Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cccc(OC2CCCC2)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To cyclopentanol (1 mL), was added sodium (36 mg, 1.56 mmol). When the sodium was consumed, the mixture was diluted with 1 mL THF and 2,6-dibromopyridine (250 mg, 1.06 mmol). The mixture was stirred at 90° C. for 3 h, sodium hydride (20 mg) was added and the mixture was stirred an additional 1 h at 90° C. The reaction was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 222 mg of 159.1 as a colorless oil. LCMS (2 min gradient) RT=2.01 min, 242.15 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[CH:20]1[CH2:25][NH:24][C:23](=[S:26])[NH:22][CH2:21]1>>[F:1][C:2]1([F:18])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([O:10][CH:20]2[CH2:25][NH:24][C:23](=[S:26])[NH:22][CH2:21]2)=[O:9])[CH2:3]1
Reactant: OC1CNC(=S)NC1
Reactant: O=C(O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Product: O=C(OC1CNC(=S)NC1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylacetic acid and 5-hydroxytetrahydropyrimidine-2(1H)-thion (cf. JP-Hei01 (1989)-128970A), the title compound was prepared by a method similar to Step 2 of Referential Example 12.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH2:3]([CH:2]1[CH2:1][O:23]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C=CCCCCCCCCCCCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCCCCCCCCC1CO1

Procedure:
In a flask equipped with a mechanical stirrer and an addition funnel was placed 19.8 g (0.1 mole) of 1-tetradecene and 150 ml of CH2Cl2. The solution was stirred and a suspension of 23 g(0.106 mole) of m-chloroperbenzoic acid in 250 ml of CH2Cl2 was added dropwise. After stirring overnight, the CH2Cl2 solution was washed with 10% aqueous NaHSO3, saturated NaHCO3 solution and then dried over Na2SO4. The residue, after removal of solvent, was distilled through a vigreux column to obtain the title compound, bp 78°-81°/0.01 mmHg as a colorless liquid.
Reaction SMILES: O=[C:2]1[CH2:20][CH2:19][N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1.C1C=CC=CC=1.[C:27](#[N:29])[CH3:28]>>[C:27]([CH:28]=[C:2]1[CH2:20][CH2:19][N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1)#[N:29]
Reactant: O=C1CCN2c3ccccc3Cc3ccccc3C2C1
Reactant: CC#N
Solvent: c1ccccc1
Product: N#CC=C1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
1 g of 2-keto-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine is mixed with 1 ml of benzene, 0.5 ml of acetonitril and 0.5 g of molecular sieve (4 A). 50 mg of sodium-ethoxyde are added and the mixture is heated for 3 hours (90°-100°C). After cooling the mixture the molecular sieve is filtered off and the filtrate evaporated. The precipitate is recrystallized from ethanol.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:15][O:14][C:12]([C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)[CH:18]=[CH:17][CH:16]=1)=[O:13]
Reactant: COC(=O)c1cccc(-c2cccc(OC)c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2cccc(O)c2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
To a −78° C. solution of methyl 3-(3-methoxyphenyl)-benzoate (1.48 g) in anhydrous methylene chloride (16 mL) was added dropwise a solution of boron tribromide in methylene chloride (1.0 M, 16.3 mL). The mixture was stirred at −78° C. for 30 min, allowed to warm to 0° C., and stirred for 2 h. The mixture was quenched by addition of saturated aqueous sodium bicarbonate (50 mL), and diluted with methylene chloride (50 mL). The mixture was placed in a separatory funnel, and the organic layer was separated, dried over sodium sulfate, filtered and concentrated to give the crude product. Purification by silica gel chromatography (eluting with 5:1 hexanes/ethyl acetate) afforded the title compound (769 mg) as a pale yellow oil.
