Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[NH2:13].CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:1]([NH:13][C:12]1[CH:11]=[C:10]([Cl:9])[CH:16]=[C:15]([Cl:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cc(Cl)cc(NCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.3 h

Procedure:
A mixture of benzaldehyde (1.04 g, 9.40 mmol), 3,5-dichloroaniline (1.71 g, 10.60 mmol), and HOAc (0.20 mL) in MeOH (35 mL) was cooled to 0° C. Then a solution of NaBH3CN (28.0 mL, 28.0 mmol, 1.0 M solution in THF) was added dropwise via a syringe pump over 0.25 h. The solution was allowed to stir an additional 0.3 h at 0° C., and then room temperature for 18 h. The excess NaBH3CN was quenched with HCl and the solvent was removed under reduced pressure. The resulting oil was dissolved in EtOAc/H2O, basified with NaOH, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The resulting oil was purified by chromatography (SiO2, 15:1 hexanes/EtOAc) to provide N-benzyl-3,5-dichloroaniline as a white solid. This compound was coupled to 2-chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride as described and purified by chromatography (SiO2, 9:1 hexanes/EtOAc) to provide the title compound (15% yield) as a white foam; m.p. 102°-104° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C:8]3[CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:7]=3[C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1.[N+](=C)=[N-].[H-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C1COCC1.CCOCC>[Br:1][C:2]1[C:10]2[N:9]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][CH:27]=3)[C:8]3[CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:7]=3[C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=C(O)CC1CCc2c1[nH]c1c(Br)cc(F)cc21
Agent: C=[N+]=[N-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)CC1CCc2c1n(Cc1ccc(Cl)cc1)c1c(Br)cc(F)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.9 %

Procedure:
To a solution of 2.13 g of the acid from Step 3 in 10 mL of THF, a solution of diazomethane in ether was added in excess until complete consumption of the acid as monitored on TLC. Then, the solvents were removed under vacuum. To a solution of the crude methyl ester thus formed in 20 mL of DMF, 539 mg of a NaH suspension (60% in oil) was added at −78° C. The suspension was stirred for 10 min at 0° C., cooled again to −78° C. and treated with 1.70 g of 4-chlorobenzyl bromide. After 5 min, the temperature was warmed to 0° C. and the mixture was stirred for 20 min. At this time, the reaction was quenched by the addition of 2 mL of AcOH and this mixture was poured into a separatory funnel containing 1N HCl/EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The alkylated material was hydrolyzed using the procedure described in Step 2. The crude material was further purified by trituration with EtOAc/hexanes to yield 2.35 g of the title compound as a pale brown solid.
Reaction SMILES: Cl.C[C:3]1[N:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][C:4]=1[C:14]1[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH:19]=1>O1CCOCC1>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:7]2[CH:3]=[C:4]([C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=3)[N:5]=[N:6]2)[CH:9]=1
Reactant: Cc1c(C2=CCN(C(=O)OC(C)(C)C)CC2)nnn1-c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Product: C1=C(c2cn(-c3cccnc3)nn2)CCNC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
A 4N solution of hydrochloric acid in dioxane (3 ml) was added to 15 mg of tert-butyl 4-[5-methyl-1-(pyridine-3-yl)-1H-[1,2,3]triazol-4-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate, the mixture was stirred at room temperature for 3 hours and the solvent was evaporated in vacuo to give 6 mg of the title compound as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8]C1C=C(CNCCCNCCCCNCCCN)C=CC=1O.O[C:32]1([CH3:58])[CH2:37][CH:36]([CH:38]([CH3:42])[CH2:39][C:40]#[N:41])[C:35]2[CH:43]=[CH:44][C:45]([CH:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH3:48])=[CH:46][C:34]=2[O:33]1.C(OCC)(=O)C>O1CCCC1>[NH2:41][CH2:40][CH2:39][CH:38]([CH:36]1[C:35]2[C:43]([OH:8])=[CH:44][C:45]([CH:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH3:48])=[CH:46][C:34]=2[O:33][CH:32]([CH3:58])[CH2:37]1)[CH3:42]
Reactant: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Reactant: CC(CCCc1ccccc1)c1ccc2c(c1)OC(C)(O)CC2C(C)CC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1CC(C(C)CCN)c2c(O)cc(C(C)CCCc3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under anhydrous conditions and a nitrogen atmosphere, to a solution of 190 mg (5 mmole) lithium aluminum hydride in 50 ml tetrahydrofuran at 10° C. is added dropwise a solution of 1.885 g (5 mmole) dl-5-hydroxy-4-(1-methyl-2-cyanoethyl)-2-methyl-7-(5-phenyl-2-pentyl)-3,4-dihydro-2H-benzopyran in 25 ml of tetrahydrofuran. After the addition is complete, the mixture is stirred at room temperature for 6 hours. Ethyl acetate is added to consume the unreacted hydride. The reaction mixture is evaporated to dryness, the residue partitioned between water and methylene chloride and the organic layer dried over anhydrous magnesium sulfate. The solvent is evaporated to provide the title compound as the free base.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.Br[CH:26]([CH3:33])[CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>C1COCC1>[O:31]=[C:30]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:33][N:1]1[CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: CC(Br)CCCC(=O)Cl
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(N2CCCCCC2=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
To a solution of benzyl 4-aminopiperidin-1-carboxylate (1.7 g) and triethylamine (1.1 mL) in THF (40 mL) was added dropwise 5-bromohexanoyl chloride (1.1 mL), and the mixture was stirred at 0° C. for 2 hours. The solvent was distilled off under reduced pressure and the residue was diluted with water, and extracted with ethyl acetate. The extract was washed with an aqueous 5% citric acid solution and a saturated saline solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in DMF (40 mL), and cooled at 0° C., sodium hydride (60% in oil; 0.60 g) was added thereto, and the mixture was stirred at 0° C. for one hour, at room temperature for one hour and at 80° C. for 15 hours. The solvent was distilled off under reduced pressure, the residue was diluted with water, and the solution was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated saline solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1 to 5/1) to obtain the title compound (0.25 g, 10%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Fc1ccc(NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 739.9 %

