Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl.Cl[CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1.[CH2:10]([OH:14])[CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][CH2:10][O:14][CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1
Reactant: OCCCO
Reactant: ClCc1c[nH]cn1
Agent: Cl
Agent: [Na]
Product: OCCCOCc1c[nH]cn1
Reaction time: 8 h

Procedure:
Sodium (13.5 g.) was added over 3 hours to propane-1,3-diol (450 ml.) under nitrogen at 70° with stirring. This solution was added over 20 minutes to a stirred solution of 4-chloromethylimidazole hydrochloride (50.0 g.) under nitrogen at 40°-60°. Subsequent heating at 60°-65° for 3 hours followed by overnight cooling, filtration and concentration gave 4-(3-hydroxypropoxy)methylimidazole. Subsequent reaction with thionyl chloride gave 4-(3-chloro-propoxy)methylimidazole hydrochloride (38.3 g.).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].C(N(CC)CC)C.[CH:20]#[C:21][CH3:22]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:20]([C:12]1[CH:2]=[C:3]2[C:4](=[CH:10][CH:11]=1)[C:5](=[O:6])[O:7][C:8]2=[O:9])#[C:21][CH3:22]
Reactant: O=C1OC(=O)c2c(Br)cccc21
Reactant: C#CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC#Cc1ccc2c(c1)C(=O)OC2=O
Temperature: 50 °C
Yield: 97.9 %

Procedure:
Bromophtalic anhydride (50.0 g, 0.22 mol), triethylamine (33.8 mL, 0.24 mol) and toluene (220 mL) were mixed in a glass reactor over nitrogen (g) atmosphere at room temperature. Bis(triphenylphosphine)palladiumchloride (0.77 g, 0.001 mol), CuI (0.42 g, 0.002 mol) and triphenylphosphine (0.87 g, 0.003 mol) were added and the temperature was raised to 50° C. Propyne (18.0 g, 0.45 mol) was slowly added through a gas inlet during 3 hours. The reaction mixture was filtered through a glass filter funnel and the solution was concentrated to dryness to give crude solid product (40.1 g, 98%). The product was re-crystallized from toluene to give a light yellow solid (24.7 g, 60%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:13]1)[CH3:2].F[B-](F)(F)F.[O:30]=[N+:31]=[O:32]>C(#N)C>[CH2:1]([O:3][C:4](=[O:24])[NH:5][C:6]1[C:7]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:20])([F:22])[F:21])[CH2:13]2)=[CH:8][CH:9]=[CH:10][C:11]=1[N+:31]([O-:32])=[O:30])[CH3:2]
Reactant: CCOC(=O)Nc1ccccc1C1CCCN(C(=O)C(F)(F)F)C1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CCOC(=O)Nc1c(C2CCCN(C(=O)C(F)(F)F)C2)cccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 53.1 %

Procedure:
A solution of 18 g of product of Step C in 180 ml of acetonitrile was cooled to -30° C. and then with stirring and under an inert atmosphere, 7.73 g of nitronium tetrafluoroborate were added in small fractions. After stirring for one hour and returning to ambient temperature, the reaction mixture was poured on to ice and extracted with methylene chloride. The extracts were washed with water, dried, taken to dryness under reduced pressure and purified by chromatography on silica (eluent: cyclohexane-ethyl acetate 7-3) to obtain 10.8 g of the expected product (RF=0.2) melting about 124° C. after crystallization from a mixture of isopropyl ether and methylene chloride (1-1).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[K+]>O.CS(C)=O>[C:12]1([CH2:11][C:2]([CH3:18])([CH3:1])[C:3](=[O:10])[CH:4]([N:5]2[CH:9]=[N:8][CH:7]=[N:6]2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(Cc1ccccc1)C(=O)Cn1cncn1
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(Cc1ccccc1)C(=O)C(Cc1ccccc1)n1cncn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
48.6 g (0.2 mol) of 3,3-dimethyl-4-phenyl-1-(1,2,4-triazol-1-yl)-butan-2-one, 27.9 g (0.22 mol) of benzyl chloride and 12.3 g (0.22 mol) of potassium hydroxide in 15 ml of water are dissolved in 300 ml of dimethylsulphoxide. The reaction mixture is stirred for a further 8 hours at 50° C. and then poured onto water. The mixture is extracted with ethyl acetate. The organic phase is concentrated and the residue is purified by column chromatography (silica gel/ethyl acetate: cyclohexane =3:1). 54.5 g (81.8% of theory) of 1,5-bisphenyl-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-pentan-3-one of melting point 45°-50° C. are obtained.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.O>C1COCC1>[C:3]1([CH2:2][CH2:2][C:3]2[C:15]3[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]=3[CH:6]=[CH:5][CH:4]=2)[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1cccc2c1Cc1ccccc1-2
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)Cc1c(CCc3cccc4c3Cc3ccccc3-4)cccc1-2

