Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([CH3:15])=[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:27]>O1CCCC1>[CH3:15][C:5]1[C:4]([CH2:3][CH:1]=[O:27])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: Cc1c(CC#N)cccc1NS(C)(=O)=O
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1c(CC=O)cccc1NS(C)(=O)=O
Temperature: 5 °C
Reaction time: 1.25 h

Procedure:
N-(3-cyanomethyl-2-methyl-phenyl)-methanesulfonamide (3.75 g) was dissolved in 50 ml of dry tetrahydrofuran and cooled in an ice bath under an atmosphere of nitrogen. To this mixture was added 67 ml of 1M diisobutylaluminum hydride (DIBAL) in tetrahydrofuran. The mixture was stirred at 5° C. for 75 minutes. Excess reagent was decomposed with methanol and the solvent was evaporated. The residue was treated with EtOAc, washed with cold 1M hydrochloric acid, washed with brine and dried, and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with methanol:dichloromethane (5:95), giving 1.1 g of N-[2-methyl-3(2-oxo-ethyl)-phenyl]-methanesulfonamide as a yellow oil.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[F:16].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:9][C:10]1[CH:11]=[C:12]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Nc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccc(F)c(F)c2)cc1
Temperature: 80 °C

Procedure:
4-Iodoaniline (800 mg, 3.7 mmol), (3,4-difluorophenyl)boronic acid (1.2 g, 7.3 mmol), Pd(dppf)Cl2 (267 mg, 0.4 mmol), and 2M aqueous K2CO3 (3.7 mL, 7.3 mmol) were dissolved in 1,4-dioxane (15 mL) and heated to 80° C. After 2 h the resulting mixture was cooled to room temperature and the layers were separated. The organic phase was concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([CH3:14])(O)[CH3:12])=[C:4]([O:15][CH3:16])[CH:3]=1.S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][CH2:10][C:11]2([CH3:14])[CH3:12])=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(Br)ccc1CCCC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(Br)cc2c1CCCC2(C)C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
5-(4-Bromo-2-methoxy-phenyl)-2-methyl-pentan-2-ol (Intermediate 62, 7.3 g, 24.6 mmol) was treated with 85% sulfuric acid (25 mL) at ambient temperature. After 30 minutes, the reaction mixture was diluted with cold water and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (5.6 g, 83%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.CO[CH2:10][Cl:11]>C(O)(=O)C>[Cl:11][CH2:10][C:6]1[CH:5]=[C:4]([CH3:7])[S:3][C:2]=1[CH3:1]
Reactant: Cc1ccc(C)s1
Reactant: COCCl
Solvent: CC(=O)O
Product: Cc1cc(CCl)c(C)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
36.4 G., 0.325 mol. of 2,5-dimethylthiophene, 24.7 g. (0.307 mol) of freshly distilled chloromethyl methyl ether (b.p. 58°-60° C.) and 87.0 g. of glacial acetic acid were combined in a glass pressure bomb and stirred at room temperature for 5 hours. After 0.5 to 1 hr. an exothermic reaction took place. The reaction mixture was cooled externally in an ice bath so that the reaction temperature did not exceed 35° C. The color of the mixture changed from green to blue. The resulting solution was poured into ice water, stirred for ten minutes and extracted four times with benzene. The combined benzene extracts were washed twice with saturated sodium chloride solution, dried and evaporated. The resulting liquid was quickly distilled and the material which boiled at 90°-125° C./18 mm. was collected. A second distillation yielded the pure product, b.p. 109°-115° C./18 mm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][CH:16]([O:23][C:24](=[O:26])[NH2:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>O1CCCC1.O>[C:24]([O:23][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:35](=[O:37])[CH3:36])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:27])(=[O:26])[NH2:25]
Reactant: NC(=O)OC(CC(=O)N1CCN(c2ccc(O)cc2)CC1)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(N2CCN(C(=O)CC(OC(N)=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The compound ‘carbamic acid 3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester (2 mmol)’ prepared in Example 18 was dissolved in tetrahydrofuran 25 mL), and triethylamine (2.4 mmol) and acetylchloride (2.4 mmol) were added to the mixture. The reslting mixture was stirred at a room temperature for 5 hours. Then, the reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: ClC1C=CC=CC=1C1C(O)=NC2N=C(S(C)(=O)=O)N=CC=2C=1.O[CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCOCC1>[CH2:25]([N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36])[CH3:24]
