Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[NH2:12]>C(O)=O.CO>[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[N:12]=[CH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1cccc(C)c1N
Solvent: CO
Solvent: O=CO
Product: Cc1cccc(C)c1N=Cc1ccccn1
Reaction time: 5 h

Procedure:
A mixture of 2-pyridine-carboxaldehyde (10 ml, 0.1 mole), 2,6-dimethylaniline (12.9 ml, 0.1 mole), 3 drops of formic acid and 30 ml methanol was stirred for five hours. The methanol was removed under vacuum. An oil-like residue was recrystallized from n-hexane. 2-(N-(2,6-dimethylphenyl)-iminomethyl)-pyridine was isolated as yellow crystals. Yield: 13.6 g (62%). 1H NMR (200 MHz; CDCl3; δ, ppm; J, Hz): 2.17 s (6H, CH3), 6.94-7.12 m (3H, C6H3), 7.39 d,d,d (1H, H(5) 3J4,5=7.5, 3J5,6=4.9, 4J3,5=1.3); 7.83 t,d,d (1H, H(4) 3J=7.7, 4J4,6=1.8, 5J=0.6); 8.28 d,t (1H, H(3) 3J3,4=7.9, J=1.1); 8.35 s (1H, HC═N); 8.71 d,d,d (1H, H(6) 3J5,6=4.9, 4J4,6=1.6, 5J3,6=1.0). 13C NMR, DEPT (50 MHz; CDCl3; δ, ppm): 18.3 (CH3), 121.2 (C(3)H), 124.0 (C(4′)H), 125.3 (C(5)H), 126.8 (C(2′,6′)), 128.1 (C(3′,5′)H), 136.7 (C(4)H), 149.6 (C(6)H), 150.3 (C(1′)), 154.4 (C(2)), 163.4 (HC═N).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:17][N:18]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:27])[C:21]=2[CH:20]=[N:19]1.N1C2C=CC=C(N)C=2C=N1>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][NH:9][C:10]([NH:27][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[CH:20]=[N:19][N:18]2[CH3:17])=[O:11]
Reactant: Cn1ncc2c(N)cccc21
Reactant: O=C=NCc1ccc(N2CCCC2)c(F)c1
Agent: Nc1cccc2[nH]ncc12
Product: Cn1ncc2c(NC(=O)NCc3ccc(N4CCCC4)c(F)c3)cccc21

Procedure:
The title compound was prepared using the procedure described in Example 89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]pyrrolidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) δ 8.98 (s, 1H), 8.18 (s, 1H), 7.63 (d, 1H), 7.12 (t, 1H), 7.10 (m, 2H), 7.01 (m, 2H), 6.75 (t, 1H), 4.22 (s, 2H), 3.99 (s, 3H), 3.30 (m, 4H), 1.89 (m, 4H); MS (ESI) (M+H)+368.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][C:8]([C:11]([NH:13][NH2:14])=[O:12])=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1.[C:15](OCC)(OCC)(OCC)[CH3:16].N12CCCN=C1CCCCC2>C(O)CCC>[Br:1][C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:12][C:15]([CH3:16])=[N:14][N:13]=3)=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNC(=O)c1ccc2occ(Br)c2n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCCCO
Product: Cc1nnc(-c2ccc3occ(Br)c3n2)o1
Yield: 22.9 %

Procedure:
A solution of 3-bromofuro[3,2-b]pyridine-5-carbohydrazide (0.16 g, 0.64 mmol) and triethyl orthoacetate (0.26 mL, 1.40 mmol) in n-butanol (3 mL) was heated under reflux for 1 hr. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.096 mL, 0.64 mmol) was added to the reaction mixture, and the resulting mixture was heated under reflux overnight. After cooling, the precipitate was collected by filtration, purified by silica gel column chromatography (hexane/ethyl acetate=3/1), and recrystallized from hexane/ethyl acetate to give the title compound (41 mg, yield 23%) as colorless crystals.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[F:13][C:14]1[C:15]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:16][C:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[N:18][CH:19]=1>C(Cl)Cl.CN(C=O)C>[C:33]([N:30]1[CH2:31][CH2:32][N:27]([C:24]2[CH:25]=[CH:26][C:21]([NH:20][C:17]3[N:16]=[C:15]([N:36]4[CH2:37][CH2:38][N:39]([C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:40][CH2:41]4)[C:14]([F:13])=[CH:19][N:18]=3)=[CH:22][CH:23]=2)[CH2:28][CH2:29]1)(=[O:35])[CH3:34]
Reactant: N#CCC(=O)O
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCNCC4)n3)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCN(C(=O)CC#N)CC4)n3)cc2)CC1
Reaction time: 0.83 h
Yield: 63.9 %

