Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[OH-].[K+].[F:14][C:15]([F:19])=[C:16]([F:18])[F:17]>CN(C)C=O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:16]([F:18])([F:17])[CH:15]([F:19])[F:14]
Reactant: FC(F)=C(F)F
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(F)(F)C(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
7.0 Grams of 2-fluoro-4-nitrophenol was dissolved in 70 ml of N,N-dimethylformamide, and 1.0 g of potassium hydroxide was added thereto. Tetrafluoroethylene was blown into the resulting solution at an inner temperature of 100° C., after which stirring was continued for 6 hours at an inner temperature of 100° C. The reaction solution was poured into ice water and extracted with ether. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue obtained was subjected to column chromatography on silica gel with toluene as an eluent to obtain 6.97 g of 3-fluoro-4-(1',1',2',2'-tetrafluoroethoxy)nitrobenzene. 1H-NMR (CDCl3): δ(ppm) 7.10-8.2(3H), 5.59(1H, tt, J=53, 3 Hz)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)c(O)c1
Temperature: 50 °C
Yield: 76.1 %

Procedure:
A solution of ethyl 3-hydroxy-4-nitrophenylacetate (5 g, Reference Example 4) was dissolved in ethanol (approximately 200 mL) was treated with ammonium formate (approximately 20 g). The mixture was warmed to 50° C. and then treated cautiously with palladium on charcoal (approximately Ig, 5%)—effervescence was observed. After 30 minutes the mixture was filtered hot through a pad of celite and the filtrate was concentrated to give the title compound (3.3 g) as a black solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:22])[NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:9]=1)[CH3:6])[CH3:2].[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([O:37][CH2:38][CH3:39])[C:35]=1[F:36])[CH:31]=O)[CH3:26].C(N(C(C)C)C(C)C)C.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:24])[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:22])[NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:31][C:30]3[CH:33]=[C:34]([O:37][CH2:38][CH3:39])[C:35]([F:36])=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=3)[CH2:20][CH2:21]2)[CH:9]=1)([CH3:23])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCN(Cc3cc(OCC)c(F)c(OCC)c3)CC2)c1
Temperature: 50 °C
Yield: 94.2 %

Procedure:
0.33 g (1.0 mmol) of 2-methyl-2-[3-(piperidin-4-ylcarbamoyl)-phenoxy]-propionic acid ethyl ester and 0.23 g (1.10 eq.) of 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), were dissolved under argon in 6 mL of MeOH; 0.39 mL (0.29 g=2.25 eq.) of N-ethyl-diisopropylamine and 0.11 mL (0.12 g=2.0 eq.) of glacial acetic acid were added and the mixture then heated for 2 h at 50° C. After cooling down to rt, 0.16 g (2.5 eq.) of sodium cyanoborohydride was added and the reaction mixture heated again for 1.5 h at 50° C. It was then poured into crashed ice, the pH was adjusted to ˜10 with sodium carbonate solution and the mixture was extracted twice with MeCl2; the organic phases were washed with water, dried over MgSO4, filtered and evaporated i.V. The crude product was purified by chromatography (silicagel, eluent:gradient of MeCl2/MeOH) to yield 0.50 g of the title compound as colorless oil. MS: 531.2 (MH+).
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([CH3:11])=[N:4][CH:3]=1.[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH2:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([CH3:11])=[N:4][CH:3]=1
Reactant: Cc1cc(C(=O)O)c(F)cn1
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: Cc1cc(C(=O)O)c(Nc2ccc(I)cc2F)cn1

