Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10]Br>CO>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: COC(CBr)OC
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CO
Product: COC(Cn1ccnc1)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve sodium spheres (2.3 g) in dry methanol (100 ml) at room temperature, add imidazole (6.3 ml) and stir for 1 hour at room temperature. Add bromoacetaldehyde dimethylacetal (11.8 ml) and heat the resultant mixture overnight at reflux. Evaporate the solvent in vacuo, partition the resultant residue between EtOAc and water, dry the organic layer over MgSO4, and evaporate the solvent. Purify the resultant residue by flash chromatography on SiO2 (250 g), eluting with 4% CH3OH in CH2Cl2. Combine the desired fractions and evaporate the solvent to obtain (1-imidazolyl)acetaldehyde dimethylacetal.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Br)[CH:20]=1>>[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][CH:8]=3)[CH2:3][CH2:2]2)[CH:20]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: COC(=O)c1cccc(CN2CCC(c3c[nH]c4ccccc34)CC2)c1
Yield: 79.2 %

Procedure:
This compound was prepared following the procedure described in example 1 (part D) starting with 0.2 g (1 mmol) of 3-piperidin-4-yl-1H-indole and 0.29 g (1.3 mmol) of 3-bromomethyl-benzoic acid methyl ester. After ionic exchange purification, 0.276 g (79% of yield) of 3-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid methyl ester were obtained.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:3][CH2:4]Br.[CH3:22][O:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26].[OH-].[K+].O>CS(C)=O.O1CCCC1>[CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][O:26][CH2:25][CH:24]([O:23][CH3:22])[CH2:27][OH:28]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCBr
Reactant: COC(CO)CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COC(CO)COCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Reaction time: 2 h

Procedure:
In a mixture of 20 ml of dimethyl sulfoxide and 12 ml of tetrahydrofuran were dissolved 2.2 g of 3-(3,7, 11,15-tetramethyl-2,6,10,14-hexadecatetraenyl bromide and 2.3 g of 2-O-methylglycerin, and 2.0 g of powdered potassium hydroxide was added. The mixture was stirred for 2 hours, poured into cold water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by chromatography on a silica gel column to give 1.15 g of the above-identified compound as light-yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([O-:13])=[O:12])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Na+].Cl>O>[C:11]([C:8]1[S:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[CH:9]=1)([OH:13])=[O:12]
Reactant: O=C([O-])c1cc2c(Cl)cccc2s1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2c(Cl)cccc2s1

Procedure:
Sodium 4-chlorobenzo[b]thiophen-2-carboxylate (2.40 g) was dissolved in water (33 ml) at 60° C. Concentrated hydrochloric acid (1.3 ml) was added to the solution at the same temperature, and the resulting mixture was stirred. The precipitated crystals were collected by filtration, washed with water, and then dried to obtain 2-carboxy-4-chlorobenzo[b]thiophene.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:18]=[C:17]([O:19][CH2:20][O:21][CH3:22])[CH:16]=[C:15]([O:23][CH2:24][O:25][CH3:26])[C:11]=1[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.ClCCl>[CH2:1]([O:8][CH2:9][C:10]1[CH:18]=[C:17]([O:19][CH2:20][O:21][CH3:22])[CH:16]=[C:15]([O:23][CH2:24][O:25][CH3:26])[C:11]=1[C:12]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1cc(COCc2ccccc2)c(C(=O)O)c(OCOC)c1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COCOc1cc(COCc2ccccc2)c(C(=O)Nc2ccccc2)c(OCOC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 476.2 %

