Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:11]([CH3:23])[C:10]([C:24]3([CH3:29])OCC[O:25]3)=[N:9]2)=[CH:4][CH:3]=1.[ClH:30]>>[ClH:30].[C:24]([C:10]1[C:11]([CH3:23])=[C:12]([O:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:13](=[O:14])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)(=[O:25])[CH3:29]
Reactant: Cc1c(C2(C)OCCO2)nn(-c2ccc(F)cc2)c(=O)c1OCc1cccnc1
Agent: Cl
Product: CC(=O)c1nn(-c2ccc(F)cc2)c(=O)c(OCc2cccnc2)c1C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(4-fluorophenyl)-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-4-(3-pyridylmethoxy)-3(2H)-pyridazinone (320 mg) in N,N-tetrahydrofuran (12 ml) was added 6N hydrochloric acid (1.4 ml), followed by stirring at room temperature for 17 hours. The solvent was removed by evaporation, a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue to adjust the pH to about 10 and then the mixture was extracted with chloroform. After washing with water and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and a 4M hydrogen chlorid/1,4-dioxane solution (10 ml) was added to the resulting residue, followed by stirring at room temperature for 10 minutes. The solvent was removed by evaporation, and the resulting residue was crystallized from ether to obtain 6-acetyl-2-(4-fluorophenyl)-5-methyl-4-(3-pyridylmethoxy)-3(2H)-pyridazinone hydrochloride (190 mg) (Compound No. 1-114).
Reaction SMILES: N.C([N:5](CC)C(C)C)(C)C.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=1>ClCCl>[Cl:11][C:12]1[N:17]=[C:16]([NH2:5])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: ClCCl
Product: Nc1nc(Cl)ncc1[N+](=O)[O-]
Yield: 90.1 %

Procedure:
Aqueous ammonia (8.0 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (10.0 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 1 hour. The precipitate was filtered off. The filter cake was recrystallized to obtain a yellow solid (8.1 g) in a yield of 90.1%. 1H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 9.02 (s, 1H), 8.60 (s, 1H) ppm.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C:9](=[C:12]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH2:16][CH2:15][C:14]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:13]2=3)[CH2:8][CH2:7]1)=O)C>S(=O)(=O)(O)O>[CH:21]1[CH:20]=[N:19][C:18]2[C:12]([C:13]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:14]=3[CH2:15][CH2:16][C:17]=2[CH:22]=1)=[C:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Agent: O=S(=O)(O)O
Product: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Temperature: 102.5 °C
Yield: 96.5 %

Procedure:
A mixture of 4-(8-chloro-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylic acid ethyl ester (loratadine) (100.0 g, 0.26 mol), and 50% aqueous sulfuric acid (300 ml) was heated to 100-105° C. for 3 hrs. The reaction mass was cooled to ambient temperature and quenched into ice cold water (300 ml). The pH of the quenched mass was adjusted to pH 4.0 to 5.0 with liquor ammonia and charcoalized (5 g decolorizing charcoal). The pH of the charcoalized solution was adjusted to >9.5 with liquor ammonia, and sticky semi-solid mass which separated was extracted into toluene (700 ml). The toluene extract was concentrated under reduced pressure at below 65° C. and degassed to obtain an off-white to white solid of desloratadine (yield 78.0 g, 96%, purity >99.0%). HPLC analysis of the sample (as per the procedure described in example 2) did not show any peak due to impurity at relative retention time of 0.85 to 0.99 (relative to desloratadine peak).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][C:32]#[C:33][CH2:34][OH:35])[N:18]=[C:17]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:42][O:43][CH:44]1[C:49](=S(=O)=O)[C:48]([O:53][CH3:54])=[N:47][C:46](C)=[N:45]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][C:32]#[C:33][CH2:34][O:35][C:46]3[N:47]=[C:48]([O:53][CH3:54])[CH:49]=[C:44]([O:43][CH3:42])[N:45]=3)[N:18]=[C:17]([C:36]3[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=3)[N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1=NC(C)=NC(OC)C1=S(=O)=O
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ccncc2)nc1OCC#CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(OCC#CCOc2nc(-c3ccncc3)nc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2Oc2ccccc2OC)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 20.1 %