Procedure:
5-[(2-fluoro-4-iodophenyl)amino]-2-methylisonicotinic acid was synthesized according to the general procedure of Method 1 as, outlined above, starting with 200 mg (1.29 mmol) of 5-fluoro-2-methylisonicotinic acid, 370 mg (1.55 mmol) of 2-fluoro-4-iodoaniline and two portions of lithium bis(trimethylsilyl)amide (3.35 ml, 3.35 mmol), and (1.55 ml, 1.55 mmol). Yield: 30 mg, 6%, LC/MS [5.5 min; 473 (M+1)]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: BrCc1ccc(Oc2ccccc2)nc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(Oc2ccccc2)nc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 5-(bromomethyl)-2-phenoxypyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 419.25 g/mol.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[OH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:27]5[CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=[C:25]([OH:24])[CH:26]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: OB(O)c1cc(O)cc(C(F)(F)F)c1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cc(O)cc(C(F)(F)F)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 3-hydroxy-5-(trifluoromethyl)phenylboronic acid (Combi-Blocks, San Diego, USA, 27 mg, 0.132 mmol) to give the title compound as a white solid. (HPLC: tR 2.83 min (Method A); M+H=454 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 10.38 (s, br, 1H), 8.98 (s, 1H), 8.18 (s, 1H), 8.12-8.07 (m, 1H), 7.93-7.87 (m, 1H), 7.58-7.53 (m, 1H), 7.21-7.16 (m, 1H), 7.13-7.09 (m, 1H), 7.07-7.03 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 1.93 (s, 3H))
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-:14].[K+].Cl.[Na+].[Cl-]>CS(C)=O.O>[OH:14][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: [OH-]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc(O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Chloro-2-nitrobenzoic acid (100 g) in 800 ml dimethylsulfoxide was treated with 112 g powdered KOH with cooling, 170 ml anhydrous alcohol added and the mixture stirred 2 hours at 25° and then left overnight. The mixture was kept at 28° for about 8 hours, then overnight at 0°, warmed to room temperature and 3.5 liters of water added. The mixture was acidified with HCl, 1 kg NaCl added and extracted with ethyl acetate. The extract was washed with water, dried, 50 g KHCO3 in 500 ml water added, diluted to 2 liters, and the ethyl acetate blown off with a stream of nitrogen. The solution was acidified and filtered to give 56 g product, m.128-30.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:6][C:5]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[CH:20][C:4]=2[NH:3]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>C1COCC1>[CH3:29][S:30]([N:26]1[CH2:25][CH:24]=[C:23]([C:22]#[C:21][C:19]2[CH:18]=[CH:17][C:5]3[N:6]=[C:7]([C:9]4[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=4)[C:12]#[N:13])[CH2:8][C:2](=[O:1])[NH:3][C:4]=3[CH:20]=2)[CH2:28][CH2:27]1)(=[O:32])=[O:31]
Reactant: N#Cc1cccc(C2=Nc3ccc(C#CC4=CCNCC4)cc3NC(=O)C2)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=C(C#Cc2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)CC1
Yield: 57 %

Procedure:
Prepared from 3-[4-oxo-7-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 140) (55 mg, 0.15 mmol) by treatment with methanesulfonyl chloride (0.012 mL, 0.15 mmol) and Et3N (0.021 mL, 0.15 mmol) in THF (3 mL) at 23° C. for 23 h. Obtained as a yellow solid (38 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:17][C:16]4[CH:28]=[CH:29][CH:30]=[N:31][C:15]3=4)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[C:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:17][C:16]4[CH:28]=[CH:29][CH:30]=[N:31][C:15]3=4)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(-c2cccc(-n3c(=O)c(Cc4ccccc4)nc4cccnc43)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(-c2cccc(-n3c(=O)c(Cc4ccccc4)nc4cccnc43)c2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 4-[3-(4-aminophenyl)phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (95 mg) and triethylamine (0.05 ml) in dichloromethane (3 ml) was added benzoyl chloride (0.03 ml). The mixture was stirred at room temperature for 20 minutes, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from methanol to give 4-[3-(4-benzoylaminophenyl)phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (73 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12][CH2:13][CH2:14][CH2:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][S:16]([CH2:15][CH2:14][CH2:13][Cl:12])(=[O:18])=[O:17]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: O=S(=O)(Cl)CCCCl
Solvent: c1ccncc1
Product: Cc1cc([N+](=O)[O-])ccc1NS(=O)(=O)CCCCl

