Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH:5]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH3:28])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[N:10]=[N:9]2)[CH2:4][CH:3]1[C:29]([NH:31][C:32]1[CH:37]=[CH:36]C=CC=1)=[O:30].[CH2:38]([O:40]CCCN)[CH3:39]>>[CH2:38]([O:40][CH2:36][CH2:37][CH2:32][NH:31][C:29]([CH:3]1[CH2:4][CH:5]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH3:28])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:11]=3[N:10]=[N:9]2)[CH:6]([OH:7])[CH:2]1[OH:1])=[O:30])[CH3:39]
Reactant: CSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)Nc4ccccc4)C(O)C3O)c2n1
Reactant: CCOCCCN
Product: CCOCCCNC(=O)C1CC(n2nnc3c(NC4CC4c4ccccc4)nc(SC)nc32)C(O)C1O

Procedure:
The subtitle compound was prepared according to the method of example 39, step a) using the product of example 20, step b) and 3-ethyoxypropylamine.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.Cl[CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.C[Si]([C:26]#[N:27])(C)C>C(Cl)Cl.O>[C:26]([CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2)#[N:27]
Reactant: ClC1c2ccccc2CCc2ccccc21
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: N#CC1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 88.9 %

Procedure:
6.0 g (23.0 mmol) of tin tetrachloride are slowly added to a solution of 21.1 g (92.3 mmol) of 5-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene [V. Mychajlyszyn et al, Coll. Czech. Chem. Comm. 24, 3955 (1959)] and 11.3 g (114 mmol) of trimethylsilylcyanide in 150 ml of methylene chloride. The reaction mixture is stirred at room temperature for 10 hours and then diluted with 150 ml of methylene chloride, and 200 ml of water are added. The organic phase is separated off, washed with dilute sodium bicarbonate solution, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallization of the residue from toluene gives 18.0 g (88.9%) of 5-cyano-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene, melting point 89°-90° C. (compound (104), Table 1).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][N:17]=1>O>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:16]2[N:17]=[CH:18][C:19]([CH:22]=[O:23])=[CH:20][CH:21]=2)[CH:10]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccnc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
To a suspension of sodium hydride (407 mg, 8.48 mmol, 50% in oil) and N,N-dimethylformamide (45 mL) was added an N,N-dimethylformamide (5 mL) solution of 3-hydroxypyridine (806 mg, 8.48 mmol) at 0° C., which was stirred for 30 minutes. An N,N-dimethylformamide (5 mL) solution of 2-chloro-5-formylpyridine (1.0 g, 7.06 mmol) was added to this reaction mixture at the same temperature, which was stirred for 5 hours at 100° C. The reaction mixture was cooled to room temperature, and water was added thereto, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (505.1 mg, 36%).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH:9](OCC)=[O:10]>>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH:9]=[O:10]
Reactant: CN(C)CCCCN
Reactant: CCOC=O
Product: CN(C)CCCCNC=O

Procedure:
A solution of 4-dimethylaminobutylamine (3.0 g) in ethyl formate (30 mL) was stirred and heated at reflux under an atmosphere of nitrogen for 3 hours. After cooling, the mixture was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM (20%) to give N-(4-dimethylaminobutyl)formamide (2.7 g) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15](OC)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1.CO.C(Cl)Cl>[OH:16][CH2:15][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10]1
Reactant: COC(=O)C1CCCC(NC(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(tert-butoxycarbonylamino)cyclohexanecarboxylate (9 mmol) in THF/MeOH/CH2Cl2 (36 ml, 10:1:1) was added NaBH4 (22.5 mmol) and stirred at rt overnight. The reaction was quenched with water and extracted with CH2Cl2 (3×10 mL). The extracts were combined and dried using anhydrous sodium sulfate. The product was purified using Biotage.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: CC1(C)OC(=O)C(=Cc2ccc(Cl)cc2)C(=O)O1

