Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][CH2:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:24]([CH:29](CO)[CH2:30][OH:31])CCCC.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9](/[CH:12]=[CH:13]/[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH:20]3[O:31][CH2:30][CH2:29][CH2:24][O:21]3)=[CH:22][CH:23]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](/C=C/CCc2ccc(C=O)cc2)CC1
Reactant: CCCCCC(CO)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](/C=C/CCc2ccc(C3OCCCO3)cc2)CC1
Reaction time: 2 h

Procedure:
a solution of 3 g of 4-[4E-(trans-4-pentylcyclohexyl)-3-butenyl]benzaldehyde and 1.7 g of 2-pentyl-1,3-propanediol in 50 ml of toluene was treated with 2 drops of 10% (vol.) sulphuric acid. The mixture was heated to boiling for 2 hours, whereby the resulting water was simultaneously distilled off. Then, 4 drops of triethylamine were added to the reaction mixture. After cooling the mixture was washed with 50 ml of 1N sodium hydrogen carbonate solution and twice with 50 ml of water each time, dried over magnesium sulphate, filtered and subsequently concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from acetone gave 1.2 g of trans-5-pentyl-2-(4-[4E-(trans-4-pentylcyclohexyl)-3-butenyl]phenyl-1,3-dioxane.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]2[CH2:23][CH2:22][S:21][C:20]=2[C:24](OC)=[O:25])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:24](=[O:25])[C:20]3[S:21][CH2:22][CH2:23][C:19]=3[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: COC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)CCS1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)SCC3)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[2-(methoxycarbonyl)-4,5-dihydro-thien-3-yl]ureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-4-fluoro-5-{1,4,6,7-tetrahydro-2,4-dioxo-thieno[3,2-d]pyrimidin-3(2H)-yl}-benzoate, m.p. 252°-254° C.,
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[CH:17][N:18]=[C:19]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[N:15]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:14]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.C1CC=CCC=1>[OH-].[OH-].[Pd+2]>[NH:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[CH:17][N:18]=[C:19]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[N:15]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:14]=2)[CH:10]=[N:9]1
Reactant: c1ccc(Cn2cc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)cn2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCC=CC1
Product: c1cncc(-c2cc3c(-c4cn[nH]c4)nn(C4CCCCO4)c3cn2)c1
Yield: 56.7 %

Procedure:
A mixture of 234 mg (0.54 mmol) of 3-(1-benzyl-1H-pyrazol-4-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine, 3.0 ml (32 mmol) of 1,4-cyclohexadiene and 400 mg of 20% palladium hydroxide on carbon was heated to reflux for 8 hours. The mixture was filtered, the filtrate concentrated in vacuum to afford 106 mg (31%) of 3-(1H-Pyrazol-4-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine over three steps. ESI MS m/z 347.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=1[C:9]1([CH2:18][CH3:19])[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]1=[O:17].Br.N>ClCCl.C(O)(=O)C>[CH2:18]([C:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[CH:2]=2)[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]1=[O:17])[CH3:19]
Reactant: CCC1(C2=C(Cl)C(=O)CCC2)CCCCN(C)C1=O
Agent: Br
Agent: N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC1(c2cccc(O)c2)CCCCN(C)C1=O

