Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:8]2[C:13](=O)[C@@H:12]3[CH2:15][CH2:16][N:9]2[C@H:10]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:34]=1[CH2:35][NH2:36]>>[C:25]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:8]2[C@H:13]([NH:36][CH2:35][C:34]3[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:33]=3[O:32][CH3:31])[C@@H:12]3[CH2:15][CH2:16][N:9]2[C@H:10]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11]3)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1[C@@H]2CCN([C@H](CCc3ccccc3)C2)[C@@H]1C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(OC)c(CN)c1
Product: COc1ccc(OC)c(CN[C@@H]2[C@@H]3CCN([C@H](CCc4ccccc4)C3)[C@@H]2C(c2ccccc2)c2ccccc2)c1

Procedure:
A compound of Example 4 were prepared from compound 7 and 2,5-dimethoxybenzylamine by the same procedure for Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH3:14])([CH3:13])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:12])[CH2:9]C=O)[CH3:2].C([O:17]C(C)(C)CCCC(C)CC=CC(=O)C)C>>[CH2:1]([O:3][C:4]([CH3:14])([CH3:13])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:12])[CH:9]=[O:17])[CH3:2]
Reactant: CCOC(C)(C)CCCC(C)CC=O
Reactant: CCOC(C)(C)CCCC(C)CC=CC(C)=O
Product: CCOC(C)(C)CCCC(C)C=O

Procedure:
Using 7-ethoxy-3,7-dimethyloctan-1-al as the starting material in the process of either Example 9, 10 or 11, there is prepared 10-ethoxy-6,10-dimethylundec-3-en-2-one.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][OH:7])[C:3]([OH:5])=[O:4].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Cl:1][CH:2]([CH2:6][OH:7])[C:3]([O:5][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])=[O:4]
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)C(Cl)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOC(=O)C(Cl)CO
Reaction time: 40 h

Procedure:
2-chloro-3-hydroxypropionic acid (4.80 g, 0.03 mol), dodecanol (6.00 g, 0.03 mol) were taken with 5 mL dry benzene in a (50 mL) RB, with a dean-stark apparatus and condenser; 25 mg (0.26 mmol) para-Toluene sulfonic acid (pTSA) was added to it and the mixture was stirred at 75° C.-80° C. for 40 h. 1H-NMR showed 85% conversion. More 2-chloro-3-hydroxypropionic acid (1.00 g, 8.00 mmol) was added to it and heated at 75° C.-80° C. for 20 h. 1H-NMR showed almost complete conversion. After cooling it down, the product was added with 100 mL of CH2Cl2. Organic phase was washed twice with 50 mL of dil. NaHCO3 aq. sol. and once with 50 mL of sat. NaCl aq. sol. and then dried over anhy. Na2SO4. After filtration and removing the solvent by rotary evaporation, yield=7.76 g (78%). It was used for the next reaction without further purification. 1H-NMR (CDCl3, 7.27 ppm): 2.18-2.40 (broad, —OH), 3.97 (m, —CH2OH), 4.21 (m, —CO2CH2), 4.39 (m, —CHCl).
Reaction SMILES: Br[C:2]1[C:7]2[C:8]([NH2:11])=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:43])[NH:28][C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=3[NH:39][C:40](=[O:42])[CH3:41])=[CH:22][CH:21]=2)O1>>[NH2:11][C:8]1[C:7]2[C:2]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:43])[NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=4[NH:39][C:40](=[O:42])[CH3:41])=[CH:22][CH:21]=3)=[N:3][CH:4]=[CH:5][C:6]=2[NH:10][N:9]=1
Reactant: CC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Nc1n[nH]c2ccnc(Br)c12
Product: CC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(-c2nccc3[nH]nc(N)c23)cc1