Procedure:
Prepared from Meldrum's acid and 4-chlorobenzaldehyde by Cope-Knoevenagel reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[CH3:25])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].O.CC(=O)OCC.C[N:36](C=O)C>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:36])[CH:8]=[C:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[CH3:25])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1[nH]cc(Cc2cccc(F)c2C)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccccc2)c(Cc2cccc(F)c2C)cn1N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound of step 4 (6.748 g, 20.00 mmol) in 60 ml of anhydrous DMF under a nitrogen atmosphere at 0° C. was added sodium hydride (60% in mineral oil, 0.960 g, 24 mmol) in small portions. After stirring for 10 min at 0° C., the mixture was allowed to warm to room temperature over 15 min. After cooling to 0° C. again, 0-(2,4-dinitro-phenyl)-hydroxylamine (cf. C. Legault et al., J. Org. Chem. 68 (2003), 7119; P. H. Boyle et al., ARKIVOC (2003) (vii), 67; 4.779 g, 24.00 mmol) was added in small portions and the mixture was stirred at room temperature for 1 h. Water (250 ml) and EA (250 ml) were added and the organic phase was washed twice with 125 ml each of a 1 N sodium hydroxide solution and 125 ml of brine, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel, first eluting with cyclohexane/DCM (40:60, then 20:80, then 0:100), then with DCM/EA (97.5:2.5, then 95:5) to give 6.33 g of the title compound as a beige solid melting at 87-88° C.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.C([O-])([O-])=[O:20].[Na+].[Na+].[OH-].[Na+]>C(O)(=O)C.CO.C([O-])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>[OH:20][CH:10]1[C:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][CH2:11]1
Reactant: c1ccc(-c2ccc3c(n2)CCCC3)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: OC1CCCc2ccc(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a stirred solution of 2-phenyl-5,6,7,8-tetrahydroquinoline (3.80 g, 18 mmol) in glacial acetic acid (10 mL) was added a 30 wt. % aqueous solution of H2O2 (2 mL) and the resulting mixture was stirred at 70° for 18 h; at this point, another portion of H2O2 solution (2 mL) was added and stirring was continued for 2 days. The solution was cooled to room temperature and Na2CO3 (10 g) and CHCl3 (20 mL) were added. The resulting mixture was allowed to sit 15 min then filtered and the aqueous phase was extracted with CHCl3 (3×20 mL); the organic fractions were then combined, dried (MgSO4) and concentrated. The residue was then taken up in acetic anhydride (20 mL) and heated at 90° C. for 4 h with stirring. Removal of the Ac2O under reduced pressure afforded a pale yellow oil which was taken up in methanol (30 mL) and treated with K2CO3 (100 mg, 0.72 mmol). The resulting mixture was stirred overnight. A solution of 4 N NaOH (10 mL) was added and the mixture was extracted with CHCl3 (3×20 mL), dried (MgSO4) and concentrated in vacuo. Purification of the crude product by column chromatography (silica gel, hexane/EtOAc 4:1) afforded 3.0 g of 8-hydroxy-2-phenyl-5,6,7,8-tetrahydroquinoline AMD 8786 (74% yield) as a white solid. 1H NMR (CDCl3) δ 1.78-1.81 (m, 2H), 1.97-2.02 (m, 1H), 2.31-2.33 (m, 1H), 2.76-2.79 (m, 2H), 4.43 (s, 1H), 4.71 (t, 1H, J=7 Hz), 7.37-7.46 (m, 4H), 7.52 (d, 1H, J=8 Hz), 7.96 (dd, 2H, J=9, 2 Hz); 13C NMR (CDCl3) δ 19.4, 27.8, 30.5, 69.0, 119.0, 126.5, 128.5, 128.7, 129.8, 137.6, 138.7, 154.0, 157.5. ES-MS m/z 226 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.C([Li])CCC.CN(C)[CH:17]=[O:18].[BH4-].[Na+]>C(OCC)(=O)C.O.O1CCCC1.C1(C)C=CC=CC=1>[CH3:9][O:8][C:4]1[N:3]=[C:2]([CH2:17][OH:18])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)n1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(CO)n1
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