Procedure:
A mixture of 4-fluoroaniline (1 g; 0.9 mmol) and tetrahydro-4H-pyran-4-one (0.98 g; 1.1 equiv.) in methanol (20 ml) was treated with acetic acid (0.67 ml; 1.3 equiv.) and sodium cyanoborohydride (0.73 g; 1.3 equiv.) then stirred at room temperature overnight. The reaction was cooled to 0° C., basified with 2M sodium hydroxide solution and the resultant solid collected by filtration, washed with water and dried under vacuum to give 1.3 g of the title compound. 1H NMR (DMSO-d6) 6.80 (2H, t), 6.48 (2H, dd), 5.25 (1H, d), 3.75 (2H, dt), 3.33-3.23 (3H, m), 1.78-1.71 (2H, m), 1.28-1.18 (2H, m).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 52 h
Yield: 89.5 %

Procedure:
Following procedure A, 4-fluoronitrobenzene (500 mg, 3.54 mmol, 1.00 eq) and 4-tert-butylphenol (671 mg, 4.46 mmol, 1.26 eq) were dissolved in DMF (6.0 mL). Anhydrous K2CO3 (857 mg, 6.20 mmol, 1.75 eq) was added and the reaction mixture was stirred at room temperature for 52 h. After extraction with EtOAc, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100) to afford the title compound as pale yellow solid (860 mg, 3.17 mmol, 89% yield). Rf=0.72 (EtOAc/PE 1:9). HRMS (ESI) calcd. for C16H18NO3+ [M+H]+ 272.1281. found: 272.1272. 1H NMR (400 MHz, CDCl3) δ 8.24-8.16 (m, 2H, aromatic H), 7.49-7.39 (m, 2H, aromatic H), 7.06-6.97 (m, 4H, aromatic H), 1.35 (s, 9H, C(CH3)3). 13C NMR (101 MHz, CDCl3) δ 163.82, 152.29, 148.59, 142.54, 127.27, 126.03, 120.15, 116.98, 34.67, 31.58.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13]CC)=O.[CH3:16][NH2:17]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:17][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc2ccccc2n1C
Reactant: CN
Product: CNC(=O)c1cc2ccccc2n1C
Temperature: 80 °C

