Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([O:3]CC)=[O:2].[OH-].[K+]>C(O)C.O>[CH2:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[C:1]([OH:3])=[O:2]
Reactant: CCOC(=O)C1Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1Cc2ccccc2C1
Yield: 69.1 %

Procedure:
Dissolve 2-(carboethoxy)indan (6.49 g, 34.1 mmol) in ethanol (95%, 150 mL) and water (75 mL). Add potassium hydroxide (9.5 g, 0.17 mol) and stir at room temperature for 1 hour. Partition between water (150 mL) and ethyl ether (2×150 mL). Acidify the aqueous phase with hydrochloric acid to pH 1. Extract with methylene chloride (2×150 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 2-indancarboxylic acid as a tan solid (3.82 g, 69%).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:31][CH3:32])=[C:7]([CH2:9][C:10]([CH:18]2[O:23][CH2:22][CH2:21][N:20](CC3C=CC=CC=3)[CH2:19]2)([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[OH:11])[CH:8]=1.O>C(O)(C)C>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:31][CH3:32])=[C:7]([CH2:9][C:10]([CH:18]2[O:23][CH2:22][CH2:21][NH:20][CH2:19]2)([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[OH:11])[CH:8]=1
Reactant: COc1ccc(F)cc1CC(O)(C1CCOCC1)C1CN(Cc2ccccc2)CCO1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(F)cc1CC(O)(C1CCOCC1)C1CNCCO1
Reaction time: 0.5 h

Procedure:
A 6 L Parr bottle is loaded with 51b (1021 g), i-propanol (3630 mL) and water (639 mL). After purging with N2, 5% Pd—C 52% wet is added (105.6 g) and the mixture is then pressurized with hydrogen (50 psi). The reaction mixture is shaken for 9 h 30 mins, then the mixture is filtered on a Hyflo Super Cel® pad (100 g) pre-imbibed with 80/20 i-propanol/water (500 mL). The catalyst is rinsed with a 80:20: i-propanol:water mixture (500 mL). The solvents are stripped off then i-propanol is added (2000 mL) to be partially removed again. Then i-propanol is re-added (1400 mL) and the heterogeneous mixture is concentrated to provide an off-white solid To this crude alcohol 52b is added i-propanol (4474 mL) and the mixture is heated to reflux until a homogeneous solution is formed. Then, the mixture is cooled slowly and the crystallization starts at 60° C. The powder is filtered at room temperature, rinsed with i-propanol (2×350 mL) and dried under reduced pressure at 40° C. to give highly pure compound 52b with 80% recovery yield (98.4% de, 99.2% ee).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:14][CH2:21][C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=Cc1ccco1
Reactant: COC(=O)c1cccc(N)c1C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cccc(NCc2ccco2)c1C(=O)OC
Reaction time: 0.08 h
Yield: 109.2 %

Procedure:
To a stired solution of 3-amino-phthalic acid dimethyl ester (8.23 g, 39.32 mmol) in methylene chloride (200 ml) under a nitrogen atmosphere, 2-furaldehyde (8.14 ml, 98.30 mmol) and acetic acid (13.57 ml, 235.92 mmol) were added. The mixture was stirred for 5 minutes, followed by addition of sodium triacetoxyborohydride (25 g, 117.96 mmol). The reaction was sitirred overnight, washed with water (2×200 ml), saturated aqueous sodium bicarbonate (2×200 ml), and brine (200 ml), and dried over MgSO4. The solvent was evaporated in vacuo to give a brown oil (12.42 g), which was used directly without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24](N(OC)C)=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:7]=1[C:8]#[CH:9].[CH3:30][Mg]Cl.Cl>O1CCCC1.O>[Cl:1][C:2]1[C:7]([C:8]#[CH:9])=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:4]([C:24](=[O:25])[CH3:30])[CH:3]=1
Reactant: C#Cc1c(Cl)cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Reactant: C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1c(Cl)cc(C(C)=O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Temperature: 20 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 4-chloro-6-[(1E)-3,3-diethyltriaz-1-en-1-yl]-5-ethynyl-3′-fluoro-N-methoxy-N-methylbiphenyl-2-carboxamide (2.7 g, 6.6 mmol) in tetrahydrofuran (26 mL) at 0° C. was treated with 3 M of methylmagnesium chloride in tetrahydrofuran (6.6 mL, 20 mmol) dropwise and stirred at 20° C. for 1 hour. The reaction mixture still contained some starting material and was, therefore, cooled to 0° C., treated with additional 3 M of methylmagnesium chloride in tetrahydrofuran (2.2 mL, 6.6 mmol) dropwise, and stirred at 20 ° C. for 2 hours. The reaction mixture was cooled to 0° C., quenched with 1 M hydrogen chloride in water (26 mL, 26 mmol), poured into 0.1 M hydrogen chloride in water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried with sodium sulfate, filtered, and concentrated to give a crude oil. Purification by flash column chromatography using ethyl acetate in hexanes (0%-20%) gave the desired product (2.3 g, 93%). LCMS for C20H20ClFN3O (M+H)+: m/z=372.1; Found: 371.9.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl.[CH3:14][NH:15][CH3:16].C(=O)(O)[O-].[K+].O>CN(C=O)C>[CH3:14][N:15]([CH3:16])[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CNC
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc([N+](=O)[O-])cc1C#N
Temperature: 80 °C
Yield: 100 %

