Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][N:5]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=1.[Cl-].[CH2:23]([O:25][C:26](=[O:38])[CH:27]([OH:37])[CH:28]([NH3+:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:24]>>[OH:37][CH:27]([CH:28]([NH:36][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[N:15][C:7]=1[N:5]1[CH:6]=[C:2]([CH3:1])[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4]1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:26]([O:25][CH2:23][CH3:24])=[O:38]
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Reactant: Cc1cn(-c2ncccc2C(=O)O)nc1-c1ccccc1
Agent: [Cl-]
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc(C)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.1 by reacting 2-(4-methyl-3-phenyl-1H-pyrazol-1-yl)nicotinic acid and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride. ESI-MS [M+H]+: 485.3
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[CH:30]=[C:31]([CH2:35][O:36][CH2:37][CH2:38]O)[CH:32]=[CH:33][CH:34]=1>C(Cl)Cl.[Al]>[Br:1][CH2:38][CH2:37][O:36][CH2:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCOCc1cccc(F)c1
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccc(COCCBr)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.3 %

Procedure:
N-bromosuccinimide (146 mg, 0.820 mmol) was added to resin-bound triphenylphosphine (274 mg, 0.822 mEquiv, Fluka) and 2-{[(3-fluorophenyl)methyl]oxy}ethanol (70 mg, 0.411 mmol) in DCM (4 mL). The reaction vial was sealed with a Teflon-lined cap, wrapped in aluminum foil, and shaken at rt for 17 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (75 mg, 78%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: C(O)C.OCC[N+](C)(C)C.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([CH:24]=[CH:25][C:26]#[N:27])=[CH:22][CH:21]=1>CO>[NH2:27][C:26]1[CH2:25][CH:24]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:29][CH:28]=2)[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=1
Reactant: N#CC=Cc1ccc(Cl)cc1
Reactant: NNc1ccccc1
Agent: C[N+](C)(C)CCO
Solvent: CCO
Solvent: CO
Product: NC1=NN(c2ccccc2)C(c2ccc(Cl)cc2)C1
Reaction time: 16 h

Procedure:
A mixture of 500 ml. of absolute ethanol, 5.0 ml. of 50% choline in methanol, 32.4 g. of phenylhydrazine and 49.08 g. of p-chlorocinnamonitrile is refluxed for 7 hours then is allowed to stand at room temperature for 16 hours, then is evaporated to dryness in vacuo. The procedure of Example 16 is followed to give 12.0 g. of the product of the Example as colorless needles, m.p. 183.5°-185.5° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].Cl.[H][H]>C(O)C.[Pt]=O>[C:1]([NH:4][CH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)NCCc1ccncc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CC(=O)NCCC1CCNCC1
Yield: 52.6 %

Procedure:
4-(2-Acetamidoethyl)pyridine (33 g.) in ethanol (250 ml.) was acidified to pH 4 with hydrochloric acid and hydrogenated at 60 p.s.i./60° C. over a platinum oxide catalyst for 18 hours, after which time the uptake of hydrogen was complete. The catalyst was then removed by filtration and the filtrate was treated with a solution of potassium hydroxide flakes in methanol (1.1 molar equivalents) and refiltered. The solvents were distilled off in vacuo, leaving a clear oil, which on standing gave 4-(2-acetamidoethyl)piperidine (18 g.) as a white solid, m.p. 60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C@@H:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[C:14]([Br:19])[CH:13]=1>C(O)(=O)C>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C@@H:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[C:14]([Br:19])[CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Br)c1)C(=O)Nc1ccccc1N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Br)c1)c1nc2ccccc2[nH]1
Yield: 98.7 %

