added cis-2,6-dimethyl piperazine (1.0 g, 8.77 mmol). After 1 hour sodium triacetoxy borohydride (2.45 g, 8.77 mmol) was added to the mixture. The solution was stirred at room temperature for an additional 4 hours. The reaction was concentrated in vacuo, diluted with ethyl acetate and extracted with 1N HCl (2×50 mL). The aqueous layer was then neutralized with NaOH and extracted with ethyl acetate (3×50 mL). The organic layer was dried (Na2SO4) and concentrated to provide cis-3,5-dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine (1.01 g, 80%). 1H NMR (400 MHz, CD3OD) δ 7.42 (d, 2H), 7.23 (d, 2H), 3.54 (s, 2H), 2.98-2.88 (m, 2H), 2.82-2.74 (m, 2H), 1.69 (t, 2H), 1.05 (d, 6H); LCMS 289.5 (M+1)+. Step 2 4-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid: The compound 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxyl-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was synthesized according to the procedure in Example 1 using cis-3,5-dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine. 1H NMR (400 MHz, CD3OD) δ 7.74-7.64 (m, 4H), 7.47 (d, 1H), 7.39-7.28 (m, 2H), 4.42 (s, 2H), 4.21-2.18 (m, 2H), 3.50-3.34 (m, 5H), 3.33-3.19 (m, 4H), 1.56 (d, 6H); LCMS 497.5 (M+1)+. Step 3 (S)-4-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid: A single enantiomer of Example 2 was obtained with the following protocol. The product from example 2 Step 1 and the product from Example 1 Step 5 were reacted using the conditions outlined in Example 9 Step 6 to yield the racemic methyl ester. Chiral separation using OJ-H, 25% methanol in CO2 (100 bar), 5 mL/min followed by hydrolysis using conditions outlined in Example 1 Step 7 provided (S)-4-(cis-2,6-dimethyl-4-(3-trifluoromethoxy)benzyl)piperazin-1-ylsulfonyl)-2,3-dihydro-1H-indene-2-carboxylic acid. 1H NMR (400 MHz, CD3OD) δ 7.66 (d, 1H), 7.46 (d, 1H), 7.41 (d, 2H), 7.36-7.30 (m, 1H), 7.19 (d, 2H), 4.08-3.99 (m, 1H), 3.94-3.8 (m, 1H), 3.56-3.49 (m, 2H), 3.43 (s, 2H), 3.40-3.22 (m, 3H), 2.57 (t, 2H), 2.09-1.92 (m, 2H), 1.56 (d, 6H); LCMS 513.5
Reaction SMILES: COC[O:4][C:5]1[CH:47]=[CH:46][C:8]2[CH:9]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35][CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])[CH:24]=3)[CH:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]COC)=[CH:15][CH:14]=3)[CH2:11][O:12][C:7]=2[CH:6]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CO>[OH:4][C:5]1[CH:47]=[CH:46][C:8]2[CH:9]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35][CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:41])([F:42])[F:43])[CH:24]=3)[CH:10]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)[CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2c2cccc(OCCCCCSCCCC(F)(F)C(F)(F)F)c2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: Oc1ccc(C2COc3cc(O)ccc3C2c2cccc(OCCCCCSCCCC(F)(F)C(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-4-[3-(5-(4,4,5,5,5-pentafluoropentylthio)pentyloxy)phenyl]-2,3-dihydro-4H-benzopyran (290 mg, 0.4 mmol) and pyridinium p-toluenesulfonate (1.05 g, 4 mmol) were dissolved in methanol (6 ml) and then refluxed for 8 hours. The reaction mixture was cooled to room temperature and then water was added thereto. The reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=1:1) to obtain 177mg (yield: 74%) of the title compound as a colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN([CH:10]=[O:11])C.[N:12]1C=C[CH:15]=[CH:14][CH:13]=1.CCOCC>C(#N)C>[C:13]([CH2:14][CH2:15][CH2:2][C:1]([O:11][CH3:10])=[O:5])#[N:12]
Reactant: c1ccncc1
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)CCCC#N
Reaction time: 0.5 h