Procedure:
1.66 g (10.0 mmol) of 2-fluoro-5-nitrobenzonitrile, 1.22 g (15.1 mmol) of dimethylamine hydrochloride and 3.46 g (25.1 mmol) of potassium bicarbonate is dissolved, under an argon atmosphere, in DMF (30 ml) then the reaction medium is heated at a temperature of 80° C. for 18 hours. The reaction mixture is cooled down to 0° C. and ice-cooled water is added. The reaction mixture is extracted with ethyl acetate and the organic phase is washed successively with 50 ml of water and 50 ml of salt water, dried over magnesium sulphate, filtered and concentrated under vacuum. The evaporation residue is purified by trituration with isopropyl ether and the solid obtained is filtered and rinsed with isopentane in order to obtain after drying 2.0 g of a solid yellow product (yield 100%). Melting point: 109-110.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]=O)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:33])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:22])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)[CH3:33])=[O:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC=O)c1=O)c1cccc(C(F)(F)F)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCN2CCOCC2)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.10 g (0.21 mmol) of 2-[3-(4-chlorophenyl)-4-(2-oxoethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 401 are dissolved in 30 ml of dichloromethane and 0.4 ml of DMF and stirred with 22 mg (0.2 mmol) of morpholine for 1 hr at RT. Next, 66 mg (0.31 mmol) of sodium triacetoxyborohydride are added and the mixture is stirred for 18 hrs at RT. The reaction mixture is treated with 10 ml of saturated sodium hydrogen carbonate solution and extracted three times with 10 ml ethyl acetate each time. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 10]. 11.0 mg (10% of theory) of the target compound are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2SC=CN=2)=[CH:4][CH2:3]1.FC(F)(F)S(O[C:37]1[C:38]2[CH:39]=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=[CH:42][C:43]=2C(C)(C)C[CH:46]=1)(=O)=O>>[CH3:30][C:2]1([CH3:1])[C:11]2[CH:6]=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:9][C:10]=2[C:5]([C:25]2[CH:42]=[CH:43][C:38]([CH3:39])=[CH:37][CH:46]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67), 200.0 mg (0.42 mmol) of ethyl 4-[(5-triflouromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 113.8 mg (0.835 mmol) of zinc chloride and 4-methylphenyllithium (prepared by adding 40.4 mg (0.42 ml, 0.63 mmol) of n-butyllithium (1.5M solution in hexane) to a cold solution (-78° C.) of 108.0 mg (0.63 mmol) of 4-bromotoluene in 1.0 ml of THF).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]1[C:13]([F:33])=[C:14]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[CH3:10].CCCCCC>C(#N)C>[Br:1][C:27]1[C:14]([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])=[C:13]([F:33])[C:12]([O:11][CH2:9][CH3:10])=[C:29]([O:30][CH2:31][CH3:32])[CH:28]=1
Reactant: CCOc1ccc(CN2C(=O)c3ccccc3C2=O)c(F)c1OCC
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: CC#N
Product: CCOc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)c(F)c1OCC
Reaction time: 6 h
Yield: 0 %

