Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:35])=[C:12]([C:16]2[CH:17]=[N:18][C:19]([CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.Cl.CCOC(C)=O>CO>[F:35][C:11]1[C:12]([C:16]2[CH:17]=[N:18][C:19]([CH:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)=[N:20][CH:21]=2)=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][OH:8]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)cn2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: OCc1cccc(-c2cnc(C3CCNCC3)nc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
tert-Butyl 4-{5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]pyrimidin-2-yl}piperidin e-1-carboxylate (170 mg) was mixed with MeOH (1.7 ml), and a 4M hydrogen chloride/EtOAc (0.17 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and 10% MeOH/CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were added to the residue. Then, the reaction mixture was concentrated under reduced pressure. 10% MeOH/CHCl3 was added to the obtained residue, followed by stirring for 30 minutes. The filtrate was concentrated under reduced pressure to obtain {2-fluoro-3-[2-(piperidin-4-yl)pyrimidin-5-yl]phenyl}methanol (96 mg).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=1.[OH-].[Na+].[CH2:19](O)C>>[CH3:15][S:12]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH3:19])[N:7]=1)[C:3]([OH:2])=[O:16])(=[O:14])=[O:13]
Reactant: COC(=O)c1cc(OC)nc(S(C)(=O)=O)c1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(C(=O)O)cc(S(C)(=O)=O)n1
Temperature: 80 °C

Procedure:
To a solution of 2-methanesulfonyl-6-methoxy-isonicotinic acid methyl ester (4.3 g, 17.5 mmol) in ethanol (75 mL) was added 2 N aqueous sodium hydroxide (35 mL, 70 mmol). The mixture was warmed at 80° C. for 4 hours and then concentrated in vacuo to remove the ethanol. The remaining aqueous solution was acidified with 1 N aqueous HCl and extracted with ethyl acetate (4×30 mL). The combined organic layers were washed with brine (2×100 mL), dried over sodium sulfate and concentrated to afford 2-methanesulfonyl-6-ethoxy-isonicotinic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]([O:11]C)=O)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][NH2:21])[CH3:14].[ClH:22]>>[ClH:22].[CH2:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][NH:21][C:9](=[O:11])[C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:14]
Reactant: COC(=O)c1ncccc1OC
Reactant: CCN1CCCC1CN
Agent: Cl
Product: CCN1CCCC1CNC(=O)c1ncccc1OC

Procedure:
10.5 g (0.063 mole) of methyl 3-methoxypicolinate and 17.6 g (0.137 mole) of 1-ethyl-2-(aminomethyl)-pyrrolidine are heated under nitrogen for 6 hours to 80° C. The excess base is distilled off in a high vacuum at 50° C and the oily residue is dissolved in methylene chloride and treated with 12 ml of 6 N ethanolic hydrochloric acid. The solvent is evaporated in vacuo and the oily residue is crystallised by trituration with ether. The crystals are collected by filtration and recrystallised from isopropanol-ethyl acetate to yield crude N-[(1-ethyl-2-pyrrolidinyl)-methyl]-3-methoxypicolinamide hydrochloride. The combined mother solutions are concentrated in vacuo and the free base is recovered as solution with 2 N sodium hydroxide solution and methylene chloride. The solution is concentrated, the residue dissolved in chloroform and chromatographed through a column of 60 g of silica gel with chloroform-methanol (98:2) as eluant. The base so obtained is again converted with ethanolic hydrochloric acid into the hydrochloride, which is recrystallised from ether. The combined crude hydrochlorides are recrystallised from isopropanol-ethyl acetate and yield pure N-[(1-ethyl-2-pyrrolidinyl)-methyl]-3-methoxypicolinamide hydrochloride with a melting point of 162°-163° C.
Reaction SMILES: [I-].C[N+](C)(C)[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[P:17]([O:22]C)([O:20][CH3:21])[O:18][CH3:19]>C1(C)C(C)=CC=CC=1>[OH:12][C:8]1[C:9]([CH3:11])=[CH:10][C:5]([CH2:4][P:17](=[O:22])([O:20][CH3:21])[O:18][CH3:19])=[CH:6][C:7]=1[O:13][CH3:14]
Reactant: COP(OC)OC
Reactant: COc1cc(C[N+](C)(C)C)cc(C)c1O
Agent: [I-]
Solvent: Cc1ccccc1C
Product: COc1cc(CP(=O)(OC)OC)cc(C)c1O
Yield: 82 %