Procedure:
6.2 15 ml of oxalyl chloride are added dropwise at from −2 to 0° to a solution of 15 ml of DMF in 300 ml of acetonitrile, and the mixture is stirred for a further 30 minutes. 23.25 g of “FA” are added dropwise at a maximum of 0°, and, after the mixture has been stirred for 15 minutes, 29 ml of pyridine are added dropwise. Ether is added, and the mixture is subjected to conventional work-up, giving 20 g of methyl 4-cyanobutyrate (“FB”) as an oil.
Reaction SMILES: ClC[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[CH:6]2.C1O[CH2:38][CH2:37]OCCOCCOCCOCCOC1.[C-]#[N:41].[K+]>C(#N)C>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:11]([CH2:37][C:38]#[N:41])[CH:10]=3)[CH:6]=[CH:7]2)(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(CCl)ccc32)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(CC#N)cc32)cc1
Yield: 449.5 %

Procedure:
A solution of 5-chloromethyl-1-(4-methylphenylsulfonyl)indole (11.1 g), 18-crown-6 (1.8 g), and potassium cyanide (4.5 g) in acetonitrile (117 ml) was stirred under a nitrogen atmosphere for 48 hr. The reaction mixture was poured onto ice and extracted with methylene chloride. The organic phase was washed (water, brine), dried (MgSO4), and evaporated to give 1-(4-methylphenylsulfonyl)indole-6-acetonitrile (9.5 g, 98%) as an ivory powder: NMR (80 MHz, CDCl3): 2.33(s, 3H, ArCH3), 3.79(s, 2H, CH2CN), 6.63(d, 1H, H3 -indole), 7.49(s, 1H, H4 -indole), 7.59(d, 1H, H2 -indole).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4]=1C(O)=O)[CH3:2].[H-].[Na+].[CH3:18][C@@H:19]1[CH2:21][O:20]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([CH2:18][C@H:19]([OH:20])[CH3:21])[CH:4]=1)[CH3:2]
Reactant: CCc1c(C(=O)O)[nH]c2ccc(F)cc12
Reactant: C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1cn(C[C@@H](C)O)c2ccc(F)cc12
Reaction time: 2 h
Yield: 62 %

Procedure:
A suspension of 1.21 g of 3-ethyl-5-fluoroindole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 2 hours and, after cooling to 0°, diluted with 29 ml of tetrahydrofuran. 218 mg of sodium hydride dispersion were added and the mixture was stirred for one hour. Subsequently, 0.61 ml of (R)-methyloxirane was added and the reaction mixture was stirred at room temperature for 90 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium sulfate. The solvent was removed and the residue was chromatographed over 120 g of silica gel with hexane-toluene (1:2) and subsequently with toluene-ethyl acetate (9:1). 0.8 g (62%) of (R)-1-(3-ethyl-5-fluoro-indol-1-yl)-propan-2-ol was obtained as pale brown crystals with m.p. 65°-67°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][Si:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH3:27])[CH3:26].Cl>CN(C)C=O>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:24][Si:25]([CH3:26])([CH3:27])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCC[Si](C)(C)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC[Si](C)(C)CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mix 2,6-di-t-butyl-4-mercaptophenol (2.4 g, 10 mmol), potassium carbonate (1.7 g, 12.3 mmol), chloromethyldodecyldimethylsilane (2.8 g, 10 mmole) and dimethylformamide (50 mL) and stir overnight at room temperature under argon atmosphere. Dilute the mixture with ice-water, acidify with aqueous hydrochloric acid and extract with ethyl ether. Wash the ethereal layer with water, then brine, filter through fluorosil-Na2SO4 and evaporate to an orange semi-solid (4.0 g). Purify the product by first distilling (180°-200° C. @0.1 mm Hg) then subjecting to silica gel chromatography (CCl4) to obtain the title compound as a colorless oil which slowly crystallizes.
Reaction SMILES: [Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:24]([O:26][CH2:27][CH3:28])C.C(O[K])(C)(C)C.[Br:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][C:47]=2C=O)=[CH:38][CH:37]=1>C1COCC1.O>[Br:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([C:46]2[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][C:51]=2[CH:28]=[CH:27][O:26][CH3:24])=[CH:38][CH:37]=1
Reactant: O=Cc1cc(Cl)ccc1-c1ccc(Br)c2ccccc12
Reactant: CCOCC
Agent: CC(C)(C)O[K]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COC=Cc1cc(Cl)ccc1-c1ccc(Br)c2ccccc12
Yield: 99 %