Procedure:
N-bromosuccinimide (1.43 g, 8.07 mol) was added to a solution of 2-(3,4-diethoxy-2-fluorobenzyl)isoindol-1,3-dione (2.52 g, 7.34 mol) in acetonitrile (30 mL) on ice. The mixture was stirred on ice for ten hours, and then at room temperature for six hours. The reaction mixture was extracted after the addition of a 5% aqueous solution of sodium thiosulfate and ethyl acetate; then the resultant organic layer was washed sequentially with 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified by silica gel column chromatography (diethyl ether, no-hexane) to give 1.12 g of the title compound (yield: 36%) as white crystals.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=O)[CH:21]=[N:22][CH:23]=1.O>C1COCC1>[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[CH:24]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[CH:21]=[N:22][CH:23]=1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: COc1cncc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cncc(OC)c1
Temperature: 0 °C
Yield: 13.9 %

Procedure:
To a suspension of 3.12 g (78.1 mmol) of sodium hydride (60% in oil) in 30 mL of anhydrous THF is added, over 45 minutes, under argon and at 0° C., 16.4 g (78.1 mmol) of methyl (diethoxyphosphoryl)acetate in 10 mL of THF. Stirring is maintained for 30 minutes at 0° C. and 5.1 g (37.2 mmol) of 5-methoxypyridine-3-carbaldehyde in 20 mL of anhydrous THF are then added dropwise at 0° C. After cooling to room temperature, the reaction mixture is treated with 150 mL of water and then extracted with EtOAc (3×100 mL). The organic phases are combined, washed successively with water (2×20 mL), dried over Na2SO4, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAC gradient of 0 to 40% EtOAc. 1 g of methyl (2E)-3-(5-methoxypyridin-3-yl)prop-2-enoate is obtained in the form of a white powder.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([CH3:10])[CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:12]([CH2:14][C:15]([NH2:17])=[O:16])#[N:13].N1CCCCC1>C(O)C>[C:12]([C:14]1[C:15](=[O:16])[NH:17][C:1]([CH3:2])=[C:4]2[C:5]=1[CH2:6][CH2:7][CH:8]([CH3:10])[CH2:9]2)#[N:13]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C1CC(C)CCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(=O)c(C#N)c2c1CC(C)CC2