Procedure:
2-(Benzyloxymethyl)-4,6-bis(methoxymethoxy)benzoic acid (35 mg, 0.0096 mmol) obtained in Step 6 of Example 22 was dissolved in tetrahydrofuran (4 mL) and dichloromethane (1 mL), and aniline (0.030 mL, 0.33 mmol), 1-hydroxybenzotriazole monohydrate (56 mg, 0.37 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.13 g, 0.68 mmol) were added to the obtained solution followed by stirring at a room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by preparative thin-layer chromatography (chloroform/methanol=100/1) to obtain 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)-N-phenylbenzamide (20 mg, 49%).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].[Li]CCCC.[CH:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>C1COCC1>[C:17]1([CH:16]([OH:23])[C:3]#[C:2][CH2:1][O:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][O:6]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#CCOC1CCCCO1
Reactant: O=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(C#CCOC1CCCCO1)c1ccccc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(prop-2-ynyloxy)-tetrahydro-2H-pyran (10.0 g, 71.4 mmol) in THF (40 mL) was added n-BuLi (2.5M, 31.4 mL, 78.6 mmol) at −78° C. The reaction mixture was kept for 1 h at −78° C. and then benzaldehyde (8.3 g, 78.6 mmol) was added at −78° C. The reaction mixture was stirred for 2 h and then slowly warmed to −30° C. before being poured into NaHCO3 (aq., 500 mL), extracted with ethyl acetate (3×200 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-phenyl-4-(tetrahydro-2H-pyran-2-yloxy)but-2-yn-1-ol as a colorless oil (17.0 g, crude).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].[Mg+2:13].[Cl-:14].[Cl-].Cl.C(N(CC)CC)C>CCCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O-:12])=[O:11].[Cl-:14].[Mg+2:13]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: O=C([O-])Cc1ccc(Cl)cc1Cl
Yield: 96 %

Procedure:
215 grams (1.05 moles) of 2,4-dichloro-phenylacetic acid are added to 95.2 grams (1 mole) of MgCl2 suspended in 2 liters of heptane. The suspension is brought to reflux temperature under a light stream of nitrogen and is maintained at boiling point until the complete development of HCl (8-12 hours). After cooling, the reaction mixture is treated with 10.1 g (0.1 moles) of triethylamine and filtered. 253.2 g (96% yield) of white solid are obtained from the filtrate, after evaporation and subsequent drying, with the following elemental analysis:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:22]C)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([O:20]C)[CH:13]=1.[BrH:24]>>[BrH:24].[Cl:1][C:2]1[C:3]([OH:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:20])[CH:13]=1
Reactant: COc1ccc(C2CNCc3c2ccc(OC)c3Cl)cc1OC
Agent: Br
Product: Oc1ccc(C2CNCc3c2ccc(O)c3Cl)cc1O

Procedure:
To 540 mg of 8-chloro-7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline, was added 11 ml of 48% hydrobromic acid, and the mixture was heated under reflux for 3 hours under an argon gas stream. After cooling, the crystals which separated out were collected by filtration, and 520 mg of 8-chloro-7-hydroxy-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide was obtained.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH:2]=[CH2:3].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C=O)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCc1cc(C=O)ccc1OC

Procedure:
Two equivalents of potassium carbonate are added slowly with stirring to a solution of 4-hydroxybenzaldehyde in acetone. A solution of allyl bromide (1.1 equivalent) in acetone is added and the mixture is refluxed for two hours, filtered to remove inorganic salts and volatiles stripped under reduced pressure. The resulting 4-allyloxybenzaldehyde is then heated for six hours at 220° C. to yield the rearrangement product, 3-allyl-4-hydroxybenzaldehyde. One equivalent of 3-allyl-4-hydroxybenzaldehyde is dissolved in acetone and two equivalents of potassium carbonate are added slowly with stirring followed by a solution of 1.1 equivalents of methyl iodide in acetone. This mixture is refluxed for several hours, filtered and stripped to yield 3-allyl-4-methoxybenzaldehyde.
Reaction SMILES: [CH2:1]([C:13]1[S:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:21]([O:29][C:30]1[CH:36]=[CH:35][C:33](O)=[C:32]([C:37]#[N:38])[C:31]=1[C:39]#[N:40])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CC=CN=2)CCCC1>C1COCC1>[CH2:1]([C:13]1[S:17][C:16]([C:18]([O:20][C:33]2[CH:35]=[CH:36][C:30]([O:29][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:31]([C:39]#[N:40])[C:32]=2[C:37]#[N:38])=[O:19])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCOc1ccc(O)c(C#N)c1C#N
Reactant: CCCCCCCCCCCCc1ccc(C(=O)O)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1ccc(N2CCCC2)nc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccc(C(=O)Oc2ccc(OCCCCCCCC)c(C#N)c2C#N)s1
Yield: 58.1 %