Procedure:
Subsequently, 9.67 g (28.2 mmol) of (methoxymethyl)triphenylphosphonium chloride and 48 mL of dry diethyl ether were charged into a 300-mL recovery flask filled with nitrogen at room temperature. The mixture was stirred. Then 28.2 mL (28.2 mmol) of 1 M tert-butoxypotassium solution in THF was added thereto. The resulting mixture was stirred for 1 hour. Subsequently, a solution of 3.90 g (11.3 mmol) of 1-bromo-4-(4-chloro-2-formylphenyl)naphthalene dissolved in 93 mL of a THF solvent was added to the reaction mixture. After the resulting mixture was stirred for another 4 hours at room temperature, water was added thereto, terminating the reaction. The separation of two phases was performed to recover the aqueous phase. Extraction of the aqueous phase was performed three times with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and concentrated to give a crude product. The crude product was then purified by silica gel column chromatography (eluent: heptane/chloroform=20/1) to give 4.17 g (yield: 99%) of 1-bromo-4-(4-chloro-2-methoxyethenylphenyl)naphthalene.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:29][C:30]#[N:31]>C(C(CC)=O)C>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([O:17][CH2:29][C:30]#[N:31])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(=O)CC
Product: N#CCOc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl

Procedure:
4.52 g of 3-chloro-2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydroindazole in 10 ml of diethyl ketone were added dropwise at approximately 20° C. to a suspension of 2.07 g of potassium carbonate and 2.49 g of potassium iodide in 150 ml of diethyl ketone. The reaction mixture was subsequently treated with 1.86 g of bromoacetonitrile in 10 ml of diethyl ketone. After the mixture had been refluxed for 10 hours, it was cooled, and the solvent was then removed. The residue was taken up in water, whereupon the solids formed were removed, washed with water and finally dried under reduced pressure at approximately 20° C. Yield: 3.20 g
Reaction SMILES: C1(O[C:8](=[O:18])[NH:9][C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:17][O:16][C:11]1[C:10]([NH:9][C:8]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1ncccc1NC(=O)Oc1ccccc1
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(C(=O)Nc3cccnc3OC)CC2)cc1
Yield: 85 %

Procedure:
Phenyl-N-(2-methoxypyridin-3-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]([CH:14]1[CH2:16][CH2:15]1)([CH3:13])[CH3:12])C(OCC)=O)[CH3:2].[Cl-].[Li+].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:11]([CH:14]1[CH2:15][CH2:16]1)([CH3:12])[CH3:13])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)(C)C1CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CC(C)(C)C1CC1
Temperature: 170 °C