Procedure:
A solution of 3-(2-chloro-3-oxocyclohex-1-enyl)-3-ethyl-hexahydro-1-methylazepin-2-one (5.68 g) in dichloromethane (60 ml) was treated with 48% HBr in acetic acid (2 ml). After 12 hours the mixture was treated with excess aqueous ammonia, the organic solvent removed under reduced pressure and the resulting solid removed by filtration to give the title compound, m.p. 178°-80° C. (EtOAc).
Reaction SMILES: Cl.[CH2:2]([C@H:5]1[CH2:9][NH:8][CH2:7][C@@:6]1([N:22]=[N+:23]=[N-:24])[C:10]([O:12][CH2:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH:3]=[CH2:4].[C:25]([O:29][C:30]([N:32]1[CH:41]([C:42](O)=[O:43])[CH2:40][C:39]2[C:34](=[CH:35][C:36]([Cl:45])=[CH:37][CH:38]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCN(CC)CC.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[CH2:2]([C@H:5]1[CH2:9][N:8]([C:42]([CH:41]2[CH2:40][C:39]3[C:34](=[CH:35][C:36]([Cl:45])=[CH:37][CH:38]=3)[CH2:33][N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])=[O:43])[CH2:7][C@@:6]1([N:22]=[N+:23]=[N-:24])[C:10]([O:12][CH2:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH:3]=[CH2:4]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2CC1C(=O)O
Reactant: C=CC[C@H]1CNC[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@H]1CN(C(=O)C2Cc3ccc(Cl)cc3CN2C(=O)OC(C)(C)C)C[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A stirred mixture of racemic 2-oxo-2-phenylethyl (3R,4S)-4-allyl-3-azidopyrrolidine-3-carboxylate hydrochloride (228 mg, 0.650 mmol) and 2-(tert-butoxycarbonyl)-7-chloro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (258 mg, 0.826 mmol) in methylene chloride (6 mL) was treated with Et3N (0.272 mL, 1.95 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 321 mg, 0.845 mmol), and the resulting nearly homogeneous mixture was stirred at room temperature. After 1 h, the reaction was diluted with methylene chloride (20 mL), washed successively with water (20 mL), 1 N aqueous HCl (20 mL), saturated aqueous NaHCO3 (20 mL) and saturated aqueous sodium chloride (10 mL), dried over Na2SO4, and concentrated. Purification by silica gel chromatography (40 g column, 15-25% ethyl acetate in hexanes) gave tert-butyl 3-({(3R,4S)-4-allyl-3-azido-3-[(2-oxo-2-phenylethoxy)carbonyl]pyrrolidin-1-yl}carbonyl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (214 mg, 54%) as a pale amber film which was used without further purification. LC-MS ESI+MS found for C31H34ClN5O6 m/z 608.2 (M+H), 630.3 (M+Na); ESI−MS m/z 606.3 (M−H).
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[C:14]([S:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[N+:24]([O-])=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>[Pd].CO>[NH2:24][C:11]1[CH:12]=[CH:13][C:14]([S:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[CH:15][C:10]=1[N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:8])[CH3:7]
Reactant: Cc1ccc(Sc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(Sc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Yield: 83.4 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-methyl-N-[5-(4-methylthiophenoxy)-2-nitrophenyl]carbamate (2.53 g), palladium on carbon (10%, 2.5 g) and methanol (55 ml) and the reaction mixture was purified to give the title compound (1.94 g).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.[OH:20][CH:21]([CH3:29])[C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CCCC)CCCC)CCC.N1C=CN=N1>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.C(OCC)C>[C:21]([CH:22]([CH2:28][C:7]1[CH:6]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)[C:4]([F:19])=[CH:3][C:2]=1[Cl:1])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[CH3:29]
Reactant: Cc1nn(-c2cc(I)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: C=C(C(=O)OCC)C(C)O
Agent: Cl[Pd]Cl
Agent: c1c[nH]nn1
Solvent: CCCCN(CCCC)CCCC
Solvent: N#Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl)C(C)=O
Temperature: 130 °C
Reaction time: 2 h
Yield: 103.7 %

