Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH:10]=[CH2:11].Cl>C1COCC1.CCOCC>[CH2:11]([C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1)[CH:10]=[CH2:9]
Reactant: Brc1ccc(Br)cc1
Reactant: C=CCBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Mg (8.76 g, 360 mmol) is suspended in THF (90 mL) under nitrogen in a three-necked flask equipped with a condenser and a dropping funnel. The dropping funnel is filled with 1,4-dibromobenzene (77.3 g, 327 mmol) in THF (40 mL). About 5% of the 1,4-dibromobenzene sol. is added carefully to the Mg-suspension and the reaction is started with the help of a heat gun. When the reaction starts, the 1,4-dibromobenzene sol. is added to such a speed so that the reaction mixture is refluxing gently (about 20 min). The mixture is stirred for further 30 min, and is cooled to 0° C. THF (100 mL) is added and the dropping funnel is filled with a sol. of allyl bromide (30.5 mL, 360 mmol) in THF (50 mL). The allyl bromide sol. is added slowly, maintaining the reaction temperature below 20° C. When the addition is complete, the mixture is stirred for further 30 min, while being cooled to 0° C. Aq. 1M HCl is added. The mixture is diluted with Et2O, and washed with aq. 1M HCl and brine. The combined aq. extracts are extracted back with Et2O. The combined org. extracts are dried over MgSO4, filtered, and the solvents are removed under reduced pressure. Distillation of the residue (11 mbar, 88-92° C.) yields the title compound (39.3 g, about 61%), together with another, unidentified impurity.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].P([O-])([O-])([O-])=[O:10].[K+].[K+].[K+]>>[C:1]([NH2:2])(=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: N#Cc1cccnc1
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC(=O)c1cccnc1
Yield: 97.3 %

Procedure:
The reaction was carried out in a reaction mixture (30 ml), comprising 500 mM 3-cyanopyridine, 40 mM potassium phosphate buffer (pH 7.0) and resting cells (dry weight 2.3 mg). During the reaction, 3-cyanopyridine (500 mM) was added 7 times as soon as it was consumed. In this manner, 4.0 M 3-cyanopyridine was added in the course of 15 h and 3.89 M (475 g/l) nicotinamide was formed, corresponding to a yield of 97.3%. Nicotinic acid was not formed.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:17]2[C:12](=[C:13]([OH:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:19]([OH:21])=[O:20].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:20][C:19]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]=1[O:7][CH2:19][C:9]1[CH:10]=[CH:11][CH:12]=[CH:17][CH:8]=1)=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc2c(O)cccc2c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc2c(OCc3ccccc3)cccc2c1OCc1ccccc1