Procedure:
A suspension of 400 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide (Example 2c), 116 mg of 4,6-dimethoxy-2-methyl-sulfonylpyrimidine and 147 mg of potassium carbonate in 15 ml of DMF was stirred at 90° C. for 16 h. Further 42 mg of 4,6-dimethoxy-2-methyl-sulfonylpyrimidine was added and stirring was continued at 90° C. for 24 h. Eventually, the solvent was removed in vacuo, and the resulting residue partitioned between 50 ml of 5% aqueous acetic acid and 50 ml of DCM. The organic layer was separated and the aqueous layer was extracted two more times with 50 ml of DCM. The combined organic layers were washed with water, dried over MgSO4 and evaporated. The remaining oil was purified by column chromatography on silica gel eluting with toluene: ethyl acetate 4:1 to 1:1. The product obtained was recrystallised from ethyl acetate:diethyl ether to give 76 mg of 4-tert.-butyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide as white crystals. LC-MS: tR=5.84 min, [M+1]+=713.35, [M−1]−=711.45.
Reaction SMILES: [F:1][CH:2]([F:21])[C:3]1[C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][N:6]=[C:5]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[N:4]=1.[OH-].[Na+].Cl>C(O)C>[F:21][CH:2]([F:1])[C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=[C:5]([C:14]([F:20])([F:19])[C:15]([F:16])([F:17])[F:18])[N:4]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)C(F)(F)F)nc1C(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc(C(F)(F)C(F)(F)F)nc1C(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.15 g (3.59 mmol) of ethyl 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carboxylate are dissolved in 4 ml of ethanol. 5.39 ml (10.8 mmol) of 2M sodium hydroxide solution are added and the reaction mixture is stirred for four hours at room temperature. 2M hydrochloric acid is added to establish a pH of 2-3. The resulting solid is filtered off with suction, washed with a small amount of water and triturated with cyclohexane. This gives 870 mg of 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carboxylic acid (83%) as a white solid.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][C:4]1[O:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[N:7][N:8]=1>O.C1COCC1.[Zn]>[CH3:3][C:4]1[O:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:7][N:8]=1
Reactant: Cc1nnc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc(N)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
Ammonium chloride (1.12 g, 21 mmol) in water (5 mL) was added to a stirred solution of 2-methyl-5-(4-nitro-phenyl)-[1,3,4]oxadiazole (530 mg, 2.6 mmol) in THF (10 mL). Zinc powder (1.4 g, 21 mmol) was added portion wise and the mixture was stirred at room temperature for 1 hour then heated to reflux at 65° C. for 5 hours. The mixture was then filtered over celite and the filtrate was concentrated. The residue was extracted with ethyl acetate and the organics were washed with brine solution, dried over Na2SO4 and concentrated. The residue was purified by column chromatography using basic alumina (4% methanol in chloroform) to afford 220 mg (48%) of 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl amine. 1H NMR: (CDCl3): δ 7.8 (d, 2H), 6.7 (d, 2H), 4.0 (s, 2H), 2.6 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=NC=2)=[CH:4][CH:3]=1.Br[C:17]1C=CC(C#N)=C[N:18]=1.BrC1C=CC(B(O)O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:17][N:18]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Br)nc1
Reactant: N#Cc1ccc(-c2ccc(Br)cc2)cn1
Agent: OB(O)c1ccc(Br)cc1
Product: N#Cc1ccc(-c2ccc(Br)cc2)nc1
Yield: 78 %

Procedure:
The same procedure described for 5-(4′-bromophenyl)-2-pyridinecarbonitrile was used by employing 2-bromo-5-cyanopyridine and 4-bromophenylboronic acid to furnish 81 in 78% yield; mp 157-159° C. 1H NMR (DMSO-d6): δ 7.74 (d, J=8.8 Hz, 2H), 8.12 (d, J=8.8 Hz, 2H), 8.22 (d, J=8.4 Hz, 1H), 8.40 (dd, J=2.4, 8.4 Hz, 1H), 9.09 (d, J=2.4 Hz, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd]>[CH2:18]([O:17][C:10]1([O:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:19]
Reactant: [H][H]
Reactant: CCOC1(OCC)CCCN(Cc2ccccc2)C1
Agent: [Pd]
Product: CCOC1(OCC)CCCNC1

Procedure:
A mixture of 15 g. of 1-benzyl-3,3-diethoxypiperidine in 100 ml. of absolute alcohol and 0.5 g. of 10% palladium on charcoal is shaken over 50 p.s.i. of hydrogen at 50° C. for six hours. The catalyst is filtered and washed with ethanol. The solvent is removed by distillation to give 3,3-diethoxypiperidine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1Cl
Temperature: 0 °C
Yield: 84.6 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (85 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09 mmol), and then the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 60/40 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (210 mg, 85%) as a colorless oil: EI-HRMS m/e calcd for C20H23N2O3SCI (M+) 406.1118, found 406.1120.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:11]([C:12](OCC)=[O:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.[OH-].[Na+]>O1CCCC1>[F:18][C:2]([F:1])([F:17])[C:3]1[C:11]([CH2:12][OH:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nn2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1c(C(F)(F)F)nn2ccccc12
Temperature: 70 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
A solution of 2.8 g (11 mmol) of ethyl 2-trifluoromethylpyrazolo[1,5-α]pyridine-3-carboxylate in 50 ml of tetrahydrofuran is added dropwise to a suspension of 0.5 g (12 mmol) of lithium aluminum hydride in 45 ml of tetrahydrofuran. The reaction medium is then stirred at 70° C. for 3 h. After dropwise addition of 2.5 ml of methanol and then of 1.8 ml of an aqueous solution of sodium hydroxide having a concentration of 2N, the reaction medium is stirred for 20 min at ambient temperature and then filtered. The filtrate is dried over magnesium sulfate, filtered and concentrated under vacuum. 2.3 g (100%) of (2-trifluoromethylpyrazolo[1,5-α]pyridin-3-yl)methanol are obtained in the form of a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:23])[CH:4]([C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[CH2:5][C:6]1[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1
Solvent: C1COCCO1
Product: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1
Reaction time: 6.5 h