Procedure:
Trimethyl(4-hydroxy-3-methoxy-5-methylbenzyl)ammonium iodide (1 g, 3.0 mmol) was suspended in 8 ml xylene, trimethyl phosphite (0.52 ml, 4.4 mmol) was added dropwise and the resulting mixture was refluxed for 14 h. The solid formed was filtered and the solvent and excess of phosphite were evaporated under vacuum to yield dimethyl (4-hydroxy-3-methoxy-5-methylbenzyl)phosphonate as a viscous oil (0.64 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([CH3:18])[C:3]=1[C:4]#[N:5].Cl.Cl[C:21]([NH2:23])=[NH:22].COCCOCCOC>O>[NH2:23][C:21]1[N:22]=[C:4]([NH2:5])[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:6]=2[CH3:18])[N:1]=1
Reactant: N=C(N)Cl
Reactant: CCCCCCC=Cc1ccc(N)c(C#N)c1C
Agent: Cl
Solvent: O
Solvent: COCCOCCOC
Product: CCCCCCC=Cc1ccc2nc(N)nc(N)c2c1C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A mixture of 0.64 g of the 2-aminobenzonitrile of Example 4, 0.30 g of chloroformamidine hydrochloride, and 5.0 ml of diglyme was heated at 140°-150° C. for 5 h. The mixture was diluted with 50 ml of water and stirred for 1 h. The precipitated solid was collected by filtration, washed with water and acetone, and dried to leave 0.58 g (78%) of a white solid. (Mixture of cis-trans isomers.) Anal. calc'd for C17H24N4.2/3HCl: C, 66.2; H, 8.05 N, 18.1. Found: C, 66.2, H; 8.05; N, 18.2.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[S:20][C:19]([NH:21]C(=O)OC(C)(C)C)=[N:18][CH:17]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C.ClCCl>[N:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[S:20][C:19]([NH2:21])=[N:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2ccccc2COc2ccncc2)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ncc(-c2ccccc2COc2ccncc2)s1
Reaction time: 4 h
Yield: 78.5 %

Procedure:
20 ml of a 4M gaseous hydrochloric acid solution in ethyl acetate are added to 1 g of tert-butyl 5-{2-[(4-pyridinyloxy)methyl]phenyl}-1,3-thiazol-2-ylcarbamate, obtained in step 7.3, in 20 ml of dichloromethane. The mixture is left for 4 hours at room temperature. The reaction medium is concentrated and it is brought to a basic pH with a 5% sodium hydrogen sulfate solution. The precipitate formed is filtered and chromatographed on a silica gel column, eluting with a dichloromethane/methanol 95/5 (V/V) mixture to give 0.58 g of a beige foam.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][CH2:13][C:14](O)=[O:15])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1>[C:5]1([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][CH2:13][C:14]([Cl:3])=[O:15])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COC(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)COC(c1ccccc1)c1ccccc1
Yield: 72.7 %