Procedure:
To a suspension of cyanoacetic acid (85 mg, 1.00 mmol) in CH2Cl2 (2 mL) (containing 2 drops of DMF) at room temperature, oxalyl chloride (0.082 mL, 0.94 mmol) was added. Gas evolved and suspension became clear. It was then stirred for 50 min. To the above solution cooled in an ice bath, a solution of 1-(4-(4-(5-fluoro-4-(piperazin-1-yl)pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (23 mg, 0.057 mmol) and TEA (0.400 mL, 2.87 mmol) in DMF (1 mL) was added drop wise. The mixture was then stirred at room temperature for 90 min. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (17 mg). MS 467.5 (M+H); UV 201.0, 269.4 nm
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[CH2:6]Cl.[Na+].[CH3:15][S:16]([O-:18])=[O:17].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][S:16]([CH3:15])(=[O:18])=[O:17])[CH:8]=[CH:9][C:10]=1[NH2:11]
Reactant: COc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(CS(C)(=O)=O)ccc1N
Temperature: 80 °C
Yield: 83.4 %

Procedure:
To a solution of 3-methoxy-4-nitrobenzyl chloride (2.76 g, 13.7 mmol) in 20 mL of absolute ethanol was added methanesulphinic acid sodium salt (1.0 g, 27.4 mmol). The reaction was heated to 80° C. for 16 h. The reaction was cooled to room temperature and poured into water and the aqueous layer was extracted with ethyl acetate. Combined organics were dried over anhydrous MgSO4, filtered, concentrated onto silica gel and purified by flash chromatography with ethyl acetate/hexanes as the eluent. The fractions containing the desired product were concentrated to dryness, then redisolved in absolute ethanol and 10% Palladium on carbon (500 mg) was added and the reaction was placed on the Fischer-Porter hydrogenation apparatus and treated with 50 psi of H2 gas overnight to afford 2-(methyloxy)-4-[(methylsulfonyl) methyl]aniline (2.46 g, 83%). 1H NMR (400 MHz, CDCl3) δ ppm 6.80 (d, J=1.7 Hz, 1H), 6.68 (d, J=8.0, 1.6 Hz, 1H), 6.57 (d, J=8.1, 1H), 4.82 (s, 2H), 4.21 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][C:12]=2[Cl:17])=[N:6][CH:7]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ncc(Br)cn2)c(Cl)c1
Yield: 78.9 %

Procedure:
Into a flask, 10.0 g of 5-bromo-2-chloropyrimidine, 7.42 g of 4-amino-2-chlorophenol, 14.26 g of potassium carbonate and 100 ml of dimethylsulfoxide were introduced, and reacted in a nitrogen atmosphere at 120° C. for 2.5 hours under stirring. After the completion of the reaction, the product was poured into water, and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then purified by silica gel column chromatography, whereby 12.26 g of oily 4-(5-bromo-2-pyrimidinyloxy)-3-chloroaniline was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[CH:11]=2)=O)[CH:6]=[C:5]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:4]=[CH:3]1.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]([C:5]2[CH:6]=[C:7]3[C:2](=[CH:3][CH:4]=2)[NH:1][C:33](=[O:35])[CH:34]=[C:8]3[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[CH:11]=2)=[O:25])=[CH:23][CH:22]=1
Reactant: NC1C=CC(C(=O)c2ccc(Cl)cc2)=CC1C(=O)c1cccc(I)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(I)c3)c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
[6-Amino-3-(4-chloro-benzoyl)-cyclohexa-2,4-dienyl]-(3-iodo-phenyl)-methan-one (60 g, 130 mMol) was dissolved in anhydrous toluene (450 mL) under an atmosphere of dry N2. To this solution was added 180 mL of triethylamine (NEt3), 50 mL of acetic anhydride (AC2O) and 1.60 g (13.0 mMol) of 4-dimethylaminopyridine (DMAP). The reaction mixture was then heated to reflux and stirred at this temperature for 20 hours. The reaction mixture was cooled to ambient temperature and the precipitate was collected via suction filtration. The solid was washed with ethyl ether (Et2O) and dried under vacuum to give of the titled compound (63 g) which was used without further purification.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C([N-]C(C)C)(C)C.[Li+].[C:15]12([C:25](Cl)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.C([O:32]C)(C)(C)C>O1CCCC1>[C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:15]12([C:25]([OH:26])=[O:32])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COC(C)(C)C
Agent: C=C(C)C(N)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)C12CC3CC(CC(C3)C1)C2
Reaction time: 0.17 h