Procedure:
To a suspension of 3-(3,5-dimethoxy-phenyl)-2-(4-hydroxy-phenyl)-acrylic acid methyl ester (2.1 g) in dioxane (60 mL) 10% palladium on carbon (50% wet, 2.1 g) was added. Hydrogenation was carried out in a Parr shaker at 70 psi for 6.5 h. Catalyst was filtered through a bed of Celite and solvent was evaporated. Yield: quantitative. Analysis: 1HNMR (CDCl3): δ7.15 (d, J=8.7 Hz, 2H), 6.74 (d, J=8.7 Hz, 2H), 6.29(t, J=2.4 Hz, 1H), 6.25(d, J=2.4 Hz, 2H), 3.78 (t, J=8.7 Hz, 1H), 3.72(s, 6H), 3.62(s, 3H), 3.31(dd, J=13.5 & 8.4 Hz, 1H), 2.93(dd, J=13.5 & 6.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7](OS(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[CH:23]=1.[Br-].[C:25]([CH2:27][CH2:28][CH2:29][Zn+])#[N:26]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([CH2:29][CH2:28][CH2:27][C:25]#[N:26])[C:6]=2[CH:23]=1
Reactant: N#CCCC[Zn+]
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(=O)oc3ccc(Cl)cc23)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: N#CCCCc1cc(=O)oc2ccc(Cl)cc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
Toluene-4-sulfonic acid 6-chloro-2-oxo-2H-1-benzopyran-4-yl ester (1.05 g, 3 mmol) is dissolved in THF (30 mL) under nitrogen and [P(o-tolyl)3]2PdCl2 (120 mg, 0.15 mmol) is added 3-cyanopropylzinc bromide (9 mL of a 0.5 M solution in THF, 4.5 mmol) is added and the resulting yellow solution is stirred at 60° C. for 2 hrs. Silica gel is added to the dark red reaction mixture, which is concentrated in vacuo and purified by flash column chromatography eluting with CH2Cl2 and gradually increasing polarity to 1% MeOH—CH2Cl2 to give a residue which is triturated with Et2O to give the title compound (0.54 g, 73%) as a cream solid. 1H NMR (DMSO-d6, 400 MHz) d 7.92 (1H, d, J=2 Hz), 7.68 (1H, dd, J=9, 2 Hz), 7.46 (1H, d, J=9 Hz), 6.47 (1H, s), 2.90 (2H, t, J=7 Hz), 2.63 (2H, t, J=7 Hz), 1.94 (2H, q, J=7 Hz). LCMS (MeCN—H2O, MeCN—H2O, Luna 3 m C18(2) 30×4.6mm; (ESI Pos.) calcd for C13H10ClNO2 m/z [M+H]=248; found [no mass ion detected].
Reaction SMILES: OS(O)(=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:12]1[N:13]=[CH:14][N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH:21]3[CH2:25][CH2:24][NH:23][C:22]3=O)[C:16]=12>O1CCCC1>[NH:23]1[CH2:24][CH2:25][CH:21]([CH:17]2[CH2:18][CH2:19][CH2:20][N:15]3[CH:14]=[N:13][CH:12]=[C:16]23)[CH2:22]1
Reactant: O=C1NCCC1C1CCCn2cncc21
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: c1ncn2c1C(C1CCNC1)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.14 ml of conc. H2SO4 are added dropwise to a suspension of 0.19 g of lithiumaluminium hydride and 10 ml of terahydrofuran at 0° C. After stirring for 30 minutes a solution of 0.41 g of 3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)pyrrolidin-2-one and 10 ml of tetrahydrofuran is added dropwise, and the mixture is then warmed to room temperature. After 1 hour, the reaction mixture is cooled to 0° C. and quenched successively with 1 ml of tetrahydrofuran/water (1:1) and 3 ml of 5% NaOH. The precipitate is filtered off and washed with tetrahydrofuran (2×)—the combined organic phases are dried with sodium sulphate and evaporated. The crude title compound is obtained from the residue.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:25])[C:23]#[N:24])=[C:18]([F:26])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2(CCC3C=CC(C4(C#N)CCC4)=C(F)C=3)CC(O)=C(CC3N=C4N=C(C)C=C(C)N4N=3)C(=O)O2)CCCC1.[CH3:67][C:68]1[CH:69]=[N:70][C:71]2[N:72]([N:74]=[C:75]([CH:77]=O)[N:76]=2)[CH:73]=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:25])[C:23]#[N:24])=[C:18]([F:26])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:77][C:75]3[N:76]=[C:71]4[N:70]=[CH:69][C:68]([CH3:67])=[CH:73][N:72]4[N:74]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc2nc(C=O)nn2c1
Reactant: CC(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(C5(C#N)CCC5)c(F)c4)(C4CCCC4)OC3=O)nc2n1
Product: Cc1cnc2nc(CC3=C(O)CC(CCc4ccc(C(C)C#N)c(F)c4)(C4CCCC4)OC3=O)nn2c1