Procedure:
0.50 g (1.69 mM) of 5-dodecylthiophene-2-carboxylic acid (M.W.: 296), 0.46 g (1.69 mM) of 2,3-dicyanohydroquinone monooctyl ether (M.W.: 272) and 20 ml of THF were mixed and stirred. To the mixture, 0.35 g (1.69 mM) of dicyclohexylcarbodiimide (M.W.: 206) and 0.05 g of pyrrolidinopyridine were added, followed by stirring overnight at room temperature. After the reaction, the reaction mixture was subjected to filtration and the filtrate was subjected to distillation to obtain a crude product. The crude product was purified by silica gel column chromatography with the use of benzene and recrystallized from ethanol to obtain 0.54 g of an objective product (yield: 58.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1Nc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-chloro-2-fluoronitrobenzene (250 mg), aniline (0.40 mL) and potassium carbonate (500 mg) were dissolved in dimethyl sulfoxide (1.5 mL) and stirred at 50° C. overnight. The mixture was added with water, extracted with ethyl acetate, and the organic layer was washed with saturated brine, and the water was removed with sodium sulfate. The reaction solution was removed of the solvent by distillation under reduced pressure, and the subsequent reaction was proceeded without further purification of the thus obtained compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([C:13](=[O:20])[CH2:14][NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:5][C:4]=1[Cl:21].[BH4-].[Na+].Cl>CO>[ClH:21].[NH2:2][C:3]1[C:8]([C:9]([F:10])([F:11])[F:12])=[CH:7][C:6]([CH:13]([OH:20])[CH2:14][NH:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[CH:5][C:4]=1[Cl:21]
Reactant: CC(C)(C)NCC(=O)c1cc(Cl)c(N)c(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)NCC(O)c1cc(Cl)c(N)c(C(F)(F)F)c1
Temperature: -15 °C

Procedure:
80 gm of 4'-amino-2-tert.butylamino-3'-chloro-5'-trifluoromethyl-acetophenone hydrochloride (decomposition between 223° and 231° C.) were dissolved in 500 ml of methanol, and the solution was cooled to -15° C. 9.5 gm of sodium borohydride were added in small portions over a period of one hour, while stirring and maintaining the temperature between -5° to -15° C. After one hour more of stirring at -15° C., the mixture was acidified with 2N hydrochloric acid, and the methanol was removed in vacuo. The remaining aqueous solution was made alkaline with 2N ammonia and was then extracted with ethyl acetate. The organic layer was washed with water, dried, and 50 ml of 4.5N isopropanolic hydrochloric acid were added. The precipitated hydrochloride of the above-mentioned substance was suction-filtered off and washed with ethyl acetate and ether. M.p. 205°-207° C. (decomp.). By concentration of the filtrate a further amount of the product was obtained.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([C:11]([O:13]CC)=[O:12])[N:7]([CH3:10])[C:8]=1[CH3:9]>O.C(O)C>[Br:3][C:4]1[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([C:11]([OH:13])=[O:12])[N:7]([CH3:10])[C:8]=1[CH3:9]
Reactant: CCOC(=O)c1c(-c2ccccc2)c(Br)c(C)n1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(Br)c(-c2ccccc2)c(C(=O)O)n1C
Yield: 68.4 %

Procedure:
A solution of potassium hydroxide (1.40 g, 25.0 mmol) in water (3 mL) was added to a solution of ethyl 4-bromo-1,5-dimethyl-3-phenyl-pyrrole-2-carboxylate (1.60 g, 4.97 mmol) in ethanol (5 mL) and the reaction mixture was refluxed overnight. The solvent was evaporated and the residue was washed with diethyl ether. The resultant filter cake was acidified with diluted HCl and extracted with ether. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-bromo-1,5-dimethyl-3-phenyl-pyrrole-2-carboxylic acid (1.0 g, 69%) as a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15]O)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15][S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCOc1c(NCCCO)c(=O)c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOc1c(NCCCS(=O)(=O)c2ccccc2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
A solution of 1-butoxy-2-(3-hydroxypropylamino)-1-cyclobutene-3,4-dione [prepared in Example 7] (1.14 g, 5.0 mmol) and pyridine (0.65 mL, 8.0 mmol) in 6.0 mL of dichloromethane cooled to 0° C. was treated dropwise with benzenesulfonyl chloride (0.65 mL, 5.1 mmol). The mixture was stirred at ambient temperature for 3 hours, then washed with water (4 times), dried and evaporated under reduced pressure to give 1.53 g (83% yield) of title compound which was used without purification in the subsequent reaction.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([NH:9]C(OC)=O)=[C:7]([F:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([NH2:9])=[C:7]([F:16])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Nc1ccc(C(C)(C)C)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1ccc(N)c(F)c1
Temperature: 90 °C
Yield: 41.3 %