Procedure:
To the total amount of the crude 2-acetyl-4methylcyclohexanone prepared in (1), 35 ml of ethanol, 3.36 g of cyanoacetamide and a small amount of piperidine were added and the obtained reaction mixture was heated under reflux for four hours. The crystals thus precipitated were filtered and recrystallized from a mixture of methanol and water to give 4.22 g of 4-cyano-1,7-dimethyl-2,3,5,6,7,8hexahydro-3-oxoisoquinoline. m.p. >290° C. NMRδTMSCF3COOH : 1.23 (3H, d), 2.60 (3H, s) and 1.8-3.3 (7H,m).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH:3]1[CH2:35][C:36]1[C:44]2[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=2[N:38](CC2C=CC=CC=2)[N:37]=1.C(O)=O>C(O)C.[Pd]>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:22])[CH3:23])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:4](=[O:34])[CH:3]1[CH2:35][C:36]1[C:44]2[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=2[NH:38][N:37]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4c3CCCC4)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4c3CCCC4)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a stirring solution of 150 mg (0.22 mmol) of 2-[2,4-Dioxo-5-phenyl-3-(4,5,6,7-tetrahydro-1-benzyl-1H-indazol-3-ylmethyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Intermediate 52, in 10 mL of a 10% solution of formic acid in absolute ethanol is added 150 mg of 10% palladium on carbon. The resulting black suspension is refluxed for 3 h, then cooled to RT. The reaction mixture is filtered through Celite to remove the catalyst and the solvent removed in vacuo. Purification of the residue via silica gel MPLC using an Si60 column and hexane/EtOAc 1/5 as eluent afforded 105 mg of the title compound as a white solid: mp 170°-173° C.; 1H NMR (CDCl3, 400 MHz) δ7.38-6.88 (m, 13H), 5.03 (m, 1H), 4.34 (d, 1H, J=16.8), 4.14 (d, 1H, J=16.8), 3.84(s, 3H), 3.58 (dd, 1H, J=6.8, 6.8), 3.46 (dd, 1H, J=7.0, 14.0), 3.30 (dd, 1H, J=7.5, 15.2), 2.60 (m, 2H), 2.36 (m, 2H), 1.70 (m, 4H), 1.08 (2×d, 6H, J=6.6); low resolution MS (FAB)m/e 592 (MH+), 591 (M+), 427; Anal. (C35H37N5O4) Calcd. C, 71.05; H, 6.30; N, 11.84; Found C, 70.20; H, 6.47; N, 11.66.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:11][S-:12].[Na+]>CN(C)C=O>[CH3:11][S:12][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: Clc1cccc2nccn12
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cccc2nccn12
Temperature: 20 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
Into 100 ml of dimethylformamide are suspended 5 g of 5-chloroimidazo[1,2-a]pyridine and 5 g of sodium methanethiolate and the mixture is stirred at 20° C. for 1 hour. The solvent is evaporated off under reduced pressure and the residue is dissolved in 200 ml of dichloromethane. The mixture is washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and purified by silica-gel column chromatography to give 3 g of the above-identified compound as an oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:9]1[N:10]([CH2:21][CH2:22][OH:23])[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)([CH3:8])[CH3:7])C.CC(C[AlH]CC(C)C)C.O>C1COCC1>[OH:23][CH2:22][CH2:21][N:10]1[C:11]2[C:16](=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)[CH:17]=[C:9]1[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CC(C)(C)c1cc2cc([N+](=O)[O-])ccc2n1CCO
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CCO)c1cc2cc([N+](=O)[O-])ccc2n1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a solution of 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-methyl-butyric acid ethyl ester (700 mg, 2.1 mmol) in THF (25 mL) was added DIBAL-H (1.0 M, 4.2 mL, 4.2 mmol) at −78° C. The mixture was stirred at room temperature for 1 h. Water (2 mL) was added and the resulting mixture was extracted with EtOAc (15 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by chromatography on silica gel (15% ethyl acetate/petroleum) to afford 3[1-(2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-methyl-butan-1-ol (300 mg, 49%). 1H NMR (300 MHz, d-DMSO) δ 8.42 (d, J=1.5 Hz, 1 H), 7.95 (dd, J=1.2, 8.7 Hz, 1 H), 6.36 (d, J=9.3 Hz, 1 H), 6.50 (s, 1 H), 5.25 (br s, 1 H), 4.46-4.42 (m, 4 H), 3.69-3.66 (m, 2 H), 3.24-3.21 (m, 2 H), 1.42 (s, 6 H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]3(OCC[O:13]3)[CH2:10]2)=[CH:5][CH:4]=1)#[CH:2]>C1COCC1.Cl.C(OCC)C>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[CH2:10]2)=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc2c(c1)CC1(CC2)OCCO1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#Cc1ccc2c(c1)CC(=O)CC2
Reaction time: 2 h
Yield: 46.7 %

Procedure:
A solution of 7′-ethynyl-3′,4′-dihydrospiro[1,3-dioxolane-2,2′(1′H)naphthalene] (0.85 g, 3.9 mmol) in THF (15 ml) and 1N HCl (5 ml) was stirred overnight at room temperature. Concentrated HCl (2×0.5 ml) was then added in two aliquots 2 hours apart. After stirring a further 2 hours the solution was diluted with diethyl ether, the aqueous phase was separated, and the solution dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (15 g) eluting with diethyl ether:hexane (1:9→1:4) to give 7-ethynyl-2-tetralone as a solid (0.31 g). 1H NMR (CDCl3, 200 MHz) δ: 2.54 (t, J=7 Hz, 2H, CH2), 3.05 (s, 1H, ethynylH), 3.06 (t, J=7 Hz, 2H, CH2), 3.56 (s, 2H, CH2), 7.18 (d, J=8 Hz, 1H, Ar), 7.26 (s, 1H, Ar), 7.34 (d, J=8 Hz, 1H, Ar).
Reaction SMILES: [C:1](O)(=O)[C:2]#C.[N:6]([C@H:9]([CH3:26])[C@:10]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])([OH:17])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)=[N+:7]=[N-:8]>C1(C)C=C(C)C=C(C)C=1>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@:10]([OH:17])([C@H:9]([N:6]1[CH:2]=[CH:1][N:8]=[N:7]1)[CH3:26])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: C[C@@H](N=[N+]=[N-])[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: C#CC(=O)O
Solvent: Cc1cc(C)cc(C)c1
Product: C[C@@H](n1ccnn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 120 °C