Procedure:
A solution of 5.51 g (36.2 mmol) of 2-methyl-4-nitroaniline and 6.41 g (36.2 mmol) of 3-chloropropanesulfonyl chloride in 20 ml of pyridine is stirred overnight at room temperature. The reaction mixture is then poured onto ice. The precipitate which deposits in the process is filtered off with suction and dried, giving N-(2-methyl-4-nitrophenyl)-3-chloropropane-1-sulfonamide as a yellowish solid; ESI 293.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([C:13]1[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:20](Cl)(=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.ClCCl>O>[CH2:6]([C:13]1[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[C:17]=1[C:20]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:29])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cc(Cc2ccccc2)sc1C
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
Tin tetrachloride (4.6 mL, 71.76 mmol) was added dropwise over a 10 minute period to a stirred, −78° C. solution of 2-benzyl-4,5-dimethylthiophene (6.6 g, 32.62 mmol), anisoyl chloride (5.90 g, 34.6 mmol) and dichloromethane (120 mL) under a dry nitrogen atmosphere. After 5 hours at −78° C., the reaction mixture was slowly warmed to room temperature over a 2 h period. The reaction mixture was added to water and extracted with ether. The ether extract was washed with sat. aq. sodium bicarbonate and brine. The solvent was removed and the resultant solid was triturated with ether to give the title compound as a off-white solid (9.62 g, 88%): mp 85-86° C.: NMR (CDCl3); δ7.80 (ddd, J=8, 8, 1 Hz, 2H), 7.24-7.10 (m, 5H), 7.92 (ddd, J=8, 8, 1 Hz, 2H), 3.93 (s, 2H), 3.88 (s, 3H), 2.28 (s, 3H), 1.90 (s, 3H); MS (EI): 336 (100%, MI); Anal. Calc. for C21H20O2S: C, 74.97; H, 5.99; N, 0.00. Found: C, 75.11; H, 6.02; N, 0.05.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>C(OCC)(=O)C>[ClH:21].[Br:20][C:17]1[CH:18]=[CH:19][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Brc1ccc(C2CCNCC2)cc1
Reaction time: 5 h
Yield: 98 %

Procedure:
To a solution of furnished 4-(4-bromophenyl)-piperidine-1-carboxylic acid tert-butyl ester (1114 mg, 3.27 mmol) in ethyl acetate (1 mL) was added 4 N hydrogen chloride in ethyl acetate (2 mL) at room temperature. After stirring for 5 h, solvent was removed in vacuo, and the resulting solid was washed with ethyl acetate and dried in vacuo to afford (4-(4-bromophenyl)-piperidine hydrochloride (884 mg, 98%) as a white solid.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19][CH2:20][C:21]2[NH:36][C:24]3=[N:25][CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=4)[CH:28]=[C:23]3[N:22]=2)[CH:14]=1>N1C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19][CH2:20][C:21]2[NH:36][C:24]3=[N:25][CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([NH:35][S:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:9])=[O:8])=[CH:31][CH:30]=4)[CH:28]=[C:23]3[N:22]=2)[CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccnc(CCc2nc3cc(-c4ccc(N)cc4)cnc3[nH]2)c1
Solvent: c1ccncc1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(NS(=O)(=O)c5ccccc5)cc4)cnc3[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.047 ml of benzene sulfonyl chloride are added to 0.115 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-(4-aminophenyl)-3H-imidazo[4,5-b]pyridine (example 27) in 1 ml of pyridine and the mixture is stirred at ambient temperature for three hours. The solvent is evaporated in vacuo and the residue is is chromatographed on a silica gel column (dichloromethane/methanol 30–20:1+1% triethylamine). Concentration of the chromatographically pure fractions and drying gives 0.093 g of the title compound as a solid of m.p. 251–253° C. The mass spectrum shows the molecular peak MH+ at 486.3 Da.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].O1CCCC1.C([Li])CCC.C([O:20][C:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])C>C(O)(=O)C>[O:20]=[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCCCCCCCCCC(=O)OCC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)CP(=O)(OC)OC
Reaction time: 0.5 h

Procedure:
84 g. of dimethyl methylphosphonate were dissolved in 400 ml. of tetrahydrofuran and cooled to -60°C. Under an atmosphere of nitrogen, n-butyllithium (prepared from 14 g. of lithium, 116 g. of n-butyl bromide and 510 ml. of diethyl ether) was added dropwise to the solution while maintaining the temperature below -50°C. and then stirred for 30 minutes. To the solution thus obtained, 38 g. of lauric acid ethyl ester in 140 ml. of tetrahydrofuran were added at below -55°C. and stirred for 16 hours. The reaction mixture was then neutralized with acetic acid, concentrated, dissolved in a small amount of water and extracted with diethyl ether. The extracts were washed with water, dried, concentrated and distilled to give 50 g. of the title compound having the following physical characteristic:
Reaction SMILES: [OH:1][C@H:2]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[O:1]=[C:2]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6]
Reactant: CCOC(=O)[C@H](CC(=O)OC(C)(C)C)[C@H](O)C(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)C(=O)OCc1ccccc1