Procedure:
8.1 g (68.1 mmole) of thionyl chloride was added to a solution of 5.5 g (22.7 mmole) of (diphenylmethoxy) acetic acid in 150 cm3 of benzene. The solution was refluxed for 5 hours, then evaporated to dryness under reduced pressure. Distillation of the residue yielded 4.3 g (yield: 73%) of (diphenylmethoxy) acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]([CH:19]=[C:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:9]2[C:18]([CH:19]=[C:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[O:32])=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2cc3ccccc3nc2Sc2ccc(Cl)cc2)S1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: O=C1NC(=O)C(=Cc2cc3ccccc3nc2S(=O)c2ccc(Cl)cc2)S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
The compound prepared in Example 224 was dissolved in CH2Cl2/CH3OH (5:1), and to this solution was added 3-chloroperoxybenzoic acid (2 eq. of 77% max. purity). The mixture was stirring at RT for 4 hrs before TLC analysis showed the disappearance of the starting compound. The reaction mixture was stirring for an additionally 2 hrs. At the end of the reaction, white crystalline product precipitated. The product was collected by filteration, washed several times with ether, and air dried for 48 hrs to provide the final product with a yield of 30%.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([OH:20])=O)[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]>>[CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([NH:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[O:20])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NN1CCCC1=O
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: O=C(NN1CCCC1=O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 14c) and 1-amino-2-pyrrolidinone (CAN 6837-14-5) as starting materials; MS (EI) 372.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2].[CH2:11]([Mg]Br)[CH3:12]>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:2][C:1]1([C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)[CH2:12][CH2:11]1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: N#Cc1ccc(C2(N)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1,4-dicyanobenzene (3.30 g, 25.8 mmol) in dichloromethane was added titanium(IV) isopropoxide (7.56 mL, 25.8 mmol) followed by ethylmagnesium bromide (3M in ether, 15.5 mL, 46.4 mmol) dropwise (exothermic, gas evolution after one eq of reagent added) and the mixture was stirred at r.t. for 45 min. Borontrifluoride diethyl etherate (5.71 mL, 46.4 mmol) was added and the mixture was stirred at r.t. for 2 h, quenched with NH4Cl and HCl and separated. The aqueous phase was washed once with ether and then the pH was adjusted to 9-10 with 10N NaOH (precipitate formation). The mixture was filtered through celite and the cake washed with water/EtOAc. The phases were separated and the aqueous phase extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the desired product as a viscous oil which solidified at −20° C. The crude was used directly without further purification.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:6]2[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[CH2:18][CH2:19]Cl.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([N:25]1[C:2]2[N:7]3[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:6]3[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=2[CH2:18][CH2:19]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1nc2c(C#N)cnn2c(Cl)c1CCCl
Reactant: CC(C)(C)N
Product: CCOC(=O)c1nc2c(C#N)cnn2c2c1CCN2C(C)(C)C

Procedure:
The intended compound was obtained in the same manner as in Synthesis Example (5) using ethyl 7-chloro-6-(2-chloroethyl)-3-cyanopyrazolo[1,5-a]pyrimidine-5-carboxylate and tert-butylamine.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].I.C(O)(=O)C>C(OCC)(=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Agent: I
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
A mixture of 432 mg of 1-bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (1 mmol), 63 mg of red phosphorous (2 mmol), 0.4 ml of aqueous 57 wt % HI (3 mmol), and 1 ml of glacial acetic acid was refluxed with stirring for 30 min. Then the reaction mixture was diluted with 25 ml of ethyl acetate, filtered by suction through a pad of celite, washed with a solution of 0.2 g of NaHSO3 in 5 ml of water, and washed two times with 5 ml of concentrated aqueous sodium bicarbonate solution. The organic phase was dried over MgSO4 and-evaporated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with hexanes:ethyl acetate (85:15). 123 mg of the title compound were obtained; 1H NMR (CDCl3): δ=11.85 (s, 1H), 8.60 (s, 1H), 8.23 (d, 1H), 7.38 to 7.63 (m, 7H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:4][CH2:5][CH3:6].FC(C(F)(F)F)(C(F)(F)F)C(OC)=[O:17].C([Mg]Br)C>>[F:1][C:2]([F:12])([F:13])[C:3]([F:11])([C:7]([F:8])([F:9])[F:10])[CH:4]([OH:17])[CH2:5][CH3:6]
Reactant: COC(=O)C(F)(C(F)(F)F)C(F)(F)F
Reactant: CCCC(F)(C(F)(F)F)C(F)(F)F
Agent: CC[Mg]Br
Product: CCC(O)C(F)(C(F)(F)F)C(F)(F)F