Procedure:
A solution of tert-butyl [(1S)-2-[(2-aminophenyl)amino]-1-(3-bromo-4-iodobenzyl)-2-oxoethyl]carbamate (640 mg, 1.14 mmol) in acetic acid (30.0 mL) was stirred at 40° C. for 2 h. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water, dried with sodium sulfate, filtered, and concentrated in vacuo to yield the desired product (610 mg, 98%). 1H NMR (400 MHz, CD3OD): δ 7.80 (d, 1H), 7.6 (m, 3H), 7.3 (m, 2H), 6.94 (d, 1H), 5.13 (m, 1H), 3.39 (m, 1H), 3.09 (m, 1H), 1.37 (s, 9H); LCMS found for C20H22BrIN3O2 (M+H)+: m/z=542, 544.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[SH2]=N.[C:7]1([NH:13][C:14](C2C=CC=CC=2C(O)=O)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(C)=O>[C:7]1([NH:13][C:14]([NH:4][CH2:3][CH2:1][OH:2])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Reactant: NCCO
Agent: N=[SH2]
Solvent: CC(C)=O
Product: O=C(NCCO)Nc1ccccc1
Yield: 26.9 %

Procedure:
A solution of 0.65 g ethanolamine with 5 ml aceton was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 10 ml aceton, under stirring. The reaction mixture was stirred for a further 30 minutes at ambient temperature, evaporated in vacuo, the residue was triturated with 20 ml water, and the obtained solid product was filtered, dried and recrystallized. There was obtained 0.25 g 1-phenyl-3-(2-hydroxyethyl)-urea, melting at 120°-122° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([N:12]([C:15]([CH:17]2[CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18]2)=[O:16])[CH2:13][CH3:14])[CH3:11])=[CH:5][CH:4]=1>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]([N:12]([C:15]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:16])[CH2:13][CH3:14])[CH3:11])=[CH:7][CH:8]=1
Reactant: CCN(C(=O)C1CCN(C(=O)OCc2ccccc2)CC1)C(C)Cc1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Product: CCN(C(=O)C1CCNCC1)C(C)Cc1ccc(OC)cc1
Reaction time: 2.5 h
Yield: 83.5 %

Procedure:
A mixture of N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-[1-(benzyloxycarbonyl)piperidin-4-ylcarbonyl]amine (3.5 grams, 8.3 mmole) and 10% palladium on carbon (0.7 grams) in ethanol (40 ml) was hydrogenated at 22° C. and 50 p.s.i. for 2.5 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to leave N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-(piperidin-4-ylcarbonyl)amine as a syrup (2.11 grams, 84%), M+H 305.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[C:7]1([C:5]2[N:6]=[C:2]([NH:1][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3)cs2)cc1

Procedure:
The title compound was prepared from 2-amino-4-phenylthiazole and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (29.8 mg) with purity >90%. MS (pos) m/z 359.2.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:28])=[CH:9][C:8]=1[CH3:29])C.[Li+].[OH-]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[S:20][C:16]([CH2:15][CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:30][CH2:31][CH3:32])[C:4]([OH:33])=[O:3])=[C:8]([CH3:29])[CH:9]=3)=[C:17]([CH3:28])[N:18]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2sc(-c3ccc(Cl)cc3)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCCc2sc(-c3ccc(Cl)cc3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-3-(4-{2-[2-(4-chloro-phenyl)-4-methyl-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-(4-{2-[2-(4-chloro-phenyl)-4-methyl-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid as light yellow solid.
Reaction SMILES: [NH2:1][C:2]([C:4]1([CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=O.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C)C=O.O.C(OCC)(=O)C>[C:2]([C:4]1([CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6][CH2:5]1)#[N:1]
Reactant: CC(C)C1(C(N)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a solution of tert-butyl 4-(aminocarbonyl)-4-isopropylpiperidine-1-carboxylate (100 mg, 0.370 mmol) in dimethylformamide (2 ml) was added cyanuric chloride (34.1 mg, 0.185 mmol). After stirring over the weekend at room temperature, the mixture was diluted with 10 ml of water, and 20 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×15 ml). The combined organics were washed with 10 ml each of saturated sodium bicarbonate solution and brine, dried (sodium sulfate), and then concentrated to provide the title compound (93 mg, 0.369 mmol, 100% yield). Mass spectrum (ESI) 153.2.0 (M-Boc).
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=[O:21].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Pd].C(O)(=O)C.O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:15]2[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=2)[CH:20]=[O:21])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(O)c(C=O)c2)CC1
Temperature: 42 °C
Reaction time: 22 h
Yield: 0.6 %