Procedure:
90.0 g of methacrylamide was dissolved in 1,350 g of tetrahydrofuran (THF), and 944 mL of a 1.12 mol/L lithium diisopropylamide (LiDA) solution was dropwise added thereto at 5° C., followed by stirring for 10 minutes. Subsequently, 900 g of THF having 231.1 g of 1-adamantanecarbonyl chloride dissolved therein was added thereto, followed by stirring at 5° C. for 18 hours. After completion of the reaction, THF and t-butylmethylether (TBME) were added thereto, followed by washing with a 1 wt % aqueous hydrochloric acid solution and pure water, and concentration under reduced pressure. n-hexane was added to the obtained solution, and crystallization was conducted at 5° C., followed by filtration. The obtained solid was dried under reduced pressure, thereby obtaining 194.4 g of 1-adamantanecarboxylic acid methacrylamide (compound (51)).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[CH3:11][C:12]1([CH3:23])[C:20]2[C:15](=[C:16]([NH2:21])[CH:17]=[CH:18][CH:19]=2)[CH:14]([CH3:22])[CH2:13]1.O>C(Cl)Cl>[CH3:11][C:12]1([CH3:23])[C:20]2[C:15](=[C:16]([NH:21][C:8]([C:4]3[S:3][C:2]([Cl:1])=[N:6][C:5]=3[CH3:7])=[O:10])[CH:17]=[CH:18][CH:19]=2)[CH:14]([CH3:22])[CH2:13]1
Reactant: CC1CC(C)(C)c2cccc(N)c21
Reactant: Cc1nc(Cl)sc1C(=O)O
Solvent: ClCCl
Solvent: O
Product: Cc1nc(Cl)sc1C(=O)Nc1cccc2c1C(C)CC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
252 mg (1.42 mmol) of 2-chloro-4-methylthiazole-5-carboxylic acid and 442 mg (1.42 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidomethiodide were dissolved in 10 ml of methylene chloride and stirred at room temperature for 1 hour. Then, to the solution was added 249 mg (1.42 mmol) of 1,1,3-trimethyl-4-aminoindan and reaction was effected for 6 hours under reflux. The reaction mixture was poured into water and extracted with methylene chloride. The organic layer was concentrated and thereafter was purified by column chromatography (eluent; n-hexane:ethyl acetate=50:50 V/V) to obtain 204 mg of N-(1,1,3-trimethyl-4-indanyl)-2-chloro-4-methylthiazole-5-carboxamide (yield 43%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH3:13]>CO>[NH2:13][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(CO)ccc1Cl
Reactant: N
Solvent: CO
Product: Nc1ccc(CO)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 6 h
Yield: 52 %

Procedure:
Fifty grams (0.27 mole) of 4-chloro-3-nitrobenzyl alcohol, 250 ml. of methanol and 200 ml. of liquid ammonia were loaded into a cold autoclave. The autoclave was sealed and heated to a temperature of 150° C. The reaction was continued for 6 hours. After cooling the autoclave was vented and the reaction mixture was evaporated in vacuo. The residue was taken up in ether and the ether solution was filtered to separate the ammonium chloride. The ether filtrate was evaporated in vacuo to yield a solid product. The product was recrystallized from 2-B ethanol/ethyl acetate to give 23.6 g. (52 percent yield) of 4-amino-3-nitrobenzyl alcohol, mp. 100°-101° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=[O:8].C(N(C(C)C)C(C)C)C.[CH3:24][N:25]1[C:29]([C:30](Cl)=[O:31])=[C:28]([C:33]([F:36])([F:35])[F:34])[C:27]([C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])=[N:26]1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30]([C:29]2[N:25]([CH3:24])[N:26]=[C:27]([C:37]([F:42])([F:43])[C:38]([F:40])([F:41])[F:39])[C:28]=2[C:33]([F:35])([F:36])[F:34])=[O:31])=[CH:13][C:6]=1[C:7](=[O:8])[NH:9][CH:10]1[CH2:11][CH2:12]1
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Cl
Reactant: Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
95.3 mg (0.45 mmol) of 5-amino-2-chloro-N-cyclopropylbenzamide, 3.7 mg (0.03 mmol) of N,N-dimethylpyridine-4-amine are dissolved in 2.5 ml of ethyl acetate. The solution is cooled to 0° C. using an ice bath and admixed with 158 μl (0.91 mmol) of N-ethyldiisopropylamine. 100 mg (0.30 mmol) of 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride are suspended in 2.5 ml of ethyl acetate and then added to the cooled reaction solution. The reaction mixture is heated for four hours at 50° C. and then stirred for 16 hours at room temperature. The reaction solution is diluted with 10.0 ml of ethyl acetate. The organic phase is washed three times with 1M hydrochloric acid, twice with 1M sodium hydroxide solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and filtered and solvent is removed under reduced pressure on a rotary evaporator. This gives 151 mg of N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (97%) as white solid.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([N:18]1[CH2:25][CH:24]2[CH:20]([C:21](=O)[C:22]3[C:28]([CH3:29])=[CH:27][S:26][C:23]=32)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C(Cl)Cl>[CH2:11]([N:18]1[CH2:25][CH:24]2[CH:20]([C:21](=[CH2:1])[C:22]3[C:28]([CH3:29])=[CH:27][S:26][C:23]=32)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1csc2c1C(=O)C1CN(Cc3ccccc3)CC21
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C1c2c(C)csc2C2CN(Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (9.6 g, 26.8 mmol) was dissolved in THF (67 ml), cooled to 0° C. and treated with potassium bis(trimethylsilyl)amide (KHMDS) (5.33 g, 26.8 mmol) producing a clear yellow solution. Next, a solution of the product from step f) (1.9 g mg, 6.70 mmol) in THF (33 ml) was added and the reaction was warmed to 22° C. After 1 hour, the reaction was diluted with CH2Cl2 (300 ml) and washed with brine (100 ml). The organic layer was dried (MgSO4) and the solvent evaporated in vacuo to give the crude subtitle product (3.1 g) that was used without further purification.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([NH:29][CH3:30])[CH3:28])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9].C(OC(=O)C)(=O)C>>[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([N:29]([CH3:30])[C:3](=[O:5])[CH3:2])[CH3:28])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CNC(C)CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(C)C(C)CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1