Procedure:
1,1,1,2-Tetrafluoro-2-(trifluoromethyl)-pentane ((CF3)2CFCH2CH2CH3) may be prepared by reacting methyl perfluoroisobutyrate with ethyl magnesium bromide followed by hydrolysis to give 1,1,1,2-tetrafluoro-2-(trifluoromethyl)-3-pentanol. The pentanol is converted to 4,5,5,5-tetrafluoro-4-(trifluoromethyl)-2-pentene by dehydration with phosphorous pentoxide and the double bond saturated by hydrogenation over a palladium on carbon catalyst.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl[S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:23]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:33][CH:34]=3)(=[O:25])=[O:24])[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2csc(NCc3cccs3)n2)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(-c2csc(N(Cc3cccs3)S(=O)(=O)c3ccc(C(=O)O)cc3)n2)cc1
Temperature: 100 °C

Procedure:
[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amine (50 mg, 0.16 mmol), 4-(chlorosulfonyl)benzoic acid (53 mg, 0.24 mmol), triethylamine (45 μL, 0.32 mmol), and DMAP (2 mg, 0.016 mmol) were combined in DCM (2 mL). The resulting reaction mixture was heated in a CEM Exployer PLS™ microwave at 100° C. for 30 min. After cooling to room temperature, saturated NaHCO3 (aq) solution (5 mL) was added. The mixture was extracted with DCM (2×4 mL). The combined organic layer was dried over Na2SO4 and concentrated. Purification of the crude product was carried out using silica gel chromatography eluting with DCM/MeOH 9:1, yielding 4-{[4-(4-isopropyl-phenyl)thiazol-2-yl]-thiophen-2-ylmethyl-sulfamoyl}-benzoic acid. LCMS m/z: 500 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:11]1([CH:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[O:6]
Reactant: Cc1ccccc1C(=O)O
Reactant: NCC(c1cccnc1)N1CCOCC1
Product: Cc1ccccc1C(=O)NCC(c1cccnc1)N1CCOCC1

Procedure:
From 2-methylbenzoic acid and (2-morpholin-4-yl-2-pyridin-3-ylethyl)amine.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9](N)=O)[CH2:2][CH2:3][CH3:4].[CH2:26]([NH:30]C1C=C(C=C(S(=O)(=O)N)C=1OC1C=CC=CC=1)C(NC)=O)CCC>>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:26][NH2:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(C(N)=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CCCCNc1cc(C(=O)NC)cc(S(N)(=O)=O)c1Oc1ccccc1
Product: CCCCNc1cc(CCN)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
By replacing in Example 289 3-n-butylamino-4-phenoxy-5-sulfamylbenzamide with an equimolar amount of 3-n-butylamino-4-phenoxy-5-sulfamyl-N-methylbenzamide and following the procedure described, (3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)methylamine is obtained with a melting point of 157°-159° C. The material (IR, analysis) is identical with the material prepared as in Example 115.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:26])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:26])/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=1)([OH:4])=[O:2]
Reactant: CCCCCc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 2 from trans-4-n-pentylcinnamic acid-N-(2-methoxycarbonyl-phenyl)-amide and sodium hydroxide solution in methanol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8]C(=O)OC(C)(C)C)=[CH:5][C:4]=1[NH:18][C:19]1[N:23]([CH3:24])[C:22]2[CH:25]=[C:26]([N:30]3[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([F:39])([F:38])[F:37])[CH2:31]3)[C:27]([Cl:29])=[CH:28][C:21]=2[N:20]=1>O1CCOCC1.O.C([O-])([O-])=O.[K+].[K+]>[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[NH:18][C:19]1[N:23]([CH3:24])[C:22]2[CH:25]=[C:26]([N:30]3[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([F:38])([F:37])[F:39])[CH2:31]3)[C:27]([Cl:29])=[CH:28][C:21]=2[N:20]=1
Reactant: Cn1c(Nc2cc(CNC(=O)OC(C)(C)C)ccc2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4 M HCl in dioxane (20 mL) was added to tert-butyl N-{4-chloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzyl}-carbamate (700 mg, 1.2 mmol) in dioxane (20 mL). The reaction mixture was stirred at rt for 2 h then diluted with water and aq. K2CO3-solution and stirred for 1 h at rt. The mixture was concentrated, filtered and the filtercake was washed with water and dried to give the sub-title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1COCC1>[CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:28](=[O:30])[CH3:29])[CH:21]=[CH:20]3)[CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(COCc2cc(Oc3ccc4[nH]ccc4c3)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)n1ccc2cc(Oc3cc(COCc4ccccc4)ncn3)ccc21