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CS(=O)(=O)c1ncc2cc(-c3ccccc3Cl)c(O)nc2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a cooled (5° C.) suspension of 0.914 g (2.7 mmol) of 6-(chlorophenyl)-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-ol, 1.041 g (5.4 mmol) of N-(2-hydroxyethyl)-phthalimide, 1.43 g (5.4 mmol) of triphenylphosphine in 15 mL of 1,4-dionxane was added dropwise a solution of 0.95 g (0.86 mL, 5.4 mmol) diethylazodicarboxylate in 5 mL of 1,4-dioxane over a period of 30 min. After addition was completed, the ice-water cooling bath was removed. The suspension soon turned into a clear light brown solution. This was allowed to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on 120 g of silica gel using 90:10:0.5 ethyl acetate/dichloromethane/ammonium hydroxide to obtain 0.38 g of the N-ethylphthalimide intermediate. A mixture of 0.18 g (0.35 mmol) of this intermediate and 0.05 g (0.42 mmol) of trans-4-aminocyclohexanol in 1 mL of NMP was heated to 120° C. for 30 min. The reaction mixture was cooled, diluted with 75 mL of water and extracted with ethyl acetate (3×75 mL). The combined ethyl acetate solution was washed with water (3×75 mL), brine, dried, filtered and concentrated. The material was purified by column chromatography on 40 g of silica eluting with 5% methanol/dichloromethane affording 45 mg of compound 65. (mass spec. MH+=544, mp 208-210° C.).
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.O1CCCC1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:36]([CH:37]([F:49])[C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)=[C:35]([CH:50]([CH3:52])[CH3:51])[CH:34]=[C:33]3[C:25]=2[C:26](=[O:53])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:20][CH:19]=1>CO>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:36]([CH:37]([F:49])[C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:47])([F:48])[F:46])=[CH:40][CH:39]=3)=[C:35]([CH:50]([CH3:51])[CH3:52])[CH:34]=[C:33]3[C:25]=2[C@@H:26]([OH:53])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:22][CH:23]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(OC(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(OC(F)(F)F)cc1)[C@@H](O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 0.6 mg (0.004 mmol) of (1R,2S)-1-aminoindan-2-ol is dissolved in 0.5 ml of abs. tetrahydrofuran, 27.5 μl (0.15 mmol) of borane/N,N-diethylaniline complex are added and the mixture is stirred at room temperature for 30 min. After this time, 20 mg (0.04 mmol) of 5-(4-fluorophenyl)-6-{fluoro[4-(trifluoromethoxy)phenyl]methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 59A), dissolved in 1 ml of abs. tetrahydrofuran, are then added at room temperature over a period of 10 min, and the mixture is then stirred at room temperature overnight. 3 ml of methanol are added, and the mixture is stirred for 15 min and then concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The crude product is purified by thick-layer chromatography (mobile phase: cyclohexane→cyclohexane/ethyl acetate 5:1). This is followed by further purification by preparative HPLC. This gives 5.3 mg (26% of theory) of the title compound as a mixture of diastereomers.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]([F:9])=[C:6]([F:8])[F:7].[C:10](=[O:12])=[O:11].Cl>C(OCC)C>[F:9][C:5](=[C:6]([F:8])[F:7])[CH2:4][CH2:3][C:10]([OH:12])=[O:11]
Reactant: FC(F)=C(F)CCBr
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: O=C(O)CCC(F)=C(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
To a stirred mixture of 2.4 grams (0.1 mole) of magnesium turnings in 100 ml of diethyl ether was added 18.9 grams (0.1 mole) of 4-bromo-1,1,2-trifluoro-1-butene. Upon completion of addition the reaction mixture was heated under reflux until the reaction was complete. The reaction mixture was cooled to 0° C. and 9.0 grams (0.2 mole) of carbon dioxide was bubbled in slowly. Upon completion of addition the reaction mixture was stirred for one hour, then 100 ml of aqueous 20% hydrochloric acid was added to destroy the excess magnesium. The reaction mixture was extracted with three 40 ml portions of diethyl ether. The combined extracts were cooled and 40 ml of aqueous 25% sodium hydroxide was added slowly. The organic layer was separated and extracted with one 40 ml portion of aqueous 25% sodium hydroxide. The combined base layers were cautiously acidified with aqueous 20% hydrochloric acid. The mixture was extracted with two 100 ml portions of diethyl ether. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 6.9 grams of 4,5,5-trifluoro-4-pentenoic acid as an oil. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.[NH2:11][C:12]1[C:21]2[C:16](=[C:17](Br)[C:18]([CH3:22])=[CH:19][CH:20]=2)[N:15]=[N:14][C:13]=1[C:24]([NH2:26])=[O:25]>>[N:10]1[N:9]=[CH:8][N:6]2[CH:7]=[C:2]([C:17]3[C:18]([CH3:22])=[CH:19][CH:20]=[C:21]4[C:16]=3[N:15]=[N:14][C:13]([C:24]([NH2:26])=[O:25])=[C:12]4[NH2:11])[CH:3]=[CH:4][C:5]=12
Reactant: Brc1ccc2nncn2c1
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccc2nncn2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 96 using 6-bromo-[1,2,4]triazolo[4,3-a]pyridine and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 2.45 (s, 3 H), 7.45 (d, J=9.35 Hz, 1 H), 7.78 (d, J=8.84 Hz, 1 H), 7.92 (d, J=9.60 Hz, 1 H), 8.34 (d, J=8.84 Hz, 1 H), 8.56 (s, 1 H), 9.25 (s, 1 H); ESI-MS m/z [M+H]+ 320.1.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]1.C([Li])CCC>CCCCCC.O1CCCC1>[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:17]([C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:16]=1)=[O:19]
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: CC1CCCCN1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1CCCCN1C(=O)c1nc(-c2ccccc2)nc2ccccc12