Reaction SMILES: C[C:2]([O-:5])(C)C.[K+].C(OC=O)C.[CH3:12][CH:13]([C:15](=[O:21])[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14]>C1COCC1.C(OCC)C>[OH:5][CH:2]=[C:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:15](=[O:21])[CH:13]([CH3:14])[CH3:12]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)CCC(=O)C(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC=O
Solvent: CCOCC
Product: CC(C)CC(=CO)C(=O)C(C)C
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 31.1 %

Procedure:
To a solution of KOtBu (15.6 g, 139 mmol) in THF (200 mL) is added ethylformate (27.4 g, 370 mmol). During the addition, the mixture is cooled with a water bath to 10° C. Strong gas evolution occurs. The mixture is stirred until the gas evolution ceases (5 min) and is then cooled to −5° C. To this mixture a solution of 2,6-dimethyl-heptan-3-one (20 g, 141 mmol) and ethylformate (13.7 g, 185 mmol) in THF (20 mL) is added slowly during 30 min. The reaction mixture is stirred for 2 h and allowed to slowly warm to rt. The reaction is diluted with diethyl ether (200 mL) and washed with 1 N aq. HCl (2×100 mL). The organic extract is dried (Na2SO4), filtered and evaporated to give 1-hydroxy-2-isobutyl-4-methyl-pent-1-en-3-one (7.35 g) as a brown resin; LC-MS: tR=0.91 min, [M+1]=171.21.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][C:8]=1[CH3:18].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=[O:25].O>CCCCCC.C1(C)C=CC=CC=1>[CH3:18][C:8]1[CH:9]=[C:10]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]2=[N:12][C:7]=1[CH:24]([C:20]1[S:19][CH:23]=[CH:22][CH:21]=1)[OH:25]
Reactant: O=Cc1cccs1
Reactant: Cc1cc2c(nc1Br)CCCCC2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc2c(nc1C(O)c1cccs1)CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
To a solution of 1.6M n-butyl lithium in n-hexane (16.5 ml) in toluene (20 ml) at -70° C., under nitrogen, was added a solution of 2-bromo-6,7,8,9-tetrahydro-3-methyl-5H-cyclohepta[b]pyridine (6 g 0.025 m) and the mixture kept at -20° C. for 0.25 hours. This was blown over into a solution of 2-thiophenecarboxaldehyde (3.0 g) in toluene (30 ml) kept at -20° C., then allowed to warm to room temperature and water added. The organic phase was extracted with 2N hydrochloric acid, then basified with solid potassium carbonate and extracted with chloroform. The combined chloroform extracts were dried (MgSO4) and evaporated. The residue was recrystallised from n-hexane to give the title compound (4.42g), m.p. 102°-4° C.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C>[CH2:10]([N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[CH:3]=[O:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 4.8 g, 120 mmol) in DMF (100 ml) was added dropwise at an ice bath temperature a solution of 2-formylpyrrole (9.5 g, 100 mmol) in DMF (10 ml). The mixture was stirred for 15 minutes at room temperature and cooled again. To the mixture was added dropwise a solution of benzylbromide (20.5 g, 120 mmol) in DMF (10 ml). The reaction mixture was stirred for 60 minutes at room temperature and poured to ice-water, and extracted with ethylacetate. The extract was washed with water and dried. The solvent was evaporated to give 1-benzyl-2-formylpyrrole (18.0 g) as an oil quantitatively.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([OH:14])=O)([O-:3])=[O:2].S(Cl)([Cl:17])=O>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([Cl:17])=[O:14])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: O=C(Cl)CCc1ccccc1[N+](=O)[O-]

Procedure:
A stirred solution of 74.2 g (0.38 mole) of 3-(2-nitrophenyl)propionic acid and 53.6 g (0.45 mole) of thionyl chloride in 250 mL of methylene chloride was heated under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in 100 mL of methylene chloride. The solution was concentrated under reduced pressure, and the residue was subjected to high vacuum to give 3-(2-nitrophenyl)propionyl chloride as an oil.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5]([NH:31]/[C:32](/[CH3:42])=[CH:33]\[C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:42]/[C:32](/[NH:31][CH:5]([CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)[C:4]([OH:43])=[O:3])=[CH:33]/[C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)N/C(C)=C\C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C/C(=C/C(=O)c1ccccc1)NC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