Procedure:
A mixture of ethyl 1-methylindole-2-carboxylate (4.06 g, 20 mmol) and methylamine (50 mL) was heated at 80° C. in a sealed glass vessel overnight. The reaction was cooled and the title compound (2.4 g, 64%) was collected by filtration as a colorless solid. MS (ES) m/e 189.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4](=[O:21])[CH:3]=1.P(Cl)(Cl)(Cl)=O.O.[OH-].[K+].CN(C)[CH:32]=[O:33]>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6](=[O:14])[N:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4](=[O:21])[C:3]=1[CH:32]=[O:33]
Reactant: CN(C)C=O
Reactant: Nc1cc(=O)n(-c2ccccc2)c(=O)n1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1c(C=O)c(=O)n(-c2ccccc2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A solution of 6-amino-1,3-diphenyluracil (10.0 g, 35.8 mmol) in dimethylformamide (100 mL) was cooled in an ice bath and phosphorus oxychloride (3.7 mL, 39.4 mmol) was dropped thereinto using a dropping funnel. The reaction mixture was stirred at room temperature for two hours and the reaction was stopped by adding 50 mL of water thereto. The pH was adjusted to 10 by a 1N solution of potassium hydroxide and stirring was carried out at room temperature for one additional hour. Crude crystals separated out therefrom were filtered and, after washing with 100 mL of water, the crude crystals were filtered. The resulting crude crystals were further recrystallized from hexane and ethyl acetate to give 6-amino-5-formyl-1,3-diphenyluracil (2.2 g) in a 40% yield.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].Cl.[CH3:14][N:15]([CH3:33])[C@H:16]1[CH2:21][CH2:20][C@H:19]([O:22][C:23]2[C:24]([CH3:32])=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][N:27]=[CH:26]3)[CH2:18][CH2:17]1.[Cl-].[Na+]>CC(C)=O.C(Cl)(Cl)Cl>[CH3:14][N:15]([CH3:33])[C@H:16]1[CH2:17][CH2:18][C@H:19]([O:22][C:23]2[C:24]([CH3:32])=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([C:9]([O:11][CH3:12])=[O:10])[N:27]=[CH:26]3)[CH2:20][CH2:21]1
Reactant: Cc1c(O[C@H]2CC[C@H](N(C)C)CC2)ccc2[nH]ncc12
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)n1ncc2c(C)c(O[C@H]3CC[C@H](N(C)C)CC3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, triethylamine (135 μl, 0.968 mmol) and methyl chloroformate (37 μl, 0.484 mmol) were added at 0° C. to a solution of monohydrochloride (100 mg, 0.323 mmol) of the trans-N,N-dimethyl-N-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine obtained in Example 412 in acetone (2 ml). After 15 minutes, the mixture thus obtained was warmed up to room temperature. After 1 hour, triethylamine (0.646 mmol) and methyl chloroformate (0.484 mmol) were further added thereto. After 1 hour, chloroform (2 ml) was added thereto. After another 3 hours, the reaction solution was poured into a saturated aqueous sodium chloride solution and extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol) to obtain methyl trans-5-{[4-(dimethylamino)cyclohexyl]oxy}-4-methyl-1H-indazole-1-carboxylate (38.7 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][NH2:27])=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:27][CH2:26][CH2:25][C:24]2[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: NCCc1ccc(F)cc1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccc(F)cc3)cc2F)cn1
Yield: 39.1 %

Procedure:
Using a method similar to Example 405, using 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.040 g, 0.154 mmol) and 4-fluorophenethylamine (0.021 g, 0.154 mmol) gives the title compound (0.0231 g, 39.2%): TOF MS ES+ 384.2 (M+H)+, HRMS calcd for C21H20N3O2F, 384.1524 (M+H)+, found 384.1509, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.8 min, 100% purity.
Reaction SMILES: [C-]#N.[Na+].C1N2CC[N:6](CC2)[CH2:5]1.[Br:12][C:13]1[CH:14]=[N:15][C:16](Cl)=[N:17][CH:18]=1>CS(C)=O.O>[Br:12][C:13]1[CH:14]=[N:15][C:16]([C:5]#[N:6])=[N:17][CH:18]=1
Reactant: C1CN2CCN1CC2
Reactant: Clc1ncc(Br)cn1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 522.6 %