Procedure:
To a solution of 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-1 H-indole (12 g, 36.2 mmol) in THF (300 mL), NaH (1.74 g, 43.5 mmol) and acetic anhydride (5.13 mL, 54.3 mmol) are added. After 1 h the reaction is quenched with aqueous ammonium chloride and extracted with EtOAc. Most of the impurities are removed passing it through a silica gel column eluting with 50:50 heptane:EtOAc to give crude 1-[5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-indol-1-yl]-ethanone. This is then dissolved in TFA (300 mL) and heated to 100° C. for 6 hours. At this point the solvent is removed and 1-[5-(6-hydroxymethyl-pyrimidin-4-yloxy)-indol-1-yl]-ethanone isolated via FCC eluting with EtOAc. MS (ESI) m/z 284.0 (M+1).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>C(O)C>[OH:25][CH2:24][CH2:26][NH:27][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: NCCO
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NCCO)ncc2c(=O)[nH]1
Reaction time: 16 h

Procedure:
A stirred mixture of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.60 g) and ethanolamine (0.25 ml) in ethanol (20 ml) was heated under reflux for 19 hours. More ethanolamine (0.75 ml) was added and stirring under reflux continued for 16 hours. A white crystalline solid which precipitated from the cooled reaction mixture was collected, washed with cold ethanol and recrystallized from ethanol to yield the title compound, 0.38 g, m.p. 204-205.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14](N)=[O:15].Cl.[C:21](=O)(O)[O-:22].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:22][CH3:21])=[O:15]
Reactant: O=C([O-])O
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(N)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Nc1ccc(C(F)(F)F)cc1Cl)C(C)C

Procedure:
A mixture of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutyramide (1 mmol) and 4 ml of methanol, saturated with HCl gas, is heated at 75° for about 40 hours. The mixture is cooled, poured into saturated aqueous sodium bicarbonate and extracted with ether. The combined ether extracts are dried over sodium sulfate and solvent removed in vacuo to yield methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, which can be further purified by prep. thin layer chromatography.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH2:24][CH3:25])[CH:17]=3)[N:12]=2)[CH:6]=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2].Cl[CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30])=[C:18]([CH2:24][CH3:25])[CH:17]=3)[N:12]=2)[CH:6]=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCc1cc(-c2nc(-c3cc(C)c(O)c(CC)c3)no2)cnc1CC
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CO)c(CC)c3)no2)cnc1CC
Reaction time: 48 h
Yield: 11.5 %

Procedure:
To a solution of 4-[5-(5,6-diethyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (100 mg, 0.296 mmol) in isopropanol (10 mL) and 3 N aq. NaOH (3 mL), (S)-3-chloro-1,2-propanediol (98 mg, 0.89 mmol) is added. The mixture is stirred at 60° C. for 24 h before another portion of (S)-3-chloro-1,2-propanediol (98 mg, 0.89 mmol) is added. Stirring is continued at 60° C. for 2 days. The mixture is diluted with EA and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with EA-heptane to give (S)-3-{4-[5-(5,6-diethyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol (14 mg) as a red oil; LC-MS: tR=0.93 min, [M+1]+=412.16.