Procedure:
5.1 g, 19.6 mmol 1-bromomethylfluorene dissolved in 50 ml THF was added dropwise to 0.24 g, 9.9 mmol Mg in 10 ml THF. After addition the Grignard was refluxed for 2 hrs, cooled and water/aqueaous HCl added. After work-up this afforded 1.5 g of CH2CH2(1-fluorenyl)2 as a beige powder. 1H NMR (CDCl3): δ 3.81 ppm (CH2), 3.14 ppm (CH2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]#[C:13][C:14]([CH3:26])([CH3:25])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(#N)C.Cl[Pd]Cl>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:12]=[C:13]([C:14]([CH3:26])([CH3:25])[C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[NH:1]2)=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C#Cc1cc([N+](=O)[O-])c(F)cc1N)C(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: CC(C)(C(=O)OCc1ccccc1)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of benzyl 4-(2-amino-4-fluoro-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (20.0 g, 56 mmol) in acetonitrile (100 mL) was added PdCl2 (5.0 g, 28 mmol) at room temperature. The mixture was stirred at 80° C. overnight. The mixture was filtered off and the solvent was evaporated in vacuo, the residue was purified by chromatography on silica gel (10% EtOAc in petroleum ether) to give benzyl 2-(6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate (18.0 g, 90%). 1H NMR (300 MHz, CDCl3) 8.96 (br s, 1 H), 8.33 (d, J=7.2 Hz, 1 H) 7.35-7.28 (m, 5 H) 7.08 (d, J=11.7 Hz, 1 H), 6.47 (s, 1 H), 5.18 (s, 2 H) 1.69 (s, 6 H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Cl)[N:14]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:11][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][N:7]=2)[CH3:10])[CH:16]=[CH:17][CH:18]=1
Reactant: Clc1cccc(Cl)n1
Reactant: C[C@H](N)c1ccc(F)cn1
Agent: Cl
Product: C[C@H](Nc1cccc(Cl)n1)c1ccc(F)cn1
Yield: 36.8 %

Procedure:
(S)-1-(5-Fluoropyridin-2-yl)ethanamine hydrochloride (prepared as described in WO2006/123113, 0.291 g, 1.37 mmol) was added to a solution of 2,6-dichloropyridine (0.203 g, 1.38 mmol) in NN-diisopropylethylamine (1.2 mL, 6.89 mmol) and the resulting mixture was stirred and heated to reflux for two days. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (0-10% ethyl acetate in hexanes) to yield the title compound (127 mg, 36%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([C:20]([O:22]CC)=O)=[N:13][N:14]([CH3:19])[C:15](=[O:18])[C:16]=1[CH3:17].C([O:27][CH2:28][CH2:29][O:30][NH2:31])=C>>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([C:20]([NH:31][O:30][CH2:29][CH2:28][OH:27])=[O:22])=[N:13][N:14]([CH3:19])[C:15](=[O:18])[C:16]=1[CH3:17]
Reactant: CCOC(=O)c1nn(C)c(=O)c(C)c1Nc1ccc(SC)cc1F
Reactant: C=COCCON
Product: CSc1ccc(Nc2c(C(=O)NOCCO)nn(C)c(=O)c2C)c(F)c1
Yield: 78 %