Procedure:
A mixture of propiolic acid (0.84 ml), mesitylene (20 ml) and (2R,3R)-3-azido-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (1 g) was heated for 3 hours at 120° C. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (silica gel 30 g, eluent: ethyl acetate/methanol=10:1) to give the Compound 6 (0.11 g) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[O:20]CC1C=CC(OC)=CC=1)=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[N:12][CH:11]=3.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>ClCCl>[F:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[OH:20])=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[N:12][CH:11]=3.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]
Reactant: COc1ccc(COc2ccc3c(c2F)OCc2cnc(NC(C)=O)cc2-3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cn1)COc1c-2ccc(O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-(7-fluoro-8-((4-methoxybenzyl)oxy)-5H-chromeno[3,4-c]pyridin-2-yl)acetamide (150 mg, 0.380 mmol) in dichloromethane (5 mL) was added TFA (0.059 mL, 0.761 mmol) at room temperature and the reaction mixture was stirred at rt for 2 h. After the completion of reaction the volatiles were removed under reduced pressure. The residue was washed with diethyl ether (7 mL) and stirred for 5 min. The solid was collected by vacuum filtration and dried under vacuum to yield N-(7-fluoro-8-hydroxy-5H-chromeno[3,4-c]pyridin-2-yl)acetamide, TFA (70 mg, 0.170 mmol, 45% yield) as a white solid. LCMS (ESI) m/e 275.0 [(M+H)+, calcd for C14H12FN2O3 275.1]; LC/MS retention time (Method E): tR=2.0 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([Cl:20])=[O:6]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)c(Br)c1
Reaction time: 1 h

Procedure:
To 3-bromo-4-chloro-benzoic acid (9.4 g, 40 mmol) in dry DCM (100 mL), was added DMF (0.5 mL) followed by addition of oxalyl chloride (22.5 mL, 55 mmol, 2M in DCM) slowly. The mixture was stirred for 1 hr, then concentrated to yield 3-bromo-4-chloro-benzoyl chloride as an off-white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[N:11]1([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2cccc3nc(N)nc(N)c23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(N)c2c(OCCN3CCNCC3)cccc2n1
Reaction time: 16 h
Yield: 88 %

Procedure:
In a 100 mL round bottom flask 4-[2-(2,4-Diamino-quinazolin-5-yloxy)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (2.3 g; 5.9 mmol) was magnetically stirred in 20 mL of dichloromethane and trifluoroacetic acid (3 mL) was added dropwise at room temperature. After 16 hours, solids were filtered and rinsed with 10 mls of dichloromethane. Title compound was obtained 2.1 g (88% yield).
Reaction SMILES: [F:1][C:2]([F:18])([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH:14][NH2:15])=[O:13])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].[CH:19](OC)(OC)OC.C(O)(=O)C>CO>[F:1][C:2]([F:18])([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]2[O:13][CH:19]=[N:15][N:14]=2)=[CH:10][CH:9]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: COC(OC)OC
Reactant: NNC(=O)c1ccc(OC(F)(F)C(F)(F)F)cc1
Solvent: CC(=O)O
Solvent: CO
Product: FC(F)(F)C(F)(F)Oc1ccc(-c2nnco2)cc1
Temperature: 120 °C
Yield: 5.1 %

Procedure:
A mixture of 4-(perfluoroethoxy)benzohydrazide (3.17 g, 11.7 mmol) in trimethyl orthoformate (11.6 mL, 106 mmol) and acetic acid (0.13 mL, 2.35 mmol) was heated at 120° C. for 5 hours. The reaction was diluted with MeOH (15 mL) and poured into a beaker containing ice water (150 mL). The white precipitate was vacuum filtered and dried in a vacuum oven to provide 166 mg of 2-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazole as an off-white solid. An orange precipitate had formed in the aqueous filtrate and was collected by vacuum filtration and adsorbed onto silica gel. Purification by flash chromatography (0-40% EtOAc/hexanes) provided 2.02 g of 2-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazole as an off-white solid giving a combined yield of 2.186 g (67%): mp 87-89° C.; 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.28-8.05 (m, 2H), 7.40 (d, J=8.9 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −85.98, −87.82; ESIMS m/z 280 ([M+H]+).