To a mixture of 2-bromo-6-methoxypyridine (500 mg, 2.66 mmol) and toluene (20 mL) was added dropwise n-butyl lithium (1.84 mL, 1.6 M hexane solution, 2.93 mmol) at −78° C., which was stirred for 30 minutes. N,N-dimethylformamide (412 μA, 5.32 mmol) was added dropwise to the mixture at the same temperature, which was stirred for 45 minutes at 0° C. Water and tetrahydrofuran were added to the reaction solution and vigorously stirred. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. Sodium borohydride (201 mg, 5.31 mmol) was added to this filtrate at 0° C., which was stirred for 2 hours at room temperature. Water was added to the reaction solution, which was then exacted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried with anhydrous magnesium sulfate, and then dried. This filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: diethyl ether=2:1) to obtain the title compound (104.8 mg, 28%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[CH2:12][CH2:11]2)[CH:9]=1)=[O:4].O[Li].O.CCOC(C)=O>C1COCC1.CO.O>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[CH2:18][C:17]([NH:16][C@@H:13]1[CH2:14][CH2:15][C@H:10]([N:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[N:7]2)[CH2:11][CH2:12]1)=[O:27]
Reactant: COC(=O)c1cn([C@H]2CC[C@@H](NC(=O)Cc3c(F)cccc3Cl)CC2)nn1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Cc1c(F)cccc1Cl)N[C@H]1CC[C@@H](n2cc(C(=O)O)nn2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
1-{cis-4-[2-(2-Chloro-6-fluoro-phenyl)-acetylamino]-cyclohexyl}-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (400 mg) was dissolved in a mixture of THF (3.2 ml)/MeOH (3.2 ml)/H2O (1.6 ml) and LiOH.H2O (43 mg) was added. The reaction mixture was stirred 1 h at 60° C., then it was poured on a mixture of H2O (35 ml) and EtOAc (35 ml). The aqueous layer was collected, acidified with 1 M HCl to pH<4 and extracted with EtOAc (2×35 ml). After drying over Na2SO4 the solvent was evaporated to yield 341 mg (88%) of product. White powder. MS 379.1 (100, [M−H]−).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:23])=[C:8]([CH:10]([OH:22])[CH2:11][CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].[NH4+].[Cl-]>C1COCC1.C1COCC1.CN(C=O)C>[C:16]([O:15][C:14]([N:13]([CH3:21])[CH2:12][CH2:11][CH:10]([C:8]1[CH:9]=[C:4]([Cl:3])[CH:5]=[CH:6][C:7]=1[CH3:23])[O:22][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:20])([CH3:19])([CH3:17])[CH3:18]
Reactant: Cc1ccc(Cl)cc1C(O)CCN(C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)COC(CCN(C)C(=O)OC(C)(C)C)c1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a suspension of NaH (0.5 g, 12.5 mmol) in THF (400 mL) at 0-5° C. was added drop wise a solution of tert-butyl 3-(5-chloro-2-methylphenyl)-3-hydroxypropyl(methyl)carbamate (1.3 g, 4.15 mmol) in anhydrous THF/DMF (24/16 mL), the reaction mixture was stirred for 1 h at room temperature. A solution of ethyl bromoacetate (2.1 g, 12.5 mmol) in anhydrous THF (13 mL) was added drop wise to the above mixture, the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous NH4Cl, and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to afford crude ethyl 2-(3-(tert-butoxycarbonyl(methyl)amino)-1-(5-chloro-2-methylphenyl)propoxy)acetate (800 mg, 60%), which was used for next step without purification. 1H NMR (CDCl3, 400 MHz) δ 1.45 (s, 9H), 1.68 (s, 3H), 1.87 (m, 2H), 2.25 (m, 2H), 2.90 (s, 3H), 4.63 (m, 1H), 7.13 (m, 2H), 7.38 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]1[O:19][C:18]([CH3:20])=[N:17][N:16]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.ClCCl>[C:21]([O:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]1[O:19][C:18]([CH3:20])=[N:17][N:16]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1nnc(C2=C(O)c3ccccc3S(=O)(=O)N2C)o1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nnc(C2=C(OC(=O)c3ccccc3)c3ccccc3S(=O)(=O)N2C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 4-hydroxy-2-methyl-3-(2-methyl-1,3,4-oxadiazol-5-yl)-1,2-benzothiazine 1,1-dioxide, (0.155 g) in pyridine (0.5 ml) was added benzoyl chloride (0.63 ml) at 5°-10° C. After being stirred at room temperature for 1 hour, the mixture was diluted with dichloromethane, washed successively with dilute HCl, water and dilute sodium bicarbonate solution and dried over sodium sulfate to give, on concentration, crude solids 0.213 g. Recrystallization from toluene gave the title compound 0.156 g (74%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[ClH:15]>[Pd]>[ClH:15].[ClH:15].[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Product: Nc1cc(F)cc(C(=O)O)c1N
Reaction time: 16 h
Yield: 79 %