Procedure:
Toluene (9.7 L) was introduced into a reactor and degassed using vacuum/nitrogen. Under nitrogen at 23° C. was palladium acetate (11.0 g, 0.049 mol, 0.01 equiv.) was loaded and the mixture was stirred until complete dissolution of palladium. A solution of tri-tert-butyl-phosphine (10.0 g, 0.049 mol, 0.01 equiv.) in toluene (0.3 L) was then added, followed by the addition of 5-bromo-2-hydroxybenzaldehyde (1000 g, 4.97 mol, 1 equiv.), tert-butyl-1-piperazine-carboxylate (1065.4 g, 5.72 mol, 1.1 equiv.) and sodium-tert-butoxide (1052.4 g, 10.9 mol, 2.2 equiv.). The resulting yellow-orange solution was stirred for 22 h at 42° C. The red-brownish slurry was mixed with a mixture (pH around 5-6) of distilled water (8 L) and glacial acetic acid (800 mL), and stirred for 10 min. The organic phase was separated from the aqueous phase and washed twice with distilled water (2×8 L). The organic phase was then dried by addition of sodium sulphate (2.5 kg), stirred for 30 min. and filtered. The resulting dark-orange organic phase was weighed (9.65 kg) and an aliquot (100 g) was taken. The aliquot was concentrated in vacuo to yield a dark-orange oil which was purified by column chromatography (SiO2, h: 30 cm, d: 4 cm, eluant: MTBE/heptane 1:1). The named compound was obtained as yellow crystals (8.9 g). Calculation of the total yield from the aliquot gave 56%. MS (ES+): 307 (M+H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]=[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH2:8][CH3:7]
Reactant: CCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(CC)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (3.53 g, 9.89 mmol) in THF (30 ml) was added potassium tert-butoxide (1.11 g, 9.89 mmol) in THF (10 ml) dropwise at 0° C. and the mixture was stirred at ambient temperature for 2 hours. Then, to this mixture was added 4-(trifluoromethyl)propiophenone (Aldrich, 1.00 g, 4.95 mmol) in THF (10 ml) at 0° C. and stirred at ambient temperature for 2 hours. The reaction was quenched with small amount of water and evaporated to remove the solvent. The crude mixture was diluted with hexane. The formed precipitates were filtered and the organic layer was separated. After evaporation of solvent, residue was applied to a silica gel chromatography column and eluted with hexane to afford 1.12 g (crude 100%) of the title compound as a red oil.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:17][O:18][C:19]1(C)C=CC(S([O-])(=O)=O)=[CH:21][CH:20]1CCC>CC(C)=O>[CH3:17][O:18][CH2:19][CH:20]([S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])[CH3:21]
Reactant: CCCC1C=C(S(=O)(=O)[O-])C=CC1(C)OC
Reactant: Oc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCC(C)Sc1ccccc1O

Procedure:
126 Parts of o-mercaptophenol are added in portions, in a nitrogen atomsphere and whilst cooling, to a stirred mixture of 138 parts of potassium carbonate, 166 parts of potassium iodide and 500 parts by volume of acetone. The mixture is thereafter heated to boiling point and 268 parts of 1-methoxy-2-propyl-p-toluenesulphonate are added drop by drop. The mixture is boiled under reflux for 24 hours, filtered and evaporated. The residue is taken up in 750 parts by volume of toluene, and washed once with water, and then twice each time with 250 parts by volume of 15% strength sodium hydroxide solution. The alkaline extract is immediately neutralised with hydrochloric acid and extracted with toluene. The toluene solution is dried over anhydrous sodium sulphate, filtered and evaporated. The residue is distilled in a high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:10]2=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.CN.[C:23]([BH3-])#[N:24].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH:10]2[NH:24][CH3:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [BH3-]C#N
Reactant: O=C1CCc2ccccc2C1c1ccc(Cl)c(Cl)c1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNC1CCc2ccccc2C1c1ccc(Cl)c(Cl)c1
Reaction time: 20 h
Yield: 66 %