Procedure:
{3-[4-(6-Isopropoxy-pyridin-3-yloxy)-phenyl]-1-methyl-propyl}-methyl-amine trifluoroacetate (27 mg, 0.086 mmol) was reacted with acetic anhydride in analogy to example 2a. M+H+: 357.2.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][C:17]1[O:18][C:19]([CH3:22])=[N:20][N:21]=1)(C)(C)C>C(Cl)Cl>[CH3:22][C:19]1[O:18][C:17]([CH2:16][CH2:15][NH2:14])=[N:21][N:20]=1
Reactant: Cc1nnc(CCNC(=O)OC(C)(C)C)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc(CCN)o1

Procedure:
TFA (1 ml) is added to a stirred solution of [2-(5-methyl-[1,3,4]oxadiazol-2-yl)-ethyl]-carbamic acid tert-butyl ester (0.077 g, 0.34 mmol) in DCM (5 ml). After 1 hour at room temperature the solvents are removed. The residue is dissolved in DCM and washed with 4M aqueous NaOH solution. The organic extract is separated, dried (MgSO4) and the solvent removed to give the titled compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[S:8])[O:5][C:6]=1[CH3:7].S(OC)(O[CH3:13])(=O)=O>[OH-].[Na+]>[CH3:1][C:2]1[N:3]=[C:4]([S:8][CH3:13])[O:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(=S)oc1C
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: CSc1nc(C)c(C)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
4,5-Dimethyl-2(3H)-oxazolethione [Bull. Soc. Chim. Belg. 70, 745, (1961)] (37.5 g, 0.29 m) in 2N aqueous sodium hydroxide (150 ml) was stirred at room temperature during the dropwise addition of dimethyl sulphate (40.0 g, 0.317 m). The mixture was stirred for 4 hours at room temperature and then warmed to 50° C, cooled, and the aqueous phase extracted with diethyl ether. Evaporation of the solvent and distillation of the residue under reduced pressure gave 33.85 g (81%) of the title product as a pale yellow oil, b.p. 82° C./13 mm.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[F-].[K+].[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:37]([NH:36][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Br:29])=[O:38])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: O=C=Nc1ccccc1Br
Agent: [F-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(C(=O)Nc3ccccc3Br)c3cnc4ccc(Br)cc4c32)cc1