Procedure:
A pressure flask capable of withstanding 150 psi. was added 2-amino-5-fluoro-3-nitrobenzoic acid (1.0 g, 5.0 mmol) dissolved in 6M hydrochloric acid (40 mL) and 10% palladium on carbon (100 mg). The reaction was placed in a Parr apparatus and the flask flushed three times with hydrogen leaving an internal pressure of 65 psi. The reaction was continued for 16 hours while maintaining a pressure of 65 psi. The reaction was filtered through celite, washed with cold water and the filtrate evaporated to dryness to give 2,3-diamino-5-fluorobenzoic acid dihydrochloride (962 mg, 79%) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[N:10]([CH3:22])[C:11](SC)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([NH2:35])[CH2:32][CH2:33][NH2:34]>>[NH2:35][CH:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[F:24])[CH2:32][CH2:33][NH:34][C:11]1[N:10]([CH3:22])[C:9](=[O:23])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:12]=1
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)n1C
Reactant: NCCC(N)c1ccccc1F
Product: Cn1c(NCCC(N)c2ccccc2F)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reaction time: 3 h

Procedure:
2-34 2-((3-Amino-3-(2-fluorophenyl)propyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone was prepared from 5-(4-fluorophenyl)-3-methyl-2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone and 1-(2-fluorophenyl)-1,3-propanediamine according to the General Procedure. The reaction was done at 190° C. for 3 h. MS (m/z): 448.1 (M+H)+; C25H23F2N5O requir. 447.5 (free base).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Cl)[CH3:2].[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].[H-].[Na+]>CN(C=O)C>[C@@H:9]1([C:8]([O:12][CH2:13][CH3:14])=[O:11])[CH2:10][C@H:5]1[C:4]([O:3][CH2:1][CH3:2])=[O:7]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl-2-chloroacetate (147 g, 1.20 mol) was added to a stirred solution of ethyl prop-2-enoate (150 g, 1.50 mol) in DMF (700 mL) at 0° C. Sodium hydride (60% w/w, 48.0 g, 1.20 mol) was added portion-wise to the reaction mixture at 0° C. over a period of 2 hours. The reaction mixture was allowed to warm to room temperature. After 16 hours, the reaction mixture was quenched with ice water (500 mL) and extracted with ethyl acetate (2×1.0 L). The organic layers were combined, washed with water (500 mL) and then brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10-20% ethyl acetate/petroleum ether, linear gradient) to afford diethyl rel-(1R,2R)-cyclopropane-1,2-dicarboxylate. 1H NMR (300 MHz, CDCl3) δ 4.20-4.10 (m, 4H), 2.10-2.05 (m, 2H), 1.48-1.40 (m, 2H), 1.35-1.20 (m, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].Br[CH2:10][CH2:11][CH2:12]Br>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:7][NH2:8])[CH2:12][CH2:11][CH2:10]1
Reactant: N#CCc1cccs1
Reactant: BrCCCBr
Product: NCC1(c2cccs2)CCC1
Yield: 55 %

Procedure:
(1-Thien-2-ylcyclobutyl)methylamine is prepared from thien-2-ylacetonitrile (3.70 g, 30 mmol), 1,3-dibromopropane (9.09 g, 45 mmol), as described in Example 1 in 55% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14]>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)/C=C/c1cc(F)c(OC)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(F)c(OC)cc1F
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a 500 mL parr shaker flask was charged with Ethyl (2E)-3-(2,5-difluoro-4-methoxyphenyl)prop-2-enoate (0.1 g, 0.41 mmol), ethyl acetate (5 mL). To the reaction mixture was added 10% Pd—C (20%) and kept for hydrogenation using bladder 1 h. After completion of the reaction, the reaction mixture was filtered through celite, washed thoroughly with ethyl acetate (20 mL) and concentrated to distill off the solvent. The product was obtained as brown solid (0.080 g, yield: 80.0%).
Reaction SMILES: [Cl-].[K+].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]>>[CH2:4]([OH:3])[C@H:5]1[O:6][C@H:7]([O:6][C@:5]2([CH2:7][OH:8])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:4]([OH:3])[C@@H:4]2[OH:3])[C@H:5]([OH:6])[C@@H:4]([OH:3])[C@@H:7]1[OH:8]
Reactant: OCC(O)CO
Agent: [Cl-]
Agent: [K+]
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reaction time: 18 h