Procedure:
1.5 0 g of 1-benzyl 3-tert-butyl 2-ethyl (1S,2R)-1-hydroxy-1,2,3-propanetricarboxylate in 30 ml of chloroform was stirred with 2.35 g of the Dess-Martin reagent (periodinane) at room temperature for 1.5 hours. The reaction solution was poured into a mixture of saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium thiosulfate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=9/1] to give 1.37 g of the title compound as a colorless oily substance
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:6]1([CH2:5][C:4]2[CH:3]=[C:2]([CH:14]=[CH:13][CH:12]=2)[O:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: N#CCCCCCBr
Reactant: Oc1cccc(CN2CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCCCCCOc1cccc(CN2CCCCC2)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N-(3-Hydroxybenzyl)piperidine (9.55 g) was heated with 6-bromohexanenitrile (10.2 g) and potassium carbonate (13.8 g) under reflux in acetone (150 ml) for 66 hours. The reaction mixture was cooled and filtered. The solvent was removed by evaporation and the residue was heated with stirring at 100° C. for one hour to remove unreacted 6-bromohexanenitrile and to yield 6-(3-piperidinomethylphenoxy)hexanenitrile as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:20](O)[CH3:21]>>[OH:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH2:20][CH3:21])=[O:8])[CH2:5][CH2:4]1
Reactant: O=C(O)CC1(CO)CC1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CC1(CO)CC1

Procedure:
7.1 g of crude (13) product was dissolved in 150 ml of ethanol. 1 ml of concentrated sulfuric acid was added and the solution was stirred at reflux for 2 hours. 50 ml of saturated aqueous sodium bicarbonate was added to the cooled mixture and the mixture was extracted twice with 100 ml of dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was distilled at 100° C. at a reduced pressure affording a slightly yellow liquid (3.2 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(C2CCNCC2)cc1
Solvent: c1ccncc1
Product: CC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a solution of 4-piperidin-4-yl)-benzoic acid (102 mg, 0.5 mmol, reference example 109) dissolved in pyridine (2 mL) was added acetic anhydride (255 mg, 2.5 mmol) and the reaction stirred overnight at room temperature. The reaction was concentrated in vacuo and residual pyridine partially removed by azeotroping with dichloromethane/methanol 1:1. The crude product was then washed with dichlormethane and the solvent decanted to yield a white solid residue (61 mg, 49%) 4-(1-acetyl-piperidin-4-yl)-benzoic acid. 1H NMR (CD3OD): δ 7.89 (d, 2H); 7.27 (d, 2H); 4.65 (d, 1H); 4.03 (d, 1H); 3.21 (dt, 2H); 2.68-2.88 (m, 2H); 1.93 (s, 3H); 1.85-2.04 (m, 2H); 1.50-1.75 (m, 3H). MS m/z 248 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.ClCCl>COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[Pd]Cl>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11][CH3:12])[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1-c1cccc(Cl)c1
Yield: 92 %

Procedure:
To a flask containing a bi-phasic mixture of 2-bromo-4-nitroanisole (15.0 g, 64.6 mmol) and 3-chlorophenylboronic acid (12.1 g, 77.6 mmol) in ethylene glycol dimethyl ether (187.5 mL) and 2.0 N aqueous cesium carbonate (97 mL) was added 1-1′-bis(diphenylphosphino)ferrocene)dichloro palladium (II), complex with dichloromethane (1:1) (1.5 g). The mixture was heated at reflux for 4 hours under a nitrogen atmosphere. The crude reaction mixture was partitioned between ethyl acetate (350 mL) and brine (250 mL) and then filtered through a Buchner funnel. Layers were separated and the organic layer was washed with brine (250 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to a dark oil. The crude residue was purified by flash chromatography on silica gel using dichloromethane as the eluent to afford 2-(3-chlorophenyl)-4-nitroanisole as a yellow solid (13.9 g, 59.4 mmol).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1>CO.Cl.[Pd]>[F:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncccc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ncccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.5 %

Procedure:
The mixture of 3-fluoro-pyridine-2-carbonitrile (0.81 g, 6.63 mmol) and Pd/C (0.20 g, 10% wt) in 10 ml of MeOH and 2.7 ml of concentrated HCl was placed under H2 which was provided by a balloon and stirred at RT for 4 h, filtered through Celite®, condensed, the residue was purified by flash column chromatography, 0.13 g of the titled compound was obtained as a light yellowish oil. MS (ES+): 127.1 (M+H)+. Calc'd for C6H7FN2—126.13.