0.333 g (0.56 mmol) [rac]-2-[1-Methyl-3-oxo-3-phenyl-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid ethyl ester were dissolved in THF/EtOH 1:1 (10 ml) and treated with 1.4 ml (1.4 mmol) aqueous sodium hydroxide solution (1 molar) and the reaction mixture was stirred for 1 hour at room temperature. It was then acidified with 1N hydrochloric acid and extracted with dichloromethane. The combined organic phases were dried over MgSO4 and evaporated. Purification by flash-chromatography (silica gel, eluent: gradient of dichloromethane and methanol) gave 0.218 g (69%) [rac]-2-[1-methyl-3-oxo-3-phenyl-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid as light yellow amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[C:17](=[C:18]2[CH2:22][CH:21]([CH2:23]I)[O:20][C:19]2=[O:25])[O:16][C@H:15]2[N:12]1[C:13](=[O:26])[CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.COC(C)(C)C>C(OCC)(=O)C.[Pd]>[CH2:1]([O:8][C:9]([CH:11]1[C:17](=[C:18]2[CH2:22][CH:21]([CH3:23])[O:20][C:19]2=[O:25])[O:16][C@H:15]2[N:12]1[C:13](=[O:26])[CH2:14]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC(CI)CC1=C1O[C@@H]2CC(=O)N2C1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: CC1CC(=C2O[C@@H]3CC(=O)N3C2C(=O)OCc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1800 mg of 10% Pd/C and 390 ml of ethyl acetate is stirred at room temperature under hydrogen atmosphere for 30 minutes. A solution of the compound of Example 41 (800 mg) in 10 ml of ethyl acetate is introduced with a syringe, and stirring is continued under hydrogen atmosphere. At time points of 1 hour 20 minutes, 2 hour 40 minutes, 4 hour and 5 hour 35 minutes further amounts of 1800 mg 10% Pd/C each are added. After a total reaction time of 6 hours 50 minutes, the mixture is filtered through celite and stripped of the solvents to obtain a residue which is subjected to chromatography thrice over SiO2 using toluene/t-butyl methyl ether (17/1). The title compound is obtained as a foam, having characterization data as indicated below.
Reaction SMILES: [N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[Si:16]([O:23][CH2:24][CH:25]1[CH2:36][CH2:35][C:34]2[S:33][C:32]3[C:27](=[C:28](Cl)[N:29]=[CH:30][N:31]=3)[C:26]1=2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1COCC1>[Si:16]([O:23][CH2:24][CH:25]1[CH2:36][CH2:35][C:34]2[S:33][C:32]3[C:27](=[C:28]([O:13][CH:10]4[CH2:9][CH2:8][CH:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[CH2:12][CH2:11]4)[N:29]=[CH:30][N:31]=3)[C:26]1=2)([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCc2sc3ncnc(Cl)c3c21
Reactant: O[C@H]1CC[C@H](N2CCOCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
For the preparation of the starting material compound 65.1, please refer to the experimental procedure for Example 65. To a solution of trans-4-(morpholin-4-yl)cyclohexan-1-ol (277 mg, 1.50 mmol, 1.50 equiv) in distilled THF (20 mL) was added sodium hydride (605 dispersion in mineral oil, 200 mg, 5.00 mmol, 5.00 equiv) slowly at 0° C. under nitrogen. After stirring for 30 min at room temperature, a solution of 3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (355 mg, 1.00 mmol, 1.00 equiv) in 5 mL of THF was added dropwise and the resulting solution was stirred for 6 h at ambient temperature. The reaction was quenched with NH4Cl (sat.), extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration and concentration in vacuo, the residue was purified by a silica gel column with EtOAc/petroleum ether (1:1-3:1) to provide 350 mg (69%) of the title 3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene as a light yellow oil. MS: (ES, m/z): 504 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][N:10]=[C:11]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:12]([O:14][CH3:15])=[O:13])=[C:4]([F:21])[CH:3]=1.[CH3:22]COC(C)=O.CO>COC(OC)N(C)C>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:22]=[C:17]([O:18][CH3:19])[C:16](=[O:20])[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10]2)=[C:4]([F:21])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: COCC(=O)C(=NNc1cc(F)c(Br)cc1F)C(=O)OC