Procedure:
4-Bromo-1H-pyrazolo[4,3-c]pyrid-3-ylamine and N-(2-{3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureido}-4-trifluoromethylphenyl)acetamide are coupled by Suzuki reaction according to a protocol similar to that for the preparation of Example 10. A yellow powder of N-(2-{3-[4-(3-amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]ureido}-4-trifluoromethylphenyl)acetamide is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]1[C:8]2[N:4]([C:5]([C:9]([C:11]3[N:12]4[C:16](=[C:17]([C:20]([O:22]CC)=[O:21])[C:18]=3[CH3:19])[CH:15]([C:25]([O:27]CC)=[O:26])[CH2:14][CH2:13]4)=[O:10])=[CH:6][CH:7]=2)[CH2:3][CH2:2]1.CO.[OH-].[K+]>O>[CH2:1]1[C:8]2[N:4]([C:5]([C:9]([C:11]3[N:12]4[C:16](=[C:17]([C:20]([OH:22])=[O:21])[C:18]=3[CH3:19])[CH:15]([C:25]([OH:27])=[O:26])[CH2:14][CH2:13]4)=[O:10])=[CH:6][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)c(C(=O)c2ccc3n2CCC3)n2c1C(C(=O)OCC)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)c2n(c1C(=O)c1ccc3n1CCC3)CCC2C(=O)O
Yield: 100.6 %

Procedure:
A mixture of the diester from Step B (1.62 g, 0.004 m), methanol (15 ml), water (5 ml), and potassium hydroxide (1.6 g, 0.026 m) was refluxed in an inert atmosphere for 5.5 hours, cooled, diluted with water (ca. 80 ml), filtered, the filtrate acidified with 2N hydrochloric acid, and the cooled, aged mixture filtered. After drying the well-washed (water) solid, 1.4 g of 5-(2,3-dihydro-1H-pyrrolizin-5-oyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-1,7-dicarboxylic acid is obtained as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26]1[CH:27]=[CH:28][C:29]([OH:39])=[C:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:27]=[CH:28][C:29]([O:39][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[C:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=1)[CH3:24]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1cc(OCC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cc(OCC)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.44 g), ethyl 3-(5-ethoxy-2-hydroxyphenyl)propionate (1.0 g), anhydrous potassium carbonate (0.58 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 3-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate as an oil (1.57 g, 72%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1.C([O-])(O)=O.[Na+]>O>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[N:11][CH:12]=1
Reactant: Cc1ccc(Cl)nc1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Nc2ccc(O)cc2)nc1
Temperature: 180 °C

Procedure:
A mixture of 4-aminophenol (2 g, 18.33 mmol) and 2-chloro-5-methylpyridine (2.57 g, 20.16 mmol) was heated neat at 180° C. in 2 h. The reaction mixture was cooled, taken up in H2O, neutralized with saturated NaHCO3, extracted with DCM (3×). The extracts were dried over MgSO4, concentrated to give the dark purple solid. MS (ESI, pos. ion) m/z: 201.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:28][CH2:27][C:10]2[C:11]3[C:12](O)([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:37])=O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:28][CH2:27][C:10]2[C:11]3[C:12]([Cl:37])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)(c1ccccc1)C(F)(F)C3
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(Cl)(c1ccccc1)C(F)(F)C3
Temperature: 70 °C

Procedure:
Into a 100 ml flask, the product from step (c) (5.78 g, 14.93 mmol) dissolved in thionyl chloride (50 ml) was added. Pyridine (120 μL, 1.49 mmol) was added and the reaction mixture heated to 70° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and the volatiles were evaporated in vacuo. The residue was partitioned between saturated aqueous Na2CO3 and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the sub-title compound as an orange semi-solid (5.9 g) that was used directly in the next step. MS: ESI (positive): 405 (M+1).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:40]>C(Cl)Cl>[CH2:1]([Br:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCBr
Temperature: 25 °C
Yield: 95.5 %