Procedure:
To a solution of tetralone 35 (400mg, 1.374 mmol) in THF (10 mL) and methanol (15mL) was added methylamine hydrochloride (1.12 g, 10 eq). The resultant mixture was stirred at 50° C. After dissolution (10 min), sodium cyanoborohydride (6.9 mL, 1M in THF, 5 eq) was added in a single portion. After 20 hours, the organic layer was evaporated, filtered through silica and an aminopropyl cartridge. The crude oil was then diluted with sodium bicarbonate solution and extracted with MTBE to give the amine (280 mg, 66%) as a mixture of four stereoisomers (1:1:1:1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:24][CH2:25][CH3:26]>CC(C)=O.C(OCC)(=O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:25][CH3:26])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCOc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 4-hydroxy-4′nitrobiphenyl in 5 ml acetone was added potassium carbonate (240 mg, 1.74 mmol) and 1-iodopropane (0.17 ml, 1.74 mmol). The reaction mixture was heated at reflux for 24 h. Additional potassium carbonate (240 mg, 1.74 mmol) and 1-iodopropane (0.17 ml, 1.74 mmol) was added and the reaction mixture was heated at reflux for 24 h. The reaction mixture was cooled to room temperature and diluted with 30 ml ethyl acetate. The ethyl acetate solution was washed sequentially with 25 ml water and 25 ml brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel), eluting with 14:1 hexane/ethyl acetate to yield the title compound (0.267 g, 89% yield) MS: 258.3 (M−1)
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]([NH:18][C@H:19]([B:32]2OC3C(C)(C4CC(C3)C4(C)C)[O:33]2)[CH2:20][C:21]2[C:22]([O:30]C)=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24]([OH:26])=[O:25])=[O:17])[CH2:11][CH2:10]1)=O)(C)(C)C.B(Cl)(Cl)Cl>>[NH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][C:16]([NH:18][C@H:19]2[CH2:20][C:21]3[CH:29]=[CH:28][CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]=3[O:30][B:32]2[OH:33])=[O:17])[CH2:13][CH2:14]1
Reactant: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Agent: ClB(Cl)Cl
Product: N[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
Prepared from 3-((2R)-2-(2-(trans-4-(tert-butoxycarbonylamino)cyclohexyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoic acid and BCl3 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 347 (MH)+.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH2:6][C:5]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])(S(C3C=CC=CC=3)(=O)=O)[CH:4]2[CH3:29])[O:2]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CC(C)=O>[OH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:5]1[CH2:6][CH2:7][CH2:8][C:3](=[O:2])[C:4]=1[CH3:29]
Reactant: CC1C2(CCCC1(CCCCCCCCCCO)S(=O)(=O)c1ccccc1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC1=C(CCCCCCCCCCO)CCCC1=O
Yield: 45 %

Procedure:
Paratoluenesulfonic acid (20 mg) was added to a solution of 388 mg of 1,1-(ethylenedioxy)-3-(10-hydroxydecyl)-2-methyl-3-(phenylsulfonyl)-cyclohexane in 30 ml of chloroform and 6 ml of acetone. The resulting mixture was reacted at 50° C. for 24 hours. To the reaction mixture was added 10 ml of a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column while using hexane-ethyl acetate, whereby 3-(10-hydroxydecyl)-2-methyl-2-cyclohexen-1-one was obtained in the form of a colorless oil. Yield: 45%
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1.[CH3:17][NH:18][CH2:19][C:20]1[NH:21][C:22]2[C:27]([C:28]=1[C:29]#[N:30])=[CH:26][CH:25]=[CH:24][CH:23]=2.C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([N:18]([CH2:19][C:20]2[NH:21][C:22]3[C:27]([C:28]=2[C:29]#[N:30])=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:17])=[O:16])=[CH:8][CH:7]=1
Reactant: CNCc1[nH]c2ccccc2c1C#N
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1[nH]c2ccccc2c1C#N)C(=O)C=Cc1ccc(N)nc1
Reaction time: 72 h
Yield: 83.6 %