Procedure:
To 303 g of 4-t-butyl-2-fluoro-N-methoxycarbonylaniline as the crude product was added 657 g of a 30% aqueous sodium hydroxide solution. The mixture was heated under reflux at a temperature around 90° C. for 4 hr and was allowed to cool. Water (1,000 mL) was then added thereto, and the mixture was extracted four times with 500 mL of hexane. The organic layers thus obtained were combined, and 2 M hydrochloric acid was added thereto, followed by vigorous stirring to convert the amino group to a hydrochloride form. Subsequently, an aqueous layer was separated and was adjusted to pH 9 by the addition of aqueous sodium hydroxide solution to bring the amino group to a free form. Extraction was carried out twice with 1,000 mL of toluene. The organic layers thus obtained were combined, and the combined organic layer was washed with saturated brine. The solvent was then removed from the organic layer by distillation to give 92.9 g of 4-t-butyl-2-fluoroaniline as an oily substantially single product (yield 65.6% (yield in two steps of t-butylation-deprotection)).
Reaction SMILES: [CH3:1][Mg+].[Br-].[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([CH3:16])([CH3:15])[C:9]([CH2:19][OH:20])([CH2:17][OH:18])[C:8]2=O.Cl>C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([CH3:16])([CH3:15])[C:9]([CH2:19][OH:20])([CH2:17][OH:18])[C:8]2=[CH2:1]
Reactant: CC1(C)Oc2ccc(Br)cc2C(=O)C1(CO)CO
Reactant: C[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1c2cc(Br)ccc2OC(C)(C)C1(CO)CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
Under nitrogen, MeMgBr solution (2.9 M in 2-methyltetrahydrofuran solution, 3.06 L, 8.88 mol) was diluted by adding into THF (8 L) at 0-5° C. A solution of 6-bromo-3,3-bis(hydroxymethyl)-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (700 g, 2.22 mol) in THF (5 L) was added dropwise via a dropping funnel to the diluted MeMgBr solution maintaining the temperature below 5° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. Then the reaction mixture was heated under reflux overnight. The mixture was cooled to room temperature followed by cooling with an ice-water bath and 6 M hydrochloric acid (3.7 L, 22.2 mol) was added dropwise via a dropping funnel over 30 minutes maintaining the temperature below 10° C. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 20 minutes. The mixture was extracted with toluene (5 L×2) and the combined extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was treated with a mixture of hexane/toluene (5:1, 2 L) and the resulting suspension was stirred for 30 minutes. The precipitate was collected by filtration, washed with hexane and dried under vacuum to give (6-bromo-2,2-dimethyl-4-methylene-3,4-dihydro-2H-chromene-3,3-diyl)dimethanol (500 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](O)=[O:11])=[N:2]1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].[OH-].[Na+]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][OH:11])=[N:2]1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1n[nH]c2ccccc12
Reaction time: 2 h

Procedure:
Commercially available indazol-3-carboxylic acid (500 mg, 3.08 mmol) was dissolved in tetrahydrofuran (THF) (10 mL) and sodium bis(2-methoxyethoxy)aluminum hydride (70% toluene solution, 1.78 g, 6.17 mmol) was added thereto under ice-cooling, under argon atmosphere, followed by stirring for 2 hours under heating and reflux. Sodium bis(2-methoxyethoxy)aluminum hydride (70% toluene solution, 2.67 g, 9.25 mmol) was further added to the mixture under ice-cooling and the mixture was stirred for 2 hours under heating and reflux. Under ice-cooling, 2 mol/L sodium hydroxide solution (10 mL) was added, and the mixture was stirred for 15 minutes at a room temperature. The organic layer was separated and the aqueous layer was extracted with THF (5 mL, 3 times). The organic layer was collected, and washed with saturated brine. The aqueous layer was extracted with ethyl acetate (5 mL, 2 times), all organic layers were collected and dried over anhydrous magnesium sulfate followed by concentration under reduced pressure. The residue was recrystallized by toluene/THF (10:1) (5 mL) and the precipitated crystal was collected by filtration, followed by washing with torulene/THF (10:1) (1 mL). The obtained crystal was dried under reduced pressure to thereby yield Compound (I) (349 mg, 2.36 mmol, 77%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[C:16]([Cu])#[N:17].Cl>N1C=CC=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[N:4]=[C:5]([CH3:7])[S:6][C:2]=2[C:16]#[N:17])=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2nc(C)sc2Br)cc1
Reactant: N#C[Cu]
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(C)sc2C#N)cc1
Temperature: 150 °C
Yield: 93.1 %