Procedure:
The title compound was prepared in 78% yield (2 steps) by the procedures described in Example 166 (steps I and J) using ethyl 4-(2-fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (50 mg, 0.14 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (44 mg, 0.43 mmol). MS APCI (−) m/z 381 (M−1) detected; 1H NMR (400 MHz, CD3OD) δ 7.10 (dd, 1H), 7.03 (dd, 1H), 6.87 (t, 1H), 3.99 (t, 2H), 3.79 (s, 3H), 3.74 (t, 2H), 2.47 (s, 3H), 1.74 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[C:32]([O:31][C:30]([F:29])([F:40])[F:41])[CH:33]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Product: FC(F)(F)Oc1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3-trifluoromethoxy-benzaldehyde. MS (ESI) m/z 553.
Reaction SMILES: [F:1][C:2]1[C:30]([F:31])=[C:29]([F:32])[CH:28]=[CH:27][C:3]=1[NH:4][C:5](=[C:16]([C:22](OCC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:23][C:22]1[C:27]2[C:3](=[C:2]([F:1])[C:30]([F:31])=[C:29]([F:32])[CH:28]=2)[N:4]=[C:5]([S:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(C(=O)OCC)=C(Nc1ccc(F)c(F)c1F)SCc1ccc(OC)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1c(SCc2ccc(OC)cc2)nc2c(F)c(F)c(F)cc2c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
A solution of diethyl [(2,3,4-trifluoroanilino)(p-methoxybenzylthio)methylene]malonate (80.9 g) in diphenyl ether (60 ml) heated at 110° C. was added dropwise to diphenyl ether (210 ml) kept at 250° to 260° C. with stirring under nitrogen stream over a period of 15 minutes. After the reaction mixture was further stirred at the same temperature for 5 minutes, the mixture was cooled to room temperature and added to hexane (3000 ml). The resulting precipitate was filtered to give the title compound (59.9 g), which was recrystallized from ethyl acetate to give yellow crystals, m.p. 174°-176° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1[CH3:8]>[Ni].CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[NH2:9]
Reactant: Cc1ccc([N+](=O)[O-])cc1C
Agent: [Ni]
Solvent: CO
Product: Cc1ccc(N)cc1C
Reaction time: 2 h

Procedure:
Reaction starting from 3,4-dimethyl-1-nitrobenzene 40.32 g (266.6 mmol) of 3,4-dimethyl-1-nitrobenzene and 22 g of Raney nickel were hydrogenated in 200 ml of methanol at 55° C. and 5 bar of H2 pressure for 2 h. According to analysis by gas chromatography, the hydrogenation to 3,4-dimethylaniline gave no byproducts. A further 22 g of Raney nickel were then added to the mixture. 40 g of 100% pure ribose and 1.0 g of boric acid, made up to 360 ml with methanol, were then pumped in over 4 h at 5 bar H2 pressure at 55° C. The reaction mixture was maintained at 5 bar H2 pressure and 55° C. for a further 2 h. The catalyst was then separated off at 60° C. on a hot suction filter. The mother liquor was concentrated to 350 g, and 350 g of hot water were then added. The reaction mixture obtained was cooled down and then stirred at room temperature for 1 h and in an ice-water bath for 3 h. The crystals obtained were filtered off with suction, washed with 50 ml each of cold water and cold methanol and dried. 58.5 g were obtained, corresponding to 86% of theory ([α]D25 =-37.2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1

Procedure:
2.74 g (8.5 mmol) of 1-t-butoxycarbonyl-4-(4-nitrophenoxy)piperidine was dissolved in 20 ml of ethanol. 20 mg of 10% palladium/carbon was added to the solution, and they were stirred at room temperature in 1 atm. hydrogen atmosphere for 3 hours. Palladium/carbon was removed by the suction filtration. The filtrate was once concentrated and then treated with dichloromethane as extractant in an ordinary manner to obtain the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:7](/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14]CC)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C.CO>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:7](/[C:10](/[CH3:17])=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C(C)=C/C(=O)OCC)n1Cc1ccccc1Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCc1ncc(/C(C)=C/C(=O)O)n1Cc1ccccc1Cl