Agent: COC(OC)N(C)C
Solvent: CO
Product: COC(=O)c1nn(-c2cc(F)c(Br)cc2F)cc(OC)c1=O
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of methyl 2-[(4-bromo-2,5-difluorophenyl)hydrazono]-4-methoxy-3-oxobutanoate (33 g, 90 mmol) in N,N-dimethylformamide dimethyl acetal (72 mL) was stirred at 110° C. for 3 h. After cooling to room temperature, the mixture was concentrated under reduce pressure. To the residue were added MeOH and silica gel The mixture was evaporated and purified by silica gel column chromatography eluting with hexane/AcOEt (1/0 to 0/1) and then AcOEt/MeOH (4/1) to give the title compound (27.9 g, 83% yield) as a brown gum: 1H NMR (300 MHz, DMSO-d5): δ ppm 3.80 (3H, s), 3.83 (3H, s), 8.01 (1H, dd, J=8.7, 6.8 Hz), 8.15 (1H, dd, J=9.8, 6.0 Hz), 8.55 (1H, d, J=1.5 Hz). LC-MS (ESI) m/z 376 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([O:28][CH3:29])=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:32][CH2:31]2)[N:25]=[C:24]([O:46][CH3:47])[N:23]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.O.C(O)(=O)C.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([O:28][CH3:29])=[C:26]([N:30]2[CH2:31][CH2:32][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:34][CH2:35]2)[N:25]=[C:24]([O:46][CH3:47])[N:23]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c(OC)c(N2CCC(c3ccc4c(n3)NCCC4)CC2)n1
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1nc(NCC(NC(=O)OCc2ccccc2)C(=O)O)c(OC)c(N2CCC(c3ccc4c(n3)NCCC4)CC2)n1
Yield: 112.7 %

Procedure:
350 mg (0.54 mmole) of tert-butyl 2-benzyloxycarbonylamino-3-{2,5-dimethoxy-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in 10 ml of dichloromethane with 2 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silica gel, eluent: CH2Cl2-MeOH-H2O-AeOH 90-10-1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is purified by chromatography on silica eluting with an elution gradient of methylene chloride-methanol of 100-0 to 90-10. 360 mg of expected product is obtained in the form of a white solid,
Reaction SMILES: [NH2:1][C:2]1[N:7]2[NH:8][C:9]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:10][C:6]2=[N:5][C:4](=[O:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29](I)[CH3:30]>CN(C)C=O>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:10]=[C:6]2[N:5]([CH2:29][CH3:30])[C:4](=[O:22])[CH:3]=1
Reactant: CCI
Reactant: COc1ccc(COCc2nc3nc(=O)cc(N)n3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(=O)cc(N)n2nc(COCc3ccc(OC)cc3)nc12
Temperature: 25 °C
Reaction time: 36 h

Procedure:
145.6 g of 7-amino-2-[(4-methoxybenzyloxy)methyl]-s-triazolo[1,5-a]pyrimidin-5-one is dissolved in 1500 ml of dimethylformamide and mixed with 76.8 g of potassium carbonate. After the addition of 45.2 ml of ethyl iodide the mixture is stirred for about 1.5 days at ambient temperature. For working up, the dimethylformamide is distilled off in vacuo and the residue remaining is taken up in 500 ml of water (distilled), 500 ml of saturated NaCl solution and 1000 ml of dichloromethane. After separation of the organic phase the aqueous phase remaining is extracted three more times with 200 ml of dichloromethane. The combined organic phases are dried over magnesium sulphate and then freed from solvent. About 180 g of a solid remain, which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][C:4]=1[NH:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][C:34]=1[C:41]([F:44])([F:43])[F:42]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([F:13])([F:14])[F:15])[C:6]2=[N:5][C:4]=1[N:16]([CH2:37][C:36]1[CH:39]=[CH:40][C:33]([F:32])=[C:34]([C:41]([F:44])([F:42])[F:43])[CH:35]=1)[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:18])=[O:19])[CH3:2]
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Reactant: CCc1c(NS(=O)(=O)c2ccccc2)nc2c(C(F)(F)F)cccn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1c(N(Cc2ccc(F)c(C(F)(F)F)c2)S(=O)(=O)c2ccccc2)nc2c(C(F)(F)F)cccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of compound 13-E (0.060 g, 0.1 mmol) in DMF (3 mL) was added Na2CO3 (0.032 g, 0.3 mmol) and 4-fluoro-3-trifluoromethylbenzyl bromide (0.028 g, 0.11 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give Compound 55 as a white solid (0.047 g, 87%); MS m/z (M+H+) 546.