Procedure:
EDC (250 mg, 1.3 mmol) was added to a solution of (E)-3-(6-Amino-pyridin-3-yl)-acrylic acid (172 mg, 1.05 mmol), 2-methylaminomethyl-1H-indole-3-carbonitrile (186 mg, 1.0 mmol), HOBt H2O (135 mg, 1.0 mmol) and DIPEA (510 μL, 3.0 mmol) in dry DMF (4 mL). After 3 d of stirring, the mixture was diluted with water (50 mL) at 10° C. The resulting precipitate was filtered, washed with water and dried to afford the title compound (277 mg, 84%). 1H NMR (300 MHz, DMSO-d6, δ): 12.1 (m, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 7.5 (m, 3H), 7.2 (m, 2H), 6.97 (m, 1H), 6.44 (s, 2H), 5.08 and 4.88 (rotamers, 2s, 2H), 3.22 and 2.96 (rotamers, 2s, 3H). MS (ESI): m/e 332 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]12([OH:16])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.C(Cl)(Cl)Cl>>[Cl:1][CH2:2][C:3]([O:16][C:6]12[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:9][CH:8]([CH2:14]3)[CH2:7]1)[CH2:15]2)=[O:4]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Product: O=C(CCl)OC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 36.9 %

Procedure:
At 10° C. and under N2, chloroacetyl chloride (9 mL, 113 mmol) was added slowly to a suspension of 1-adamantanol (11.4 g, 75 mmol) and MgO (4.5 g, 113 mmol) in CHCl3 (150 mmol). The mixture was heated to slight reflux for 43 h and cooled to RT. The insoluble material was removed by filtration and the solvent was evaporated. The residue was crystallized in hexanes to afford 2 as a white solid (6.324 g, 37%). U.S. Pat. No. 4,456,611; Helv. Chim. Acta 1988, 71, 1553.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5](Cl)=[O:6])[CH3:3].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:15]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([NH2:32])=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[C:16]2[CH2:21][CH2:20][CH2:19][N:17]2[N:18]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:1][N:2]([CH3:3])[CH2:4][C:5]([NH:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([C:15]3[C:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=4)=[N:18][N:17]4[CH2:19][CH2:20][CH2:21][C:16]=34)=[CH:23][CH:24]=[N:25]2)=[CH:30][CH:29]=1)=[O:6]
Reactant: CN(C)CC(=O)Cl
Reactant: Nc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CN(C)CC(=O)Nc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1

Procedure:
A mixture of dimethylamino-acetyl chloride (620.0 mg, 13.33 mmol), 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ylamine (75 mg, 0.23 mmol), and 4-N,N-dimethylaminopyridine (10.2 mg, 0.09 mmol) in dry pyridine (1 mL) is refluxed for 72 h. The mixture is treated with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer is washed with brine, dried (sodium sulfate), concentrated in vacuo, and the residue chromatographed on SiO2 ((5% to 20% methanol in dichloromethane) to yield a yellow oil, 62.3 mg (67%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12]O)=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:16][CH2:12][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[N:4]=1
Reactant: Cc1ccc(C(F)(F)F)nc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C(F)(F)F)nc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3-methyl-6-(trifluoromethyl)pyridin-2-yl)methanol (29) (0.18 g, 0.94 mmol) in DCM (5 ml) was added thionyl chloride (0.112 g, 0.95 mmol) and stirred at rt for 2 h. After completion of the reaction, mixture was concentrated and washed with hexane to afford 2-(chloromethyl)-3-methyl-6-(trifluoromethyl)pyridine (30). The crude solid was taken directly for the next step (180 mg, 91.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C:8](=O)[CH2:7]1)=[O:5])[CH3:2].O[C@@H:13](C1C=CC=CC=1)[CH2:14][N:15]1C2(CCN(C)CC2)CCN2C(=O)C=C(C3C=CN=CN=3)N=C12>>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C:8](=[CH:13][C:14]#[N:15])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CN1CCC2(CC1)CCn1c(nc(-c3ccncn3)cc1=O)N2C[C@@H](O)c1ccccc1
Reactant: CCOC(=O)N1CCC(=O)C1
Product: CCOC(=O)N1CCC(=CC#N)C1

Procedure:
The product was obtained by analogy with the method described in example 1.1 (step1.1)and using 3-oxo-pyrrolidine-1-carboxylic acid ethyl ester prepared according to Visconti, M et al. Helvetica Chimica Acta 1967, 50 (5) 1289-93.