Procedure:
Octadecan-1-ol (1a) (520 mg, 1.92 mmol) and Ph3P (550 mg, 2.10 mmol) were dissolved in CH2Cl2 (25 mL). The mixture was cooled in an ice bath and CBr4 (630 mg, 1.90 mmol) was added with stirring. The mixture was allowed to warm to r.t. and was stirred overnight, then it was concentrated under a stream of N2 and the residue was subjected to flash column chromatography on silica, eluting with hexane, to afford 1-bromooctadecane (2a) (605 mg, 96%) as a waxy solid; mp 26-28° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH3:20])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:30][CH:29]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:20])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(NCCc2ccc(OC)c(C)c2)nc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: CCc1cnc(N(CCc2ccc(O)c(C)c2)Cc2ccc(C(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]pyrimidin-2-amine and 4-trifluoromethylbenzyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]2[CH3:25])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:26]([O:28]C)=[O:27])[CH:15]=2)[N:10]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]2[CH3:25])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:26]([OH:28])=[O:27])[CH:15]=2)[N:10]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3F)c(N3CCCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a solution of (S)-methyl 2-(2,4-difluorophenyl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate (100 mg, 0.25 mmol) in methanol (30 mL) and water (1.0 mL) was added sodium hydroxide (40 mg, 1.00 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (10 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford (S)-2-(2,4-difluorophenyl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (55.5 mg, 57.5%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([O:15]C)[CH:6]=1)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=[O:4]
Reactant: COc1cc(C(=O)CBr)cc([N+](=O)[O-])c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 29.0 g of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone in 700 ml of dry methylene chloride is treated at -20° within 30 minutes with a solution of 125.3 g of boron tribromide in 300 ml of dry methylene chloride. After the addition the mixture is stirred at -20° for a further 1 hour and at room temperature for 16 hours, then evaporated, the residue is treated cautiously with water while cooling with ice and stirred at 50° for 30 minutes. After cooling the mixture is extracted with ether, the ethereal phase is washed with water, dried over sodium sulfate, filtered and evaporated. There is obtained 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone of m.p. 138°-140° (from methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][NH2:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][C:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][NH:34][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[NH:10]1)=[O:28]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(C)(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CCNC(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Yield: 29.5 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with 3,3-dimethylbutylamine (30.36 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)pyrrolidine-2-carboxylic acid (3,3-dimethyl-butyl)-amide (30.4 mg, 29.5%).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=O)[C:2]=1[C:10]([OH:12])=[O:11]>C(OC(=O)C)(=O)C.C(O)(=O)C>[C:10]1(=[O:11])[O:12][C:7](=[O:9])[CH:3]2[CH2:4][CH2:5][CH2:6][CH:1]=[C:2]12
Reactant: O=C(O)C1=CCCCC1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1OC(=O)C2CCCC=C12
Yield: 49.9 %

Procedure:
A stirred solution of 5.0 grams (0.029 mole) of cyclohexene-2,3-dicarboxylic acid in 30 ml of acetic anhydride and 100 ml of acetic acid was heated under reflux for four hours. The reaction mixture was concentrated under reduced pressure to a residual oil. The oil was washed with petroleum ether and evacuated under high vacuum to yield 2.2 grams of 2,3,4,5-tetrahydrophthalic anhydride as a semi-solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([CH2:24][NH:25][C:15]([C:14]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[NH:3][C:2](=[O:1])[C:11]=3[NH:12][CH:13]=2)=[O:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Product: O=C(NCC1CCCCC1)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 7.5 %

Procedure:
This compound is prepared according to synthesis 79 from 75 mg (0.33 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75) and 47 μL (0.36 mmol) of C-cyclohexyl-methylamine. After recrystallization from methanol, 8 mg (8%) of N-(cyclohexylmethyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:15]/[C:16]([OH:18])=[O:17])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)O)c([N+](=O)[O-])c1
Temperature: 125 °C
Yield: 65.2 %

Procedure:
To a mixture of 4-methoxy-2-nitrobenzaldehyde (20 g, 0.11 mol) and malonic acid (28.8 g, 0.28 mol) in pyridine (200 mL) is added piperidine (1 mL, catalytic amount) and the mixture is refluxed at 125° C. under nitrogen for 12 h. After cooling to room temperature, the solvent is removed under reduced pressure and the residue is acidified with 1.5 N HCl. The product is extracted with EtOAc and the organic layer is washed with water and brine then dried over Na2SO4. The solvent is removed under reduced pressure to afford 16 g (65%) of the title compound as a pale brown solid. 1H NMR (DMSO-d6, 400 MHz) δ 12.59 (bs, 1H), 7.91-7.93 (m, 1H), 7.68-7.72 (m, 1H), 7.56 (s, 1H), 7.31-7.33 (m, 1H), 7.46-7.50 (m, 1H), 3.87 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C(O)(C)C.[CH3:16][S:17]([OH:20])(=[O:19])=[O:18]>O.[Pd]>[CH3:16][S:17]([OH:20])(=[O:19])=[O:18].[F:11][C:8]([F:9])([F:10])[CH:6]1[CH2:5][CH2:4][NH:3][C:2]([NH2:1])=[N:7]1
Reactant: Nc1nccc(C(F)(F)F)n1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: NC1=NC(C(F)(F)F)CCN1
Yield: 96 %