Procedure:
A mixture of 2-(1-cyclopropyl-1-methylethyl)malonic acid diethyl ester (5.10 g, 21.2 mmol), lithium chloride (1.79 g, 42.2 mmol), water (0.5 mL) and DMSO (40 mL) was heated at 170° C. for 24 h, and then poured into ice-water. The product was extracted with ethyl acetate (3×200 mL), and the extracts were washed with brine (200 mL), dried over sodium sulfate and concentrated to give 3-cyclopropyl-3-methylbutyric acid ethyl ester, which was used without further purification.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:22]#[CH:23])[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].[H][H]>N1C=CC=CC=1.C(=O)([O-])[O-].[Ca+2].[Pd+2].C(=O)([O-])[O-]>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([CH:22]=[CH2:23])[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: [H][H]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccncc1
Product: C=C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
Shake 13β-ethyl-17α-ethynyl-17β-hydroxy-gon-4-en-3-one (0.5 g.) in pyridine (20 cc.) containing a 2% palladium-calcium carbonate catalyst (150 mg.) with hydrogen at atmospheric pressure until one molecular equivalent of hydrogen has been absorbed. Recrystallise the product twice from ether-hexane and dry for 4 hours at 65°/0.005 mm. to yield the title compound, m.p. 108°-111°; ultraviolet absorption peak at 240 (ε15,200); infrared absorption peak at 10.9μ.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:28]1[CH2:33][CH2:32][CH:31](O)[CH2:30][CH2:29]1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)[CH:3]=1
Reactant: OC1CCOCC1
Reactant: Oc1cncc(Br)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Brc1cncc(OC2CCOCC2)c1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a mixture of 5-bromo-3-pyridinol (5.22 g, 30 mmol), toluene (150 mL), triphenylphosphine (11.8 g, 45 mmol) and tetrahydropyran-4-ol (4.7 g, 45 mmol) was slowly added diethyl azodicarboxylate (7.1 mL, 45 mmol). The mixture was heated at reflux for 20 h, then cooled to room temperature, washed with water (3×100 mL) and then brine (100 mL), then dried (MgSO4), filtered and concentrated by rotary evaporation. The crude oil was treated with diisopropyloxide (50 mL) and the solid thus obtained was filtered and washed with diisopropyloxide (20 mL). The combined filtrates were concentrated by rotary evaporation and purified by column chromatography on silica gel, eluting with ethyl acetate/cyclohexane (20/80, v/v). Selected fractions containing the product were concentrated via rotary evaporation to give 5 g (65%) of a yellow oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11](OS(C(F)(F)F)(=O)=O)=[N:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:22]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:23][C:24]#[CH:25]>CN(C=O)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH3:1].[N:26]1([CH2:22][CH2:23][C:24]#[C:25][C:11]2[CH:10]=[CH:9][C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:13][N:12]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=S(=O)(Oc1ccc(CN2CCCCC2)cn1)C(F)(F)F
Reactant: C#CCCN1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C(#Cc1ccc(CN2CCCCC2)cn1)CCN1CCCCC1
Product: N
Temperature: 80 °C
Yield: 3 %
Yield: 20.7 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 5-piperidin-1-ylmethyl-pyridin-2-yl ester (0.10 g, 0.31 mmol), 1-but-3-ynyl-piperidine (0.051 g, 0.37 mmol), and TEA (2 mL) in dry DMF (1 mL) was added dichlorobis(triphenylphosphine)-palladium(II) (0.004 g, 0.006 mmol) and copper(I) iodide (0.004 g, 0.016 mmol). The reaction mixture was heated at 80° C. for 4 h, cooled to rt, diluted with DCM (25 mL), and filtered through a pad of diatomaceous earth. The mixture was diluted with 1 N NaOH (25 mL) and extracted with DCM (3×25 mL). The organic layers were combined, dried (Na2SO4), and concentrated, and chromatography of the resulting residue (SiO2: 3-6% 2 M NH3 in MeOH/DCM) gave the title compound (0.01 g, 10%). MS (ESI): exact mass calcd. for C20H29N3, 311.2; m/z found, 312.5 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.45 (d, J=2.0, 1H), 7.62 (d, J =8.3, 1H), 7.25 (d, J=8.1, 1H), 3.47 (s, 2H), 2.74-2.70 (m, 4H), 2.62-2.59 (m, 4H), 2.37 (br s, 4H), 1.65-1.55 (m, 8H), 1.46-1.44 (m, 4H).
Reaction SMILES: [Na+].[CH2:2]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH2:16][CH3:17])=[C:7]([C:18]([O-])=[O:19])[C:6]=1[C:21]([O-])=[O:22])[CH3:3].[Na+].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:28]([F:38])[CH:27]=1>C(O)(=O)C.O>[CH2:16]([O:15][C:8]1[C:7]2[C:18](=[O:19])[N:25]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:28]([F:38])[CH:27]=3)[C:21](=[O:22])[C:6]=2[C:5]([O:4][CH2:2][CH3:3])=[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)[CH3:17]
Reactant: CCOC(=O)Cc1ccc(N)cc1F
Reactant: CCOc1c(C(=O)[O-])c(C(=O)[O-])c(OCC)c2ccccc12
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.5 %