Reaction SMILES: [CH3:1]N(C=O)C.[H-].[Na+].[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][N:22]2[CH3:27])=[O:18])=[CH:9]1.CI>C1COCC1>[CH3:1][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][N:22]2[CH3:27])=[O:18])=[CH:9]1
Reactant: CN(C)C=O
Reactant: CN1CCCCC1COC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1CCCCC1COC(=O)c1cn(C)c2ccccc12
Reaction time: 0.25 h

Procedure:
To a DMF (10 ml) suspension of 60% sodium hydride (0.09 g, 2.3 mmol) was dropwise added a DMF (5 ml) solution of (1-methyl-2-piperidyl)methyl 1H-indole-3-carboxylate (0.50 g, 1.8 mmol) at room temperature over a period of 5 min. Onto the reaction mixture stirred for 15 min. was poured a THF (5 ml) solution of methyl iodide (0.29 g, 2.0 mmol). After stirring overnight, a reaction solution was poured onto water followed by extraction with EtOAc. The organic layer was washed successively with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product thus produced was purified by column chromatography on silica gel (20 g, CHCl3) to give 0.43 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:18][OH:19]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=[N:18][OH:19])[CH2:12][CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCOCCCCN1CCC(=O)CC1
Agent: Cl
Product: CCCCOCCCCN1CCC(=NO)CC1

Procedure:
1-(4-Butoxybutyl)-4-piperidone oxime is prepared from 1-(4-butoxybutyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[S-:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+]>C(O)C>[Cl:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:12])[CH:2]([S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10]2
Reactant: [S-]c1ccccc1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccc(Cl)cc2CC1Sc1ccccc1

Procedure:
2.5 g of 2-bromo-5-chloroindan-1-one and 2.8 g of sodium thiophenoxide was suspended in 30 ml of ethanol and heated under reflux for 3 h. The cooled reaction mixture was concentrated and purified chromatographically on silica gel using toluene/ethyl acetate 10/1. This gave 5-chloro-2-phenylsulfanylindan-1-one of melting point 89° C.
Reaction SMILES: C[O-].[Na+].[O:4]=[C:5]1[C:13]2[S:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[N:10][C:9]=2[CH2:8][CH2:7][CH2:6]1.[CH:18](OCC)=[O:19].Cl>CN(C)C=O.C1C=CC=CC=1>[CH:18]([CH:6]1[CH2:7][CH2:8][C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:17])[CH3:16])[S:12][C:13]=2[C:5]1=[O:4])=[O:19]
Reactant: CC(=O)Nc1nc2c(s1)C(=O)CCC2
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2c(s1)C(=O)C(C=O)CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
20 g (0.37 mol) sodium methoxide are suspended in 50 mL dimethylformamide, a suspension of 21 g (0.1 mol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide in 100 mL dimethylformamide is added dropwise. The mixture is stirred for 15 minutes, then cooled to 0° C. A mixture of 29.9 mL (0.37 mol) ethyl formate and 60 mL benzene is added dropwise and the reaction mixture is diluted with another 100 mL benzene. A precipitate gradually settles out and stirring is continued at 0° C. for 3.5 hours. The suspension is hydrolysed with 370 mL 1 molar hydrochloric acid, the solid precipitated is suction filtered. The two phases of the mother liquor are separated, the aqueous phase is extracted with dichloromethane. The resulting organic phase is dried and evaporated to dryness. The solid and the residue from the extraction are recrystallised from acetonitrile. Yield: 20 g