Procedure:
K2CO3 (2.45 g, 17.7 mmol), Dry DMF (5.4 mL), 1,5-Dihydroxy-naphthalene-2-carboxylic acid (0.539 g, 2.64 mmol), benzyl chloride (1.5 mL) Yield: 0.68 g of product (54%, 2 steps) Rf=0.38 (SiO2, 15% Hexanes/CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 5.12 (s, 2H), δ 5.25 (s, 2H), δ 5.40 (s, 2H), δ 6.98 (d, J=7.3 Hz, 1H), δ 7.30-7.53 (m, 16H), δ 7.83 (d, J=8.7 Hz, 1H), δ 7.89 (d, J=8.7 Hz, 1H), δ 8.14 (d, J=8.7 Hz, 1H).
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([N:19]1[CH2:24][CH2:23][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:4]([O:3][C:1]([N:19]1[CH2:24][CH2:23][C:22]([N:25]([CH3:27])[CH3:26])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:21][CH2:20]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN(C)C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)C1(c2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
500 ml (10 eq) Cbz chloride were added dropwise to 50 g (1 eq) 1-benzyl-N,N-dimethyl-4-phenylpiperidin-4-amine over a period of 1 h and the reaction mixture obtained was stirred for 2 h at room temperature. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCl3). Once the conversion was complete, the reaction mixture was cooled to 0° C., made alkaline with saturated sodium hydrogen carbonate solution and extracted 3 times with 300 ml EtOAc. The combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 50% EtOAc/heptane). 12 g (21%) of product were obtained in the form of an oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[C:20]([CH3:21])=[CH:19][NH:18][N:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[C:20]([CH3:21])=[CH:19][NH:18][N:17]=1
Reactant: Cc1c[nH]nc1I
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1c[nH]nc1C#Cc1c(-c2ccccc2)noc1C
Yield: 53 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (73 mg, 0.40 mmol) was converted [using 3-iodo-4-methyl-1H-pyrazole (prepared according to Liebigs Ann. Chem. 595, 200, 1955) instead of 2-chloro-4-iodopyridine] to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 56 mg, 53%) which was obtained as a light brown solid. MS: m/e=264.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:22])([CH3:21])[C:19]#[N:20].[CH:23]1([CH:26]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH2:39]O)[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[C:19]([C:18]([CH3:22])([CH3:21])[CH2:17][C:11]1[CH:12]=[C:13]([O:16][CH2:39][C:35]2[CH:34]=[C:33]([CH:26]([CH:23]3[CH2:24][CH2:25]3)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:38]=[CH:37][N:36]=2)[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])#[N:20]
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C#N)c1
Reactant: CCOC(=O)CC(c1ccnc(CO)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C#N)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a solution of 3-(2′-fluoro-4-hydroxy-5′-methoxybiphenyl-2-yl)-2,2-dimethylpropanenitrile (151 mg), ethyl 3-cyclopropyl-3-(2-(hydroxymethyl)pyridin-4-yl)propanoate (168 mg) and tributylphosphine (0.25 mL) in toluene (5.0 mL) was added 1,1′-(azodicarbonyl)dipiperidine (256 mg), and the mixture was stirred at room temperature for 3 hr. Hexane was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (234 mg) as a colorless oil.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1)(C)(C)C.[OH-].[Na+]>Cl>[NH2:14][C@@H:12]([C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=1)[CH3:13]
Reactant: C[C@@H](N)c1ccc(OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](N)c1ccc(O)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
(R)-1-(4-tert-Butoxyphenyl)ethylamine (89.4 g, 0.463 mol) was dissolved in 10% hydrochloric acid (200 ml) and heated to 85° C. At approx. 80° C., vigorous gas evolution set in. The mixture was stirred at 85° C. for another three hours, after which the gas evolution had stopped. The pale yellow mixture was allowed to cool to room temperature and then 20% NaOH was added dropwise up to a pH of 10.2. The deprotected phenol precipitated out overnight in the form of a pale yellow powder. It was filtered off with suction and dried in a drying cabinet overnight. For purification, the crude product was digested with tert-butyl methyl ether (200 ml). The suspension was filtered and the filter residue was dried again under reduced pressure. 51.3 g (63%) of (R)-4-(1-aminoethyl)phenol were obtained in the form of a pale yellow powder.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31](O)=[O:32])[CH:20]=[C:19]1[CH:34]1[CH2:36][CH2:35]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(O[N:41]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)N)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C@H:21]([C:31](=[O:32])[NH2:41])[CH:20]=[C:19]1[CH:34]1[CH2:35][CH2:36]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:7])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-4-cyclopropyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 267, 2.33 g, 4.45 mmol) following the procedure described for Intermediate 20. The desired product was obtained as a tan foam (1.47 g, 63%).
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12].OS(O)(=O)=O.[CH3:18]O>>[CH3:18][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([OH:11])[C:2]([Br:1])=[C:3]([OH:12])[CH:4]=1
Reactant: O=C(O)c1cc(O)c(Br)c(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)c(Br)c(O)c1
Yield: 100 %

Procedure:
To a solution of 4-bromo-3,5-dihydroxybenzoic acid (13.89 g, 59.6 mmol) in methanol (50 mL) was added H2SO4 (concentrated, 1 mL). The reaction mixture was heated to reflux overnight. The mixture was quenched with H2O (500 mL) and extracted with 10% MeOH in CH2Cl2 (5×500 mL), dried over MgSO4 and concentrated in vacuo to give a white solid (14.8 g, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 2 H) 7.00 (s, 2 H) 3.80 (s, 3 H); LCMS for C8H7BrO4 m/z 249.10 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:17][O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[CH:21]=[N+:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:17][O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[CH:21]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccccc1C=[N+]1CCCC1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [Cl-]
Product: COc1ccccc1C(c1c(-c2ccccc2)[nH]c2ccccc12)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-phenyl-1H-indole and 1-(2-methoxy-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 24.
Reaction SMILES: [ClH:1].C([O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[NH:10][C:11]=1[CH3:12])(C)C.Cl>O>[ClH:1].[OH:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[NH:10][C:11]=1[CH3:12]
Reactant: COc1ccc(-c2nc(COC(C)C)c(C)[nH]2)cc1
Agent: Cl
Solvent: O
Product: COc1ccc(-c2nc(CO)c(C)[nH]2)cc1
Reaction time: 4 h
Yield: 94.6 %