Procedure:
A mixture of 1,4-bis(ethyloxy)-2,3-naphthalenedicarboxylic acid sodium salt (526 g, 1.51 mol) and ethyl (4-amino-2-fluorophenyl)acetate (539 g, 2.73 mol) in glacial acetic acid (5100 mL) was heated to reflux for 6 hours, with reaction progress monitored by 1H-nmr spectroscopy. The reaction mixture was allowed to cool to room temperature, stirred for 18 hours, diluted with water (14 L) and stirred for a further 30 minutes. The product was isolated by filtration, washed with water (5 L) and dried in a vacuum oven at 60° C. to give the desired product as an off-white solid (587 g, 84% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[N:8].[CH3:9][O-:10].[Na+]>CO>[CH3:9][O:10][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[NH:8]
Reactant: C[O-]
Reactant: N#Cc1ccccn1
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Pyridine-2-carbonitrile (Sigma-Aldrich, St. Louis, USA) (1 eq, 190 mmol, 20 g) is dissolved in MeOH (150 ml), then NaOMe (5.4 M in MeOH, 1.1 eq, 209 mmol, 38.7 ml) is added. The resulting mixture is stirred for 16 h at r.t. The solvents are removed in vacuo, then water is added, and the resulting aqueous mixture is extracted with DCM. The organic layer is dried with MgSO4, filtered, and the solvent is removed in vacuo yielding the title compound; [M+H]+=138.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([S:10]([NH:13][CH:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23](OC)=[O:24])=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)(=[O:12])=[O:11])[CH3:9]>O1CCCC1>[OH:24][CH2:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[CH:14]([NH:13][S:10]([CH:8]([CH3:9])[CH3:7])(=[O:12])=[O:11])[CH2:15][CH2:16]2
Reactant: COC(=O)c1ccc2c(c1)CCC2NS(=O)(=O)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)NC1CCc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
At 0° C. lithium aluminium hydride (2.102 mL, 5.04 mmol) was added dropwise to a stirred solution of methyl 1-(1-methylethylsulfonamido)-2,3-dihydro-1H-indene-5-carboxylate (1 g, 3.36 mmol) in tetrahydrofuran (dry) (25 mL). Mixture warmed to rt and stirred for 4 hr. After this time the reaction mixture was again cooled to 0° C. and more lithium aluminium hydride (2.102 mL, 5.04 mmol) added and the whole stirred at room temperature for 30 min before being carefully quenched with H2O (10 mL) and 2N NaOH (10 mL). The resulting mixture was filtered and partitioned between EtOAc and brine. The organic layer was separated, dried on Na2SO4 and solvent evaporated in vacuo to give a dark yellow oil. Purification by flash chromatography (0-100% EtOAc in Hept.) afforded the title compound as a colourless oil (670 mg 2.5 mmol, 74%). MS (ESI): m/z [M−H]− 268.0.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.ClCCl.[CH3:8][C:9]([CH3:11])=O.[C:12]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]2[CH2:13]1>C(Cl)(Cl)Cl>[CH:1]1([N:4]2[C:9]([CH3:11])([CH3:8])[CH:13]([C:12]([OH:18])=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:17])[CH2:3][CH2:2]1
Reactant: CC(C)=O
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: NC1CC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1(C)C(C(=O)O)c2ccccc2C(=O)N1C1CC1
Temperature: 0 °C
Reaction time: 9 h

Procedure:
To type-I neutral alumina (16 g) is added cyclopropylamine (4.2 mL, 60 mmol) followed by dichloromethane (10 mL). The resulting slurry is cooled to 0° C. and acetone (6 mL, 82 mmol) is added slowly. The slurry is brought to room temperature and permitted to stir for 9 h, at which time the reaction mixture is filtered through a fritted funnel. The alumina cake is washed with chloroform (150 mL) and homophthalic anhydride (10.0 g, 62 mmol) is added to the combined filtrate. The resulting yellow solution is permitted to stir for 15 h at which time it is concentrated in vacuo and the resulting residue is dissolved in glacial acetic acid (130 mL) and placed at reflux for 4 h. The reaction mixture is then cooled to room temperature and concentrated to dryness in vacuo. The reaction mixture is then purified by silica gel flash chromatography [(6% ethyl acetate/0.08% acetic acid/93.92% dichloromethane) to (18% ethyl acetate/0.24% acetic acid/81.76% dichloromethane)] to afford 2-cyclopropyl-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid as an off-white powder; MS (ESI) m/z 260.1 (M+H).