Procedure:
To a solution of sodium cyanide (168.35 mg, 3.36 mmol), triethylenediamine (60 mg, 0.52 mmol) in a mixture of DMSO (0.7 mL) and water (1.4 mL) was added a solution of 5-bromo-2-chloropyrimidine (500 mg, 2.59 mmol) in DMSO (1.3 mL). The solution was stirred at rt overnight, diluted with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give 5-bromopyrimidine-2-carbonitrile (500 mg, yield 100%, crude).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:23][CH2:22][N:21]([C:24]4[C:29]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:20][C:12]=3[N:13]=[C:14](S(C)(=O)=O)[N:15]=2)=[CH:5][CH:4]=1.[O-:36][CH2:37][CH3:38].[Na+]>O1CCOCC1.C(O)C>[CH2:37]([O:36][C:14]1[N:15]=[C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:35])[F:34])=[CH:8][CH:7]=2)[C:11]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:20][C:12]=2[N:13]=1)[CH3:38]
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1S(C)(=O)=O)C2
Reactant: CC[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1S(C)(=O)=O)C2
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylsulfonyl)-7-(3-(methylsulfonyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4-amine (150 mg, 0.27 mmol) was suspended in dioxane (5.0 mL) and ethanol (2.0 mL), sodium ethoxide (20 mg, 0.28 mmol) was added and the mixture was stirred at at 80° C. for 2 hrs. Solvent was removed and the residue was purified by flash chromatography over silica gel and then by preparative TLC to obtain the product as a white solid (102 mg).
Reaction SMILES: Cl.Cl.C1(C[N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.O>[NH:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1
Reactant: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: C1CC(N2CCOCC2)CCN1

Procedure:
10.00 kg (30.00 mol) 4-[1-(phenylmethyl)-4-piperidinyl]-morpholine-dihydrochloride (M) were suspended in 50.0 L tert-butanol and 10.0 L water and heated to 45° C. At 45° C. a solution of 10.37 kg (75.01 mol) potassium carbonate in 24.0 L water was metered in. Then the aqueous phase was separated off at 45° C. and 20.0 L solvent were distilled off in vacuo. The mixture was then hydrogenated at a pressure of 4 bar and an internal temperature of 60° C. until no further uptake of hydrogen could be detected. After the reaction was complete, the catalyst was filtered off and the residue was washed with 20.0 L tert-butanol.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][C:29](=[O:31])[O:28][N:27]=3)=[CH:16][C:15]=2[F:32])=[C:9]([CH2:33][CH2:34][CH3:35])[N:8]2[N:36]=[CH:37][N:38]=[C:7]12.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[F:32][C:15]1[CH:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][C:29](=[O:31])[O:28][N:27]=2)[CH:18]=[CH:19][C:14]=1[CH2:13][C:10]1[C:11](=[O:12])[NH:6][C:7]2[N:8]([N:36]=[CH:37][N:38]=2)[C:9]=1[CH2:33][CH2:34][CH3:35]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(Cc2ccc(OC)cc2OC)c2ncnn12
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)[nH]c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.8 %

Procedure:
A mixture of 4-(2,4-dimethoxybenzyl)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.3 g), trifluoroacetic acid (5 mL) and toluene (5 mL) was stirred at room temperature for 16 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.022 g, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([CH2:12]C(O)=O)#[N:11].N1C=CC=CC=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[CH:12]/[C:10]#[N:11]
Reactant: N#CCC(=O)O
Reactant: O=Cc1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: CC(C)O
Product: N#C/C=C/c1cccc(Cl)c1