Procedure:
A mixture of 4-isopropoxymethyl-2-(p-methoxyphenyl)-5-methylimidazole hydrochloride (48.9 g, 0.164 mole) in 500 ml of water is stirred and refluxed. To this mixture is added 50 ml of concentrated hydrochloric acid and stirring and refluxing are continued for 4 hrs. The mixture is then chilled and filtered to give about 39.5 g (94%) of 4-hydroxymethyl-2-(p-methoxyphenyl)-5-methylimidazole hydrochloride which is recrystallized from isopropyl alcohol, m.p. 146°-148° C (dec.). Treatment with alkali (e.g., NaOH) affords the corresponding base form.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1>>[Cl:1][C:2]1[C:3]2[O:10][C@@H:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][C@@H:12]3[CH2:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C1=Cc2ccccc2C1
Reactant: OCc1cccc(Cl)c1O
Product: Clc1cccc2c1O[C@@H]1c3ccccc3C[C@@H]1C2

Procedure:
3-Chloro-2-hydroxybenzyl alcohol (20.0 g) (prepared by the method of Zincke, Hanus and Ziegler, J.Prakt. Chem., (2), 152 126(1939)), and indene (15 ml) were heated together at 190°-200° for 2.5 hr. The crude product was chromatographed on silica gel, eluting with toluene/60°-80° petroleum ether to yield a colourless oil (2.34 g) which was distilled in vacuo to give an oil which crystallised on standing (1.70 g., b.pt. 115°-120°/0.05 mmHg m.pt. 60°-63°). The recrystallised product, from ethanol was identified, by 1H-n.m.r., as cis-6-chloro-4b,10,10a,11-tetrahydrobenz(b)indeno(2,1-e) pyran, (1.20 g., m.pt-63°-65°).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C1CN([P+](O[N:37]2[N:45]=[N:44][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C1(C)C=CC(S(N2C=CC([C@@H](N)CC)=N2)(=O)=O)=CC=1>CN(C=O)C.O>[NH:45]1[CH:42]=[CH:43][C:38]([C@@H:39]([NH:44][C:17]([C:16]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:19])[CH2:40][CH3:41])=[N:37]1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC[C@H](N)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1cc[nH]n1
Reaction time: 0.5 h

Procedure:
To a room temperature solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (185 mg, 0.800 mmol) in DMF was added PyBOP (360 mg, 0.72 mmol) and Et3N (152 mg, 1.50 mmol). After 30 minutes, (S)-1-[1-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-propylamine (201 mg, 0.720 mmol) was added. After 3 hours, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by reversed-phase HPLC. The major fractions were combined and the solvent was removed in vacuo to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[N:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[N:12][C:22]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:23])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=NC(=O)N1CCOCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
100 mg (0.5 mmol) (RS)—S-(4-nitrophenyl)-S-methylsulphoximide in 4 ml dimethylformamide are treated at room temperature with 23.97 mg sodium hydride (55%, 0.55 mmol). The mixture is stirred for 30 minutes at room temperature and for 30 minutes at 50° C. After cooling to room temperature 0.063 ml (0.55 mmol) 4-morpholinylcarbonyl chloride are added. The mixture is stirred for 30 minutes at room temperature and for 2 hours at 50° C. and finally quenched with methanol. After chromatographic purification (silica gel, hexane/ethyl acetate (0-50% ethyl acetate)), 87 mg (0.28 mmol, corresponding to 56% of theor.) of the desired product is obtained.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1)(=O)=O.O[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:29]=[C:28]([C:30]#[N:31])[C:27]3[N:32]=[CH:33][N:34]([CH3:35])[C:26]=3[CH:25]=2)=[CH:20][C:19]=1[C:36]([F:39])([F:38])[F:37].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:30]([C:28]1[C:27]2[N:32]=[CH:33][N:34]([CH3:35])[C:26]=2[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][C:18]([O:5][CH2:6][C:7]3[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=3)=[C:19]([C:36]([F:39])([F:38])[F:37])[CH:20]=2)[N:29]=1)#[N:31]
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(O)c(C(F)(F)F)c3)cc21
Reactant: COC(=O)c1cccc(COS(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cccc(COc2ccc(-c3cc4c(ncn4C)c(C#N)n3)cc2C(F)(F)F)n1
Temperature: 80 °C
Yield: 78.8 %

Procedure:
A mixture of methyl 6-((methylsulfonyloxy)methyl)picolinate (733 mg), 6-(4-hydroxy-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (950 mg), sodium iodide (44 mg) and potassium carbonate (830 mg) in acetonitrile (20 ml) was heated at 80° C. for 14 hours. After cooling to room temperature, water (30 ml) was added, the white precipitate was collected by filtration and washed with cold methanol (20 ml) to give methyl 6-((4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)methyl)picolinate (1.1 g). 1H NMR (DMSO) δ: 8.81 (s, 1H), 8.71 (s, 1H), 8.53 (m, 2H), 8.20 (m, 1H), 8.11 (m, 1H), 7.83 (d, 1H), 7.63 (d, 1H), 5.60 (s, 2H), 4.06 (s, 3H), 3.98 (s, 3H). MS m/z 468 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([NH2:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[CH2:27]([O+](CC)CC)[CH3:28]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17](=[NH:19])[O:18][CH2:27][CH3:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: CC[O+](CC)CC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCOC(=N)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.4 %