Procedure:
The title compound was prepared according to Example 1(v) by using ethyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-3-methyl-2-propenoate in place of ethyl-(E)-3-[2-n-butyl-1-{(2-chlorgphenyl)methyl}-1H-imidazol-5-yl]-2-methyl-2-propenoate. The title compound was a white solid, and was converted to the hydrochloride salt to give 82 mg (41%); mp 198°-199.5° C. (from ethyl acetate/methanol).
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][CH2:24][CH:25]([OH:27])[CH3:26]>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][CH2:24][CH:25]([OH:27])[CH3:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CC(O)CN
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NCC(C)O)cn1
Yield: 3 %

Procedure:
As described for example 9, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (150 mg, 0.49 mmol) was converted, using rac-1-amino-2-propanol instead of rac-2-amino-1-propanol, to the title compound (5 mg, 3%) which was obtained as a yellow oil after purification by chromatography (silica, 0 to 6% methanol in dichloromethane). MS: m/e=348.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)[N:9]2[CH3:24])[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:30][C:26]([NH:25][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)[N:9]2[CH3:24])[CH:3]=1)([CH3:31])[C:27]([OH:29])=[O:28]
Reactant: CC(C)(N)C(=O)O
Reactant: CN1c2ccc(C(F)(F)F)cc2C(C)(C)CC1c1cccc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1c2ccc(C(F)(F)F)cc2C(C)(C)CC1c1cccc(NC(C)(C)C(=O)O)c1
Temperature: 25 °C
Yield: 30.1 %

Procedure:
A solution of 2-(3-bromo-phenyl)-1,4,4-trimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (398.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-methyl-2-[3-(1,4,4-trimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-propionicacid (126.4 mg, 30.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 421.3.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15](Cl)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C([NH:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][N:44](C(=O)C(F)(F)F)[CH2:43][CH2:42]2)=[CH:37][CH:36]=1)=O>C(#N)C>[C:7]1([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[CH:39][CH:40]=2)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Nc1ccc(N2CCN(C(=O)C(F)(F)F)CC2)cc1)C(F)(F)F
Reactant: O=C(Cl)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CC(c1ccccc1)(c1ccccc1)c1ccccc1)Nc1ccc(N2CCNCC2)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
To an ice cooled and stirred solution of 4-(4-aminophenyl)piperazine (4.29 g, 24.2 mmol) in dichloromethane (100 mL) containing Et3N (7.42 mL, 52.5 mmol) was added trifluoroacetic anhydride (7.52 mL, 53.2 mmol) in dichloromethane (25 mL) over a 5 minute period. The mixture was allowed to warm to room temperature and stirred two days, then stirred with ice water. The pink solid that separated was isolated by filtration, washed with dichloromethane, aqueous sodium bicarbonate, and water, and dried to obtain 1-(4-(trifiuoroacetamido)phenyl)-4-trifiuoroacetylpiperazine (4.09 g, 46%, mp 193°-194° C.). To a mixture of this material (0.37 g, 1 mmol) and anhydrous potassium carbonate (1.1 g, 8.0 mmol) in acetonitrile (50 mL) was added 3,3,3-triphenylpropionyl chloride (0.54 g) and the mixture stirred at 80° C. for two days. With tlc monitoring, four additional lots of the acid chloride (4×0.54 g) and potassium carbonate (4×1.1 g) were added at 3 hr intervals, with continued reflux until complete disappearance of the starting piperazine by tlc. The solvent was removed in vacuo, the residue triturated with methanol, the solids removed by filtration and the flitrate evaporated to dryness in vacuo. The residue was stirred with 20% KOH in methanol (15 mL) for 3 hr and then evaporated to dryness in vacuo. The residue was partitioned between water and ethyl acetate and the organic layer extracted with 2N HCl. The acid extract was basified with 2N NaOH to pH 9.5 and extracted with ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate and evaporated to dryness to give the title compound as a tan solid (0.40 g, 87%), mp 193°-195° C. 1H NMR (CDCl3) δ 7.33 (m,15H), 6.89 (d, J=8.9, 2H) 6.73 (d, J=8.9, 2H), 6.26 (s, 1H), 3.70 (s, 2H), 3.00 (d, J=10.0, 8H). IR 3056, 1665, 1598, 1515, 1447, 1239, 700 cm-1. MS 462 (MH+). Anal. calcd. for: C31H31N3O.0.5 H2O: C, 79.12; H, 6.85; N, 8.93. Found: C, 78.84; H, 6.66; N, 8.64.
Reaction SMILES: C([O:5][C:6]([CH2:8][NH:9][C:10]([NH:33][C:34]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41])=[N:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>>[C:6]([CH2:8][NH:9][C:10]([NH:33][C:34]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41])=[N:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1)([OH:7])=[O:5]
Reactant: COc1cc2c(N=C(NCC(=O)OC(C)(C)C)Nc3c(C)cccc3C)ncnc2cc1OCCN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(N=C(NCC(=O)O)Nc3c(C)cccc3C)ncnc2cc1OCCN1CCOCC1
Yield: 74 %