Procedure:
To a suspension of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 0.050 g, 0.12 mmol) and potassium fluoride (0.010 g, 0.18 mmol) in dry benzene (6 ml) was added 1-bromo-2-isocyanatobenzene (0.036 g, 0.12 mmol) at RT. The reaction was stirred at reflux temperature for 6 hours. The reaction mixture was cooled and poured into cold water, extracted with ethyl acetate (2×20 ml). Organic layer was washed with water dried over sodium sulfate and concentrated. The crude product was crystallized in ethyl acetate\pet ether to obtain the title compound. Yield: 0.017 g (22%); 1H NMR (DMSO-d6, 300 MHz): δ 11.82 (s, 1H), 8.78 (s, 1H), 7.90 (d, 1H, J=9 Hz), 7.81 (d, 2H, J=8.1 Hz), 7.61-7.65 (m, 3H), 7.28 (d, 1H, J=8.1 Hz), 6.95-7.05 (m, 2H), 6.74 (d, 1H, 7.8 Hz), 6.41 (t, 1H, 7.2 Hz), 1.79 (s, 6H); MS: m/z 606 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:5]=2[S:4][CH:3]=1.C1C(=O)N([Br:19])C(=O)C1.O>C(Cl)Cl>[Br:19][C:3]1[S:4][C:5]2[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2c1C(=O)CCC2
Solvent: ClCCl
Solvent: O
Product: Cc1c(Br)sc2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a stirred solution of 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzothiophene (500 mg, 3.01 mmol) in CH2Cl2 (15 mL) was added NBS (536 mg, 3.01 mmol) at room temperature, and the mixture stirred for 3 hours at room temperature. The reaction mixture was poured into water (50 mL) and the whole was extracted with diethyl ether (100 mL). The organic layer was washed with water (100 mL×2), brine, dried over MgSO4, and concentrated in vacuo to provide the title product (686 mg, 93% yield)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][C:6]=1[CH:7]([C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH:16]=[CH:17][CH:18]=1)[O:8]2.[OH-].[Na+]>CO.O.Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][C:6]=1[CH:7]([C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:16]=[CH:17][CH:18]=1)[O:8]2
Reactant: CCOC(=O)CCCc1cccc(C2Oc3cccc(OC)c3-c3ccc(NS(C)(=O)=O)cc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc2c1-c1ccc(NS(C)(=O)=O)cc1C(c1cccc(CCCC(=O)O)c1)O2
Yield: 101.6 %

Procedure:
A solution of Example 150 (0.78 g, 1.6 mmol) and NaOH (0.67 g, 16.7 mmol) in MeOH-H2O (3 mL, 1:1) was stirred for 6 hours, diluted with aqueous HCl (50 mL, 1M) and extracted with ethyl acetate (3×35 mL). The combined ethyl acetate was dried (MgSO4), filtered and concentrated under reduced pressure to provide the titled compound (0.76 g, 99%) of the title compound. 1NMR (CDCl3 300 MHz) δ 1.95 (quintet, J=7 Hz, 2H), 2.31 (t, J=7 Hz, 2H), 2.68 (t, J=7 Hz, 2H), 2.95 (s, 3H), 3.94 (s, 3H), 5.93 (s, 1H), 6.55 (d, J=3 Hz, 1H), 6.65 (d, J=9 Hz, 1H), 6.69 (dd, J=2 Hz, 8 Hz, 1H), 6.89 (s, 1H), 7.15 (t, J=8 Hz, 1H), 7.15-7.24 (m, 3H), 7.25-7.32 (m, 4H), 8.42 (d, J=9 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]([N:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][CH:24]([O:1][C:2]2[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:23][CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(SC)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(SC)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
The methyl 2-hydroxy-4-(methylthio)benzoate (4.00 g, 20.2 mmol) was dissolved in THF (300 mL). The solution was cooled to 0° C. and the 1-Boc-4-hydroxypiperidine (4.07 g, 20.2 mmol) and triphenylphosphine (6.35 g, 24.2 mmol) were added, followed by diethyl azodicarboxylate (4.0 mL, 25.4 mmol). After 5 minutes, the reaction was allowed to warm to room temperature and left overnight. The reaction was concentrated in vacuo and the crude material was purified by flash column chromatography (about 500 g silica, 15% EtOAc/hexanes through 20% EtOAc/hexanes) to give the desired product (7.185 g, 18.83 mmol, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.FC(F)(F)[C:16](O)=[O:17].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:11])([F:12])[F:13])=[CH:5][C:4]=1[CH:16]=[O:17]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(OC(F)(F)F)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(OC(F)(F)F)cc1C=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Combine 2-methoxy-5-trifluoromethoxybenzene (1.0 g, 5.2 mmol) and trifluoroacetic acid (200 mL). Add slowly portionwise hexamethylenetetraamine (26 g, 185.7 mmol). Heat at 60° C. After 24 hours, cool to ambient temperature and pour the reaction mixture into a 2M aqueous solution of sulfuric acid (500 mL). Cool and extract ten times with diethyl ether. Dry the combined organic layers over Na2SO4, filter, and evaporate invacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/4 ethyl acetate/hexane to give 2-methoxy-5-trifluoromethoxybenzaldehyde.