Procedure:
(2S)-1-[(4-Fluorophenyl)sulfonyl]-2-piperidinecarboxamide (286 mg) [see Preparation 40] was added to a solution of triethyloxonium hexafluorophosphate (304 mg) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 18 hours after which time the mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulphate and the solvent was removed under reduced pressure to afford ethyl (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboximidate (290 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([Cl:16])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)c(Br)c1Cl
Product: O=C(Cl)c1cc(F)c(F)c(Br)c1Cl

Procedure:
A solution of 3-bromo-2-chloro-4,5-difluorobenzoic acid (9.0 g) in thionyl chloride (33 ml) was refluxed for 2.5 hours, and then concentrated. The resulting residue was purified by distillation to give the title compound (8.8 g), bp 109° C./22 mmHg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:23][CH:24]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Reaction time: 0.17 h
Yield: 29.2 %

Procedure:
To a solution of methyl 4-[3-(benzyloxy)phenyl]benzoate (1.2 g) in tetra hydrofuran (20 mL) was added lithium aluminum hydride (0.21 g) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes, and stirred at room temperature for 2 hours. To the reaction mixture was added ethyl acetate (10 mL), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was acidified by addition of 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-2/1) to give 4-[3-(benzyloxy)-phenyl]benzyl alcohol (0.32 g). This material was dissolved in ethyl acetate (4 mL). To the solution was added triethylamine (0.20 mL). To the mixture was added methanesulfonyl chloride (0.094 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The insoluble material was removed by filtration. To the filtrate were added ethyl acetate (6 mL) and lithium bromide monohydrate (0.58 g), and the mixture was stirred at 55° C. for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1) to give the title compound (0.36 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([C:12]([O:14]C)=[O:13])=[CH:9][CH:8]=2)[O:4][N:3]=1.Cl>[OH-].[Na+].C(O)C>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=2)[O:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2nc(C)no2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1noc(-c2ccc(C(=O)O)s2)n1
Temperature: 65 °C
Yield: 85 %

Procedure:
A mixture of methyl 5-(3-methyl-1,2,4-oxadiazol-5-yl)-2-thiophenecarboxylate, prepared according to Example 81, (1.09 g, 4.86 mmole) in 35 ml of 2N sodium hydroxide was diluted with 5 ml of ethanol and warmed to 65° C. for thirty minutes. The solution was cooled in an ice bath and acidified to pH 2 with concentrated hydrochloric acid. Filtration and drying furnished 870 mg (85% yield) of the title compound as an off-white solid. The analytical sample was recrystallized from methanol, m.p. 226°-8° C. Analysis: Calculated for C8H6N2O3S: C, 45.70; H, 2.88; N, 13.33%. Found: C, 45.57; H, 2.75; N, 13.37%. EIMS (m/z): 210 (M+, base) and 153 (M+ --C2H3NO, 99%); 1H-NMR (DMSO-d6) delta, 7.97 (1H, d, J 3.9 Hz), 7.82 (1H, d, J=3.9 Hz) and 2.40 (3H, s); ir (potassium bromide): 3112 (br), 1699, 1289, 1112 and 840 cm-1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C:11]1[C:12]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:13][C:14]2[O:18][C:17]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:16][C:15]=2[C:23]=1[C:24]([CH3:27])([CH3:26])[CH3:25])(=O)C.O.[OH-].[Na+]>O1CCCC1>[C:24]([C:23]1[C:15]2[CH2:16][C:17]([CH2:19][CH3:20])([CH2:21][CH3:22])[O:18][C:14]=2[CH:13]=[C:12]([C:28]([CH3:29])([CH3:31])[CH3:30])[C:11]=1[OH:10])([CH3:25])([CH3:27])[CH3:26]
Reactant: CCC1(CC)Cc2c(cc(C(C)(C)C)c(OC(C)=O)c2C(C)(C)C)O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(CC)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
Lithium aluminum hydride (76 mg) was suspended in tetrahydrofuran (5 ml) under a nitrogen atmosphere. A solution of 5-acetoxy-4,6-di-tert-butyl-2,2-diethyl-2,3-dihydrobenzofuran (0.17 g, 0.5 mmol) in tetrahydrofuran (5 ml) was added dropwise to the suspension. After heating under reflux for 3 h, the reaction mixture was cooled to room temperature and water was added dropwise. After addition of 1N aqueous sodium hydroxide (5 ml), the mixture was subjected to extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 4,6-di-tert-butyl-2,2-diethyl-5-hydroxy-2,3-dihydrobenzofuran [130 mg (yield, 87%)] as a pale yellow oil.