Procedure:
To a 50 mL roundbottom flask equipped with a mechanical stirrer and a thermometer were added 8.12 grams (0.02 mole--1.0 equiv.) of 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, 2.88 grams (0.02 mole--1.0 equiv.) of ethyl 3-hydroxy-2-methylenebutanoate, 7.4 grams (0.04 mole--2.0 equiv.) of tributylamine, and 0.077 gram (0.0002 mole--0.01 equiv.) of bis(benzonitrile)dichloropalladium(II). The reaction mixture was heated to 130° C., where it stirred for two hours. After this time TLC analysis of the reaction mixture indicated 100% conversion of the triazole starting material. To the reaction mixture was then added 50 mL of diethyl ether. The resulting mixture was washed with 6M sulfuric acid, water, and an aqueous saturated sodium chloride solution and then concentrated, yielding 8.7 grams of 75.5% pure ethyl α-acetyl-2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenzenepropanoate (84.9% yield). The 75.5% pure product was distilled at 200° C. and 0.01 mm of mercury, yielding 6.0 grams of 95.5% pure ethyl α-acetyl-2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenzenepropanoate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Mg].C(Br)C.CN([CH:18]=[O:19])C>C1COCC1>[CH3:10][O:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([Cl:8])[CH:5]=1)[CH:18]=[O:19]
Reactant: COc1cc(Cl)cc(Cl)c1
Reactant: CN(C)C=O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: COc1cc(Cl)cc(C=O)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
3,5-Dichloroanisol (1.1 g; 6.8 mmol) was added in portions to magnesium chips (0.20 g; 8.2 mmol) in THF (dry, 20 mL). After the first addition, EtBr (0.1 mL) was added to start the reaction. After total addition the reaction mixture was stirred at 60° C. overnight, whereafter the mixture was cooled to 0° C., and DMF was added. After stirring for 1 hour, the mixture was poured onto HCl/aq, concentrated, and extracted with ether (3×50 mL). The combined organic phase was washed with water, dried (Na2SO4), and concentrated, yielding 2.35 g of the sub-title compound.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1.[C:15](=O)(O)[O-].[Na+]>CO>[NH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1
Reactant: O=C([O-])O
Reactant: NC1CCC(C(=O)O)CC1
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCC(N)CC1
Reaction time: 14 h

Procedure:
Thionyl chloride (4.15 g, 34.92) was added to a cold (0° C.) stirred solution of 4-aminocyclohexane carboxylic acid (1 g, 6.98 mmol) in MeOH (10 mL). The reaction mixture was stirred under reflux conditions for 12-16 h. The reaction mixture was then concentrated under reduced pressure. The residue obtained was diluted with ice cold water, basified with aqueous sodium bicarbonate solution and extracted with DCM. The DCM layer was washed with water followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 650 mg of the title compound as a brown liquid. MS (ESI): m/z 158 (M+H)
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:25]([CH3:27])([CH3:26])[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:28]([O:30]C)=[O:29])[CH:22]=3)[NH:17]2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[C:25]([CH3:27])([CH3:26])[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:28]([OH:30])=[O:29])[CH:22]=3)[NH:17]2)=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)c3ccccc3)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NC(=O)c2ccccc2)cc1
Yield: 79.6 %

Procedure:
A mixture of methyl 2-(4-benzamidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (67 mg, 0.16 mmol) in methanol (8 mL) and aqueous sodium hydroxide solution (1 M, 1.2 mL, 1.2 mmol) was heated to reflux for 5 h, LC-MS showed the reaction was complete. The solvent was removed in vacuo and the residue was acidified with 2 M hydrochloric acid solution until lots of yellow solid precipitated, which was collected by filtration to afford 51 mg of 2-(4-benzamidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid in 80% yield. MS (ESI+APCI) M+1=401.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[CH:16]=[CH:15][C:14]([C:18]#[N:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:20]#[N:21])[CH:10]=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[F:24][C:25]([F:34])([F:33])[C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].O>CS(C)=O>[CH2:1]([N:5]1[C:17]2[CH:16]=[CH:15][C:14]([C:18](=[NH:19])[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[C:26]([C:25]([F:33])([F:34])[F:24])[CH:27]=3)=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:20]#[N:21])[CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c2ccc(C#N)cc2c2cc(C#N)ccc21
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCn1c2ccc(C#N)cc2c2cc(C(=N)Nc3cccc(C(F)(F)F)c3)ccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 28.3 %