Procedure:
The title compound was prepared analogously to example A(236) substituting 2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-propionitrile from example A(241) in place of 1-(4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclobutanecarbonitrile and 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in place of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. 1H NMR (400 MHz, CDCl3) δ: 1.66-2.00 (m, 8H), 2.30 (s, 2H), 2.36 (s, 2H), 2.49-2.62 (m, 4H), 2.69-2.85 (m, 3H), 3.49-3.59 (m, 1H), 3.89-3.94 (m, 1H), 4.01-4.08 (m, 2H), 4.18 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 4-benzylpiperidine (10.5 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (11.5 mg). Calcd for C23H24N2O2: 360.1838, found 360.1842.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[C:17]([NH:25][CH3:26])[N:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([NH:4][CH:1]([CH3:3])[CH3:2])[C:18]([N+:22]([O-:24])=[O:23])=[C:17]([NH:25][CH3:26])[N:16]=1
Reactant: CC(C)N
Reactant: CNc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Cl)nc(NC(C)C)c1[N+](=O)[O-]
Yield: 82.1 %

Procedure:
Isopropylamine (4.5 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitro-6-methylaminopyrimidine (11.5 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for half an hour. Purification was conducted by a column chromatography to obtain a yellow solid (10.4 g) in a yield of 82.1%. 1H NMR (400 MHz, CDCl3): δ8.17 (s, 1H), 4.48 (m, 1H), 2.78 (s, 3H), 1.31 (d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:17])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]([CH2:13][CH:14]=O)[C:10](=[O:16])[CH:9]=[CH:8]2)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.CO.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[C:4]([F:17])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]([CH2:13][CH2:14][N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:22][CH2:23]1)[C:10](=[O:16])[CH:9]=[CH:8]2)[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCc1c(F)cnc2ccc(=O)n(CC=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCc1c(F)cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c12
Reaction time: 3 h
Yield: 77.9 %

Procedure:
(8-Ethyl-7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde (0.168 g, 0.718 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (0.172 g, 0.860 mmol) was dissolved in CHCl3 (6 ml) and MeOH (0.6 ml) at rt under argon, whereupon NaBH(OAc)3 (0.497 g, 2.34 mmol) was added, after which it was stirred for 3 h. The reaction was then purified by chromatography on silica gel using a 0-20% MeOH in EtOAc gradient to give the title compound as a yellow oil (0.234 g, 72%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][N:31]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f27) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]([OH:21])=O)[NH:16][C:15]2=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:24](C)C=O.C(Cl)(=O)C(Cl)=O>O1CCCC1.O>[C:19]([C:17]1[NH:16][C:15](=[O:22])[N:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:18]=1)(=[O:21])[NH2:24]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)O)[nH]c2=O)CC1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(N)=O)[nH]c2=O)CC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (355 mg, 1.140 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL,) and N,N-dimethylformamide (15 μl, 0.194 mmol). Mixture was cooled to −10° C. Oxalyl chloride (150 μL, 1.714 mmol) was added to the mixture drop-wise. Reaction mixture was warmed to room temperature and held with stirring for 1 hour. Another 60 μL of oxalyl chloride was added to the mixture. Reaction stirred at room temperature for 30 minutes. Mixture was cooled to −10° C. Ammonia gas was bubbled through the mixture for 5 minutes. Reaction was held at −10° C. with stirring for 30 minutes. Mixture was warmed to room temperature and then diluted with water. Material was extracted three times with ethyl acetate and the aqueous phase was discarded. Material was washed with brine and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as off-white solid in 79% yield. MS (M−H)−=309.2.