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), 2-methylpiperidine (3 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethanol, 2-methyl-1-[(2-phenylquinazolin-4-yl)-carbonyl]-piperidine (1.7 g), melting at 150° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH:17](OCC)[O:18][CH2:19][CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:16]=[CH:17][O:18][CH2:19][CH3:20]
Reactant: CCOC(CBr)OCC
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC=CSc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromothiophenol (10.50 g, 55.87 mmol) in dry DMF (50 mL) under nitrogen is added cautiously potassium carbonate (9.2 mL, 61.46 mmol, 1.10 equiv.). Once bubbling has subsided, 2-bromo-1,1-diethoxyethane (8.46 g, 61.46 mmol, 1.10 equiv.) is added to the mixture and stirred for 2 h at room temperature. The resulting suspension is poured onto 200 mL of iced water and extracted with diethyl ether (3×50 mL). The organic layers are washed with brine, dried over MgSO4 to afford after solvent removal the title compound as a viscous orange oil, used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9](OC)=[O:10])=[C:4]([N+:15]([O-])=O)[CH:3]=1>C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8]([CH3:14])([CH3:13])[C:9](=[O:10])[NH:15]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1ccc(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1(C)C(=O)Nc2cc(F)ccc21
Temperature: 100 °C
Reaction time: 5.5 h
Yield: 93.2 %

Procedure:
A mixture of methyl 2-(4-fluoro-2-nitrophenyl)-2-methylpropanoate (2.53 g, 0.010 mol, step 1 of Example 15) and iron powder (2.34 g, 0.042 mol) in acetic acid (30 mL) was stirred at 100° C. for 5.5 h. The reaction mixture was rinsed with methanol and it was filtered through a pad of Celite. The filtrate was concentrated. It was added water and the aqueous layer was extracted with ethyl acetate (20 mL×3). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:6 to 1:4) to give 1.67 g (89%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:36]=[CH:35][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[C:21]([CH2:29][C:30]([O:32]CC)=[O:31])=[N:20]2)=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O.Cl>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[C:21]([CH2:29][C:30]([OH:32])=[O:31])=[N:20]2)=[CH:35][CH:36]=1)=[O:12]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2cc(F)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2cc(F)ccc12
Yield: 85.4 %

Procedure:
Ethyl 2-[1-[4-(2-naphthamido)benzyl]-6-fluoro-1H-indazol-3-yl]acetate (205 mg, 0.426 mmol) was dissolved in tetrahydrofuran (15 mL), and in an ice bath 10 mL aqueous solution dissolving lithium hydroxide monohydrate (54 mg, 1.29 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid 165 mg, at a yield of 85.4%.
Reaction SMILES: [CH2:1]([C:4]1([CH2:17][NH2:18])[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7][CH2:6][O:5]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)CC.C(C1(C(N)CC)C2NC3C(C=2CCO1)=CC=CC=3)C.C(C1(C(C2C=CC=CC=2)N)C2NC3C(C=2CCO1)=CC=CC=3)C.C(C1(C(N)CC2C=CC=CC=2)C2NC3C(C=2CCO1)=CC=CC=3)CCC.ClC1C=C2C(=CC=1)NC1C(C(N)C)(C)OCCC2=1.[N+](C1C=C2C(=CC=1)NC1C(C(N)C)(C)OCCC2=1)([O-])=O.FC(F)(F)C1C=CC=C2C=1C1CCOC(C(N)C)(C)C=1N2>>[CH3:1][C:4]1([CH2:17][NH2:18])[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7][CH2:6][O:5]1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: CCCC1(CN)OCCc2c1[nH]c1ccccc21
Agent: CC(N)C1(C)OCCc2c1[nH]c1ccc(Cl)cc21
Agent: CC(N)C1(C)OCCc2c1[nH]c1ccc([N+](=O)[O-])cc21
Agent: CC(N)C1(C)OCCc2c1[nH]c1cccc(C(F)(F)F)c21
Product: CC1(CN)OCCc2c1[nH]c1ccccc21