Procedure:
A slurry of 9-butyl-3,6-dicyanocarbazole (4 g, see Example 1C) and sodium hydride (50% in oil, 1.41 g) in 20 ml of anhydrous dimethylsulfoxide is treated dropwise with m-trifluoromethylaniline (4.72 g). The reaction mixture is stirred at room temperature for four days and then poured into 500 ml of water and stirred vigorously for two hours. The resultant precipitate is collected by filtration and purified by column chromatography using one liter of silica gel. Elution with dichloromethane and 1% ethyl acetate/dichloromethane yields 1.8 g of 9-butyl-6-cyano-N-[3-(trifluoromethyl)-phenyl]-9H-carbazole-3-carboximidamide. Elution with 20% ethyl acetate/dichloromethane and ethyl acetate/dichloromethane/methanol (2:7:1) yields 1.6 g of the desired diamidine, which is recrystallized from two liters of water containing 15 ml of 10% hydrochloric acid to yield 1.5 g of the title compound, melting point 205°-210° C.
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:7]([CH2:15]CC(O)=O)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.[H-].[Na+].O.[CH3:31]N(C)C=O>C1(C)C=CC=CC=1>[CH3:31][O:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:7]([CH3:15])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)CCC1=C(c2ccccc2)c2ccc(O)cc2Sc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)Sc1ccccc1C(C)=C2c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
7-hydroxy-11-[(2-carboxy)ethyl]-10-phenyldibenzo[b,f]thiepin (1.87 g) in dry dimethylformamide (25 ml) was treated with sodium hydride (0.4 g of 75%) and stirred, first at room temperature and then at 50° C. until effervescence ceased. A solution of 1-chloro-2-NN-dimethylamino-ethane in toluene (15 ml of 1 M) was added and the mixture was heated with stirring under argon to 100° C. After 1.5 hours the mixture was allowed to cool, treated with water and extracted three times with ethyl acetate. The ethyl acetate solution was evaporated and the residue dissolved in methanol (10 ml) and 10% aqueous sodium hydroxide (5 ml) and refluxed for 20 minutes. The solvent was mostly removed and the sodium salt was dissolved in 200 ml of boiling water. Carbon dioxide was passed through the boiling solution until the pH fell to 8. This was extracted three times into ethyl acetate with a little methanol. The solution was dried and evaporated.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.Cl[CH2:32][C:33]1[C:38]([C:39]#[N:40])=[CH:37][CH:36]=[CH:35][N:34]=1>O>[C:39]([C:38]1[C:33]([CH2:32][N:4]2[C:5](=[O:16])[C:6]3[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:17])=[N:34][CH:35]=[CH:36][CH:37]=1)#[N:40]
Reactant: N#Cc1cccnc1CCl
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1ncccc1C#N)c(=O)n2C
Temperature: 70 °C
Reaction time: 19 h

Procedure:
202 g (0.68 mol) of 3-methyl-7-(2-butin-1-yl)-8-bromoxanthine, 188.5 g (1.36 mol) of anhydrous potassium carbonate and 1.68 liters of N-methyl-2-pyrrolidone are initially charged in the reactor and heated to 70° C. Subsequently, 119 g (0.75 mol) of 2-chloromethyl-3-cyanopyridine in 240 ml of N-methyl-2-pyrrolidine (NMP) are added dropwise. The reactor contents are stirred at 70° C. for 19 hours. After the reaction has ended, 2.8 liters of water are added to the reaction mixture and it is cooled to 25° C. The product is filtered off, washed with 2 liters of water and dried at 70° C. in a drying cabinet under inertization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: O=C(C=Cc1ccc(Cl)c(Cl)c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 3,4-dichlorobenzaldehyde and acetophenone, 3-(3,4-dichlorophenyl)-1-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [K].[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[NH:15][C:14](=[O:16])[C:13]([F:17])=[CH:12][N:11]=1>C1(C)C=CC=CC=1>[O:8]([C:10]1[NH:15][C:14](=[O:16])[C:13]([F:17])=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(Cl)ncc1F
Reactant: Oc1ccccc1
Agent: [K]
Solvent: Cc1ccccc1
Product: O=c1[nH]c(Oc2ccccc2)ncc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
A 11.7 g quantity of metal potassium is added to 200 ml of absolute toluene, and a mixture of 28 g of phenol and 100 ml of absolute toluene is further added dropwise to dissolve the potassium. Subsequently 14.9 g of 2-chloro-5-fluoropyrimidin-4-one is added to the solution, and the mixture is stirred at 100° C for 8 hours. The reaction mixture is thereafter treated in the same manner as in Example 6 to give 13.2 g of white crystalline 2-phenoxy-5-fluoropyrimidin-4-one in a yield of 64.1 %, m.p. 224°-225° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(Cc2ccc(F)cc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCN1CCC(Cc2ccc(F)cc2)CC1