Procedure:
A mixture of 6 g of 10% Pd/C and 60 g (370 mmol) of 2-amino-4-(trifluoromethyl)pyrimidine dissolved in 80 mL of water, 250 mL of isopropanol and 24 mL (370 mmol) of methanesulfonic acid is hydrogenated at 5 bar, at 40° C., for 5 hours in an autoclave. The resulting mixture is then filtered and rinsed with isopropanol and with water. The filtrate is then concentrated under reduced pressure and the residue obtained is dried under vacuum to give 93.5 g of 4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine methanesulfonate in the form of a white solid. The white solid is dissolved in 250 mL of methyl isobutyl ketone. 100 mL of 10 N sodium hydroxide are then added. The mixture is stirred at room temperature for 15 minutes. The phases are separated by settling and the aqueous phase is re-extracted with methyl isobutyl ketone. The organic phases are combined and then evaporated under vacuum. 59.50 g of 4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine are thus obtained, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](/[C:11](=[N:13]/[OH:14])/[NH2:12])=[C:4]2[CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].N12CCCN=C1CCCCC2>O1CCOCC1.Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]([C:11]3[NH:12][C:23](=[O:24])[O:14][N:13]=3)=[C:4]2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2/C(N)=N/O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2nn3ccc(Br)cc3c2-c2noc(=O)[nH]2)cc1
Yield: 78.1 %

Procedure:
A mixture of Example 19G (0.74 g, 2.049 mmol), 1,1′-carbonyldiimidazole (0.365 g, 2.254 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.340 mL, 2.254 mmol) in dioxane (10 mL) was refluxed for 1 hour, cooled and diluted with 1 M aqueous HCl. The resulting solid was collected by filtration, washed with water and dried. The solid was triturated twice with 1% methanol in dichloromethane to give the title compound (0.62 g, 78%). MS (ESI+) m/z 387/389 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:32])[C:15]#[C:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([OH:24])[CH2:20][CH2:19]2)=[CH:10][CH:9]=1.CC(C)=O>CCOCC>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([OH:32])[CH:15]=[CH:16][CH2:17][N:18]2[CH2:19][CH2:20][C:21]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([OH:24])[CH2:22][CH2:23]2)=[CH:12][CH:13]=1
Reactant: OC(C#CCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: OC(C=CCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 124.3 %

Procedure:
To an ethereal solution (14 ml) of lithium aluminum hydride (0.37 g) was added a solution of 1-[4-(p-fluorophenyl)-4-hydroxy-2-butynyl]-4-(p-chlorophenyl)-4-hydroxypiperidine (1.20 g) in ether (13 ml) under ice-cooling. After stirring at 10° C for 1.5 hours and further at 25° C for 4 hours, acetone was added thereto in order to consume excess of lithium aluminum hydride. The resulting mixture was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated to afford 1-[4-(p-fluorophenyl)-4-hydroxy-2-butenyl]-4-(p-chlorophenyl)-4-hydroxypiperidine (1.50 g) as white needles, M.P. 149° - 151° C.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][CH:6]([CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13].[N:17]#[C:18]Br>>[CH3:14][CH:6]1[C:7]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:13][C:18]2=[N:17][CH:3]=[CH:4][N:5]12
Reactant: COC(CNC(C)c1ccccc1N)OC
Reactant: N#CBr
Product: CC1c2ccccc2Nc2nccn21

Procedure:
4 g of crude N-(2,2-dimethoxyethyl)-α-methyl-o-amino-benzylamine and 1.9 g cyanogen bromide are reacted and the product is worked up in the same manner as in Example 1e to afford the heading compound. M.p. 171°-172° (crystallisation from ethanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH:21]=[N:20][CH:19]=1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:22]3[CH:21]=[N:20][CH:19]=[N:18][CH:23]=3)=[CH:31][CH:30]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(-c2cncnc2)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cncnc3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-pyrimidin-5-yl-benzaldehyde, of Preparation 26, using the method described in Example 3, Step A, except that the reaction time for imine formation was 1.5 hand no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.93 (s, 2H), 7.65 (m, 1H), 7.48 (m, 3H), 7.24 (m, 1H), 6.94 (m, 2H), 6.77 (d, 1H), 4.51 (s, 2H), 3.85 (s, 2H), 3.79 (s, 2H), 1.46 (s, 9H); MS 406 (M+1).