Procedure:
1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-methanamine, 1-(1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)propanamine, α-(1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)-benzenemethanamine, α-(1-butyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)-benzeneethanamine, 1-(6-chloro-1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)-ethanamine, 1-(6-nitro-1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)-ethanamine and 1-(5-trifluoromethyl-1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)-ethanamine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[N:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O>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.O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cnc(Cl)nc1-c1ccncc1
Temperature: 90 °C
Yield: 49.3 %

Procedure:
A mixture of 2,4-dichloro-5-methoxy-pyrimidine (3.0 g, 1.0 eq.), 4-pyridinylboronic acid (2.26 g, 1.1 eq.), Pd(PPh3)2Cl2 (0.58 g, 0.05 eq.), K3PO4—H2O (10.67 g, 3.0 eq.), H2O (3 ml) and 1,4-Dioxane (20.0 ml) was heated at 90° C. and refluxed overnight. The solvent was removed in vacuo, and the residue was extracted with EA and water. The combined organic layers was wash with brine, dried and evaporated in vacuo. The crude was purified by chromatography to give a yellow thick liquid (1.83 g, 49.26%).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:24]([F:27])([F:26])[F:25])[CH2:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH2:23])(=[O:22])=[O:21])([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>ClCCl>[Si:1]([O:8][CH:9]([C:24]([F:25])([F:27])[F:26])[CH2:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[CH:30][N:31]([CH3:33])[CH3:32])(=[O:21])=[O:22])([CH3:13])[CH3:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1ccccc1S(N)(=O)=O
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: CN(C)C=NS(=O)(=O)c1ccccc1C(C)(C)CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a round bottom flask was added 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1,1-dimethylbutyl]benzenesulfonamide (750 mg, 1.76 mmol) in 25 mL of dry dichloromethane, followed by the addition of N,N-dimethylformamide dimethyl acetal (420 mg, 3.53 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under high vacuum to afford 820 mg (100%) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1,1-dimethylbutyl]-N-[1-dimethylaminomethylidene]benzenesulfonamide. MS (ES+) m/z 481 [M+H]+.
Reaction SMILES: [Cu]C#N.[C:4]1([Mg]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([O:14][C:15](=[O:37])[C:16](=[CH:22][C:23]1[CH:24]=[N:25][C:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:27][CH:28]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([CH:22]([C:23]1[CH:24]=[N:25][C:26]([NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:27][CH:28]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:15]([O:14][CH2:12][CH3:13])=[O:37])[CH3:21]
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)C(=Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C(=O)OCC)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.8 %

Procedure:
To a vigorously stirred suspensin of copper(I)cyanide (1.71 g, 19.06 mmol) in dry THF (18 mL) was added a solution of phenylmagnesium bromide (12.7 mL 3 M in ether, 38.11 mmol) at 0° C. under argon. The mixture was allowed to warm to room temperature, giving a dark brown solution. After 150 minutes a solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethylene)-malonic acid diethyl ester (1.74 g, 4.76 mmol) in dry THF (19 mL) was added at 0° C. The mixture was left stirring for 3 days then aqueous ammonium chloride was added. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with brine and dried. Removal of the solvent in vacuo gave a residue, which was suspended in hexane. Filtration of the crystals gave 2-[(6-tert-butoxycarbonylamino-pyridin-3-yl)-phenyl-methyl]-malonic acid diethyl ester (1.85 g, 88%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([O:8][CH3:9])[CH:7]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[N:17][CH:18]=1>>[F:10][C:5]1[CH:4]=[CH:3][C:2]([NH:21][CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:23])([F:11])[F:22])=[CH:18][N:17]=2)=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: COc1cc(Br)ccc1F
Product: COc1cc(NCCc2ccc(C(F)(F)F)cn2)ccc1F

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-fluoro-3-methoxy-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 315.1 [M+H]+) was prepared from 5-bromo-2-fluoro-anisole instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1[O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCCCc1cccc(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cccc(CCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a solution of 0.18 g of 4-(3-fluorophenyl)-1-butanol, 0.30 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol and 0.27 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran, a solution of 0.20 ml of N,N-diisopropylazodicarboxylate dissolved in 5 ml of tetrahydrofuran was added dropwise, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.38 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3-fluorophenyl) butyloxy)benzene (83% yield), nD25.0 1.5620.