Procedure:
Sucrose density gradients (8-30%) were prepared in TT buffer containing 0.4 M KCl. In some experiments (as indicated) the gradients were made 8-30% in TT buffer containing 10% glycerol with or without 0.4 M KCl. Samples to be analyzed were layered on the gradient together with 14C-labelled sedimentation markers. The gradients were centrifuged at 50,000 rpm in an SW60 rotor for 18 h at 2° C. Gradients were fractionated into individual 0.1 ml fractions, scintillation fluid was added, and radioactivity counted.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1Cl.O.[NH2:13][NH2:14]>C(O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH:13][NH2:14]
Reactant: NN
Reactant: O=[N+]([O-])c1cncc(Br)c1Cl
Solvent: CCO
Solvent: O
Product: NNc1c(Br)cncc1[N+](=O)[O-]
Yield: 79.5 %

Procedure:
A solution of 3-bromo-4-chloro-5-nitro-pyridine (500 mg, 2.106 mmol), hydrazine hydrate (158.1 mg, 153.6 μL, 3.159 mmol) in ethanol (5.000 mL) was stirred at RT for 1 h. The bright yellow precipitate was filtered, washed with methanol and dried under vacuum to leave 3-bromo-4-hydrazinyl-5-nitropyridine (390 mg, 79.5%). MS (ES−) 232.8.
Reaction SMILES: S(=O)(=O)(O)O.O=[C:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH:8]1[C:20]1[C:21](=[O:26])[NH:22][CH:23]=[CH:24][CH:25]=1>C(#N)C.C(=O)([O-])[O-].[K+].[K+]>[NH:22]1[CH:23]=[CH:24][CH:25]=[C:20]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:7]=3[O:26][CH:21]12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(c2ccc[nH]c2=O)C1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC#N
Product: C1=CNC2OC3=C(CNCC3)C2=C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated Sulfuric acid (1.0 mL, 18.8 mmol) was added to tert-butyl 4-oxo-3-(2-oxo-1,2-dihydropyridin-3-yl)piperidine-1-carboxylate (350 mg, 1.20 mmol). The resulting thick solution was stirred at room temperature overnight. The reaction was heated at 60° C. until reaction complete by LCMS. The reaction was diluted with 90% Acetonitrile 10% Water and solid potassium carbonate was added cautiously to neutral pH (Effervescence), the slurry was filtered and the filtrate evaporated, the resulting residue was used without further purification.
Reaction SMILES: C([O:8][C:9]([CH:11]([CH2:25][CH2:26][C:27]([O:29]CC1C=CC=CC=1)=[O:28])[CH2:12][P:13]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:15])[OH:14])=[O:10])C1C=CC=CC=1>O.[Pd]>[C:19]1([CH2:18][CH2:17][CH2:16][P:13]([CH2:12][CH:11]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:9]([OH:10])=[O:8])([OH:15])=[O:14])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CCC(CP(=O)(O)CCCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: O=C(O)CCC(CP(=O)(O)CCCc1ccccc1)C(=O)O
Yield: 87 %

Procedure:
2,4-Di(benzyloxycarbonyl)butyl(3-phenylpropyl)phosphinic acid (15) (1.4 g, 2.8 mmol) in 20 mL of water containing 150 mg of 10% Pd/C was hydrogenated on a Parr hydrogenator at 40 psi overnight. Filtration through a Celite pad followed by evaporation on high vacuum gave 0.8 g (89%) of 2-[(3-phenylpropylhydroxyphosphinyl)methyl]pentanedioic acid (4, R=CH2CH2CH2Ph)as a light yellow viscous oil).