Procedure:
A solution of 2-{2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethyl}-isoindole-1,3-dione (0.087 g, 0.24 mmol) in ethanol (20 ml) is treated with hydrazine hydrate (1.0 ml, 2 mmol) and heated under reflux for 1.5 hours. Most of the solvent is evaporated and the resultant solution is ice cooled for 0.5 hours. The precipitate is filtered off and the filtrate is evaporated to afford 2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethylamine which is used directly, without further characterisation, in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH2:17][CH2:18][NH2:19])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:21]1([C:24]2[C:29]([C:30](O)=[O:31])=[CH:28][N:27]=[C:26]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)[N:25]=2)[CH2:23][CH2:22]1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH2:17][CH2:18][NH:19][C:30]([C:29]2[C:24]([CH:21]3[CH2:23][CH2:22]3)=[N:25][C:26]([C:33]3[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:37][CH:38]=3)=[N:27][CH:28]=2)=[O:31])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(CCN)cc(OC)c1
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Product: CCOC(=O)C(C)(C)Oc1cc(CCNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc(OC)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-5-methoxy-phenoxy]-2-methyl-propionic acid ethyl ester (example 93A]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-[3-(2-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-ethyl)-5-methoxy-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 90 %

Procedure:
To ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (2.2 g) are added conc. hydrochloric acid (5 ml), water (2 ml) and acetic acid (20 ml), and the mixture is refluxed for 2 hours. After cooling, the precipitated crystals are separated by filtration, and washed with water, ethanol and diethyl ether in this order to give 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.8 g) as a white crystal, m.p. 240°-243° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:27][CH2:26][C:16]1([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:28])[CH2:14][CH2:15]1)=[O:7]
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(Cl)c1F
Product: O=C(NCC1(c2ccc(F)nc2)CCC(F)(F)CC1)c1cccc(Cl)c1F

Procedure:
From 3-chloro-2-fluorobenzoic acid and (4,4-difluoro-1-(6-fluoropyridin-3-yl)cyclohexyl)methanamine. LCMS (MH+): m/z=401.2, tR (minutes, Method D)=0.75
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].CS(O)(=O)=O.[CH2:19](O)[CH3:20]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:19][CH3:20])=[O:12]
Reactant: CCO
Reactant: O=C(O)CCCCCCCCCBr
Agent: CS(=O)(=O)O
Product: CCOC(=O)CCCCCCCCCBr
Yield: 100 %

Procedure:
A solution of 4.4 g (0.018 mole) of 10-bromodecanoic acid, 3 ml of methane sulfonic acid, and 250 ml of absolute ethanol was heated at reflux for 2 h. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to yield 5.0 g (100%) of ethyl 10-bromodecanoate as a yellow oil. A mixture of 4.6 g (0.015 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol, 4.2 g (0.015 mole) of ethyl 10-bromodecanoate, 6.4 g (0.015 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in 50 ml of N,N-dimethylformamide was heated on a steam bath fo 6 h. The mixture was poured into 1 L of water and extracted three times with 250 ml portions of ethyl acetate. The ethyl acetate extracts were combined, washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give a dark oil. The oil was purified by high pressure liquid chromatography (Water Associates Prep LC/System 500A; PrepPAK® 500/silica; ethyl acetate-hexane 2:1; flow rate 150 ml/min). The fractions containing the desired product were combined and concentrated under reduced pressure to yield 4.5 g (60%) of the title compound as a golden, viscous oil.