Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20](Cl)=[O:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20]([NH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:21]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)C(N)Cc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 2 h

Procedure:
To a solution of methyl 2-amino-3-(4-nitrophenyl)propanoate 2 (9.5 g) in CH2Cl2 (40 ml) is added, at 0° C., 2,6-dichlorobenzoyl chloride (7.71 g) dissolved in CH2Cl2 (40 ml). DIPEA (2 equ.) is then added dropwise to the mixture at 0° C. The reaction is then risen at RT and pH is brought to 7-8 by addition of DIPEA. The mixture is stirred for 2 h, then evaporated and the residue is placed in AcOEt (175 ml). The organic phase is washed one time with 5% NaHCO3 (150 ml), one time with water, one time with 10% KHSO4 (150 ml) and one time with brine, dried over MgSO4 and evaporated. No further purification is needed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)\[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.Cl>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Agent: Cl
Solvent: ClCCCl
Product: CC(C)(C)C(O)C(=Cc1ccc(Cl)cc1)n1cncn1
Yield: 61.7 %

Procedure:
88 Milligrams (0.53 mmole) of the present compound obtained in Example 1 was dissolved in 2 ml of 1,2-dichloroethane, and 2 ml of a 1,2-dichloroethane solution containing 290 mg (1.0 mmole) of (E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=95.8/4.2) was added dropwise thereto. After reaction at room temperature for 24 hours, 2% hydrochloric acid was added to separate the reaction solution into an aqueous and organic layers. After concentrating the organic layer, the residue was purified by column chromatography on silica gel to obtain 180 mg of 1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol. The ratio of E-form alcohol to Z-form alcohol was 95.6 to 4.4, and the enantiomer ratio of the E-form alcohol was: (+)-isomer: (-)-isomer=19:81.
Reaction SMILES: [CH3:1]S.[C:3]([NH:6][C:7](SC)([CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:5])[CH3:4]>[Ni].CC(C)=O>[C:3]([NH:6][CH:7]([CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[C:8]([O:10][CH3:1])=[O:9])(=[O:5])[CH3:4]
Reactant: COC(CCC(NC(C)=O)(SC)C(=O)O)OC
Reactant: CS
Agent: [Ni]
Solvent: CC(C)=O
Product: COC(=O)C(CCC(OC)OC)NC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Four (4.0) cc of Raney nickel was suspended in 15 ml of acetone, and stirred for 2 hours at room temperature to be deactivated. To the system then 417 mg of 2-acetylamino-2-methylthio-5,5-dimethoxyvaleric acid methanethiol was added, followed by 18 hours' stirring at room temperature. After removing the insoluble matter by filtration, the filtrate was concentrated under reduced pressure. The residue was parted by a column chromatography (silica gel and ethyl acetate), to provide 310 mg of methyl 2-acetylamino-5,5-dimethoxyvalerate as a colorless oil. The yield was 89%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][C@@H:41]5[CH3:46])=[O:39])=[CH:34][N:33]=4)[C:28](=[O:47])[N:27]([CH3:48])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][C@@H:41]5[CH3:46])=[O:39])=[CH:34][N:33]=4)[C:28](=[O:47])[N:27]([CH3:48])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H]1COCCN1C(=O)c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1COCCN1C(=O)c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
A solution of 136d (140 mg, 0.21 mmol) in methanol/dichloromethane (4/4 mL) was added NaBH4 (16 mg, 0.63 mmol). The mixture was stirred at room temperature for 1 h and quenched with water (2 mL). It was then evaporated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 136 (40 mg, 28%) as a white solid. MS-ESI: [M+H]+ 654.3. 1H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.77 (d, J=8.0 Hz, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.53 (d, J=2.5 Hz, 1H), 8.25 (d, J=2.5 Hz, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.78 (d, J=1.0 Hz, 1H), 7.65-7.63 (m, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.53 (d, J=5.0 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 4.91-4.89 (m, 1H), 4.45-4.39 (m, 2H), 4.17-4.13 (m, 1H), 3.79-3.67 (m, 2H), 3.58-3.53 (m, overlap, 5H), 3.41-3.36 (m, 1H), 3.29-3.25 (m, 1H), 1.39 (s, 9H), 1.22 (d, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:23])[C:10]2[N:11]=[CH:12][C:13]3[N:18]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[S:16][C:14]=3[N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:24]([C:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])([CH3:28])[CH3:27])#[N:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:20]([NH:19][C:17]1[S:16][C:14]2[N:15]=[C:10]([N:9]([CH3:23])[C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([C:26]([C:24]#[N:25])([CH3:27])[CH3:28])[CH:30]=4)[CH:3]=3)[N:11]=[CH:12][C:13]=2[N:18]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1nc2cnc(N(C)c3ccc(F)c(N)c3)nc2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(N(C)c3ccc(F)c(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)nc2s1
Yield: 44.2 %