Procedure:
m-Chlorobenzaldehyde (210.75 g; 1.5 m), cyanoacetic acid (127.5 g; 1.5 m) and pyridine (150 ml.) were refluxed for two days. The solution was evaporated to give an oil which was distilled to give a mixture of isomers (72% trans/23% cis; 5% aldehyde), Yield (129 g; 53%), b.p. 70°-85°C. at 0.8 mm. The material was dissolved in isopropanol and allowed to fractionally crystallise at 0°C. The solid was filtered and freeze-dried. Yield of pure trans isomer was 15 g (6.1%) b.p. 104°-106°C. at 1 mm; m.p. 26°-28°C.
Reaction SMILES: [CH3:1][C:2]1(B(O)O)[CH:6]=[C:5]([CH3:7])[O:4][NH:3]1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]2[CH2:19][CH2:20][CH2:21][C:14]=2[N:13]=1.N#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:11][C:12]1[N:17]=[C:16]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:7])[C:15]2[CH2:19][CH2:20][CH2:21][C:14]=2[N:13]=1
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Reactant: CC1=CC(C)(B(O)O)NO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1nc(Cl)nc2c1CCC2
Temperature: 27.5 °C
Reaction time: 10 h
Yield: 74.4 %

Procedure:
3,5-Dimethylisoxazole boronic acid (0.4 g, 2.8 mmol) was added to a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (0.75 g, 4 mmol) in tetrahydrofuran (10 mL). The mixture was flushed with N2 before addition of palladium acetate (0.07 g, 0.28 mmol) and triphenylphosphine (0.14 g, 0.56 mmol). Thereafter, 2M aqueous sodium carbonate solution was added and the mixture was reflushed with N2. The mixture was stirred at a temperature in the range of 20° C. to 50° C. for 8 to 12 hours and then cooled to about 20 to 35° C. The mixture was diluted with water and the organic layer was separated. The aqueous layer was re-extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel) to afford the title compound as a light yellow liquid (0.52 g, 53% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6]OC2C3NC(C)=C(C)C=3C=NC=2)=[CH:4][CH:3]=1.Cl.[Cl:22][C:23]1[CH:41]=[CH:40][C:26]([CH2:27][O:28][C:29]2[C:30]3[NH:37][C:36]([CH3:38])=[C:35]([CH3:39])[C:31]=3[CH:32]=[N:33][CH:34]=2)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+].C(Br)C1C=CC=CC=1>>[ClH:1].[CH2:6]([N:37]1[C:30]2[C:29]([O:28][CH2:27][C:26]3[CH:40]=[CH:41][C:23]([Cl:22])=[CH:24][CH:25]=3)=[CH:34][N:33]=[CH:32][C:31]=2[C:35]([CH3:39])=[C:36]1[CH3:38])[C:5]1[CH:19]=[CH:20][CH:2]=[CH:3][CH:4]=1
Reactant: Cc1[nH]c2c(OCc3ccc(Cl)cc3)cncc2c1C
Agent: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Product: Cc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(Cl)cc3)cncc12
Yield: 38.8 %

Procedure:
In accordance with the same procedures as in Example 2, except for using 7-(4-chlorobenzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-c]pyridine obtained by treating the compound of Example 18 with a saturated sodium bicarbonate solution and benzyl bromide, the titled compound was obtained as a white solid. (Yield: 38.8% )
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([CH:13]=[O:14])[CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([CH2:13][OH:14])[CH:3]=1
Reactant: CS(=O)(=O)Oc1ccc(F)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Oc1ccc(F)cc1CO
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
To a mixture of 0.760 g (3.49 mmole) of methanesulfonic acid 4-fluoro-2-formyl-phenyl ester and 10 mL of methanol at 0 degrees was added, portionwise over 10 minutes, 0.200 g (5.4 mmole) of sodium borohydride. The mixture was stirred at 0 degrees for 10 minutes and then concentrated under reduced pressure. The residue was partitioned between 50 mL of ethyl acetate and 50 mL of water while 1 M hydrochloric acid was carefully added. The mixture was stirred at room temperature until gas evolution ceased. The aqueous layer was extracted three times with 20 mL of ethyl acetate. The combined organic layers were washed with 30 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.740 g of methanesulfonic acid 4-fluoro-2-hydroxymethyl-phenyl ester as a yellow oil.