Procedure:
To a solution of 5-Bromo-4-(4-methoxy-phenyl)-2-methyl-thiazole (2.0 g, 7.0 mmol) in 15 ml of pyridine was added CuCN (3.10 g, 35.2 mmol) and the reaction mixture was heated to 150° C. in microwave for 2 h. After the completion of the reaction pH was adjusted to 3-4 with 1 N HCl solution and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 12% EtOAc-Hexane) to get the desired product (1.5 g, 92%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].[Cl:18][CH2:19][CH2:20]Cl>CN(C=O)C>[Cl:18][CH2:19][CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: COc1ccc(C=O)cc1O
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCCCl
Temperature: 67.5 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
A mixture of 3-hydroxy-4-methoxybenzaldehyde (14) (10.0 g, 65.7 mmol), K2CO3 (45.4 g, 329 mmol), 1,2-dichloroethane (104 mL, 1.31 mol), and DMF (300 mL) was stirred at 65-70° C. for 16 h. After cooling, 1,2-dichloroethane was removed under reduced pressure, the remaining slurry was poured onto ice and the mixture was extracted with Et2O (3×250 mL) and EtOAc (4×250 mL). The combined organic layers were washed with water (4×400 mL) and brine (2×400 mL), dried (MgSO4), and the solvent was removed in vacuo. Crystallization from EtOAc/hexane provided 15 (11.9 g, 84%) as colorless needles. 1H NMR (200 MHz, CDCl3): δ=3.88 (t, J=6.1 Hz, 2 H, 2′-H2), 3.97 (s, 3 H, OMe), 4.35 (t, J=6.1 Hz, 2 H, 1′-H2), 7.01 (d, J=8.1 Hz, 1 H, 5-H), 7.43 (d, J=1.8 Hz, 1 H, 2-H), 7.51 (dd, J=8.1, 1.8 Hz, 1 H, 6-H), 9.86 (s, 1 H, CHO) ppm; 13C NMR (50.3 MHz, CDCl3): δ=41.5 (C-2′), 56.2 (OMe), 68.9 (C-1′), 111.0, 111.3 (C-2, C-5), 127.4 (C-6), 129.9 (C-1), 148.1 (C-3), 154.9 (C-4), 190.7 (CHO) ppm; MS (70 eV, EI): m/z (%)=214 (100) [M]+, 151 (57) [M-CH2)2Cl]+; C10H11ClO3 (214.65): calcd. C, 55.96; H, 5.17; found C, 56.04; H, 4.97.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1I.C([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(OC(C)(C)C)=O.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: FC(F)(F)c1ccc(I)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: FC(F)(F)c1ccc(N2CCNCC2)c(Cl)c1
Temperature: 100 °C
Yield: 10 %

Procedure:
A mixture of 0.5 g (1.6 mmol) of 3-chloro-4-iodobenzotrifluoride 0.7 g (3.8 mmol), N-Boc-piperazine, 41 mg (0.04 mmol) Tris(dibenzylideneacetone)dipalladium chloroform complex, 0.44 g (4.43 mmol) sodium-t-butoxide and 48 mg (0.16 mmol) tri-o-tolylphosphine in 6 ml dioxane was heated overnight at 100° C. The solution was allowed to cool to room temperature, taken up in ether (30 ml) and washed with brine (25 ml). The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was chromatographed over on silica gel: Eluent: Heptane-AcOEt 0-10% over 15 min to provide the title compound (0.06 g, 10%) as a brown oil, MS (m/e): 365.1 (MH+, 100%).