Procedure:
Using an analogous procedure to that described in Example 4, N-(tert-butoxycarbonylmethyl)-N′-(2,6-dimethylphenyl)-N″-[6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl]guanidine was reacted with trifluoroacetic acid to give the title compound in 74% yield; NMR Spectrum: (DMSOd6, 100° C.) 2.17 (s, 6H), 3.27 (t, 4H), 3.5 (t, 2H), 3.6 (s, 3H), 3.8 (t, 4H), 4.48 (m, 4H), 7.15 (s, 1H), 7.2 (d, 2H), 7.26 (t, 2H), 8.7 (s, 1H); Mass Spectrum: M+H+ 509.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O1CCCC1.CO.O.[OH-].[Li+]>O>[CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(CN2CCCCC2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CN2CCCCC2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
To a solution of methyl 2-methyl-4-(piperidin-1-ylmethyl)benzoate (1.8 g, 7.3 mmol) in the mixture solution of tetrahydrofuran:methanol:water=3:1:1 (20 mL) was added lithium hydroxide monohydrate (1 g, 42 mmol). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuo and quenched with hydrochloride acid aqueous (1N, 5 mL). To the residue, water (50 mL) was added. The mixture was extracted with dichloromethane (50 mL). The combined organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, methanol/dichloromethane=1:15) to give the product 2-methyl-4-(piperidin-1-ylmethyl)benzoic acid (360 mg, 21%) as pale solid.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([C:11]2[C:15]([NH2:16])=[C:14]([C:17](OCC)=[O:18])[S:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1>CO>[CH3:1][NH:2][C:17]([C:14]1[S:13][N:12]=[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:23])([F:22])[F:3])[CH:6]=2)[C:15]=1[NH2:16])=[O:18]
Reactant: CCOC(=O)c1snc(-c2cccc(C(F)(F)F)c2)c1N
Reactant: CN
Solvent: CO
Product: CNC(=O)c1snc(-c2cccc(C(F)(F)F)c2)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
One hundred ml. of methanol were saturated with gaseous methyl amine. Two grams of ethyl 3-(3-trifluoromethylphenyl)-4-amino-5-isothiazolecarboxylate were added. The reaction mixture was stirred at ambient temperature for about 30 minutes and was then heated to refluxing temperature for about 30 minutes. TLC indicated some amide had formed. Gaseous methylamine was bubbled through the refluxing reaction mixture for about 4 additional hours, at which time TLC indicated starting material was no longer present. The reaction mixture was poured into an ice-water mixture. N-methyl 3-(3-trifluoromethylphenyl)-4-amino-5-isothiazolecarboxamide formed in the above reaction precipitated and the precipitate collected by filtration. M.P. 113° C. (after vacuum drying). Yield 1.4 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[C:11]([N:17]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]3)[C:12]([CH:15]=O)=[N:13][CH:14]=2)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[C:11]([N:17]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]3)[C:12]([CH:15]=[N:25][OH:26])=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)cnc2C=O)n1
Agent: Cl
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)cnc2C=NO)n1

Procedure:
Was prepared according to example 20 from 5-(4-chloro-phenylamino)-3-(3,5-dimethyl-pyrazol-1-yl)-pyrazine-2-carbaldehyde and hydroxylamine, hydrochloride.