Procedure:
A solution of N-{5-[(3-amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (100 mg, 301 μmol), 3-(1-cyano-1-methylethyl)benzoic acid (172 mg, 902 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (342 mg, 902 μmol) in pyridine (4 mL) was stirred at 90° C. for 5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→97/3), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (67 mg, 44%) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=2)[CH:2]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=2)[CH:2]=1
Reactant: O=C(NCc1cccnc1)c1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Product: O=C(NCc1cccnc1)c1cccc(-c2ccccc2)c1

Procedure:
Using Preparation Method 2, N-(3-pyridylmethyl)-3-bromobenzamide was reacted with phenylboronic acid. The resulting reaction mixture was purified using SiO2 with CH2Cl2/MeOH 98:2 to 90:10. A colourless oil was obtained (87%). NMR 1H (ppm, CDCl3): 8.87 (s, 1H), 8.73 (d, J4=4.5 Hz, 1H), 8.28 (t, J4=2.0 Hz, 1H), 8.03-7.94 (m, 3H), 7.89 (d, J3=6.9 Hz, 2H), 7.75-7.50 (m, 5H), 6.17 (br. t., 1H), 4.91 (d, J3=5.9 Hz, 2H).
Reaction SMILES: [CH:1]1([C:4]2[CH:28]=[CH:27][C:7](/[CH:8]=[C:9]3\[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH:24]5[CH2:26][CH2:25]5)=[CH:17][CH:16]=4)[O:12][C:13]\3=[O:14])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[NH2:29][CH2:30][CH2:31][OH:32]>C(O)C>[CH:24]1([CH2:23][CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([C:11]([NH:10]/[C:9](/[C:13]([NH:29][CH2:30][CH2:31][OH:32])=[O:14])=[CH:8]\[C:7]3[CH:27]=[CH:28][C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:5][CH:6]=3)=[O:12])=[CH:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: O=C1OC(c2ccc(OCCC3CC3)cc2)=N/C1=C\c1ccc(C2CC2)cc1
Reactant: NCCO
Solvent: CCO
Product: O=C(NCCO)/C(=C/c1ccc(C2CC2)cc1)NC(=O)c1ccc(OCCC2CC2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To an ethanol (1.6 mL) solution of (4Z)-4-(4-cyclopropylbenzylidene)-2-[4-(2-cyclopropylethoxy)phenyl]-1,3-oxazol-5(4H)-one (95 mg, 0.25 mmol) prepared in Example 1 (1c) was added 2-aminoethanol (20 μL, 0.33 mmol), and the mixture was stirred at 60° C. for one hour. The solvent was evaporated, and the residue was washed with n-hexane:ethyl acetate (3:1, V/V). The precipitate was collected by filtration and dried under reduced pressure to give 95 mg of the title compound (white powder, yield: 86%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH2:24]Br)=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH:15]=1.[C-:26]#[N:27].[Na+].O>CN(C=O)C.O.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH2:24][C:26]#[N:27])=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH:15]=1
Reactant: N#Cc1cccc(-c2cc(-c3nc4ccccc4o3)ccc2CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1-c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5′-(1,3-benzoxazol-2-yl)-2′-(bromomethyl)-1,1′-biphenyl-3-carbonitrile (183 mg, 0.47 mmol) and sodium cyanide (46 mg, 0.94 mmol) in DMF:H2O (5:1, 18 mL) and DMF (20 mL) was stirred at rt for 3 h. H2O was added to the reaction mixture and it was extracted with EtOAc (3×). The organics were combined, washed with brine (2×), dried over Na2SO4, and evaporated to dryness to give an orange oil. The crude was purified by flash chromatography on silica gel eluting with a gradient of EtOAc:hexanes (0 to 30 min: 0 to 20% EtOAc) to afford the desired 5′-(1,3-benzoxazol-2-yl)-2′-(cyanomethyl)-1,1′-biphenyl-3-carbonitrile as a colorless solid (M.p. 175–176° C.). 1H NMR (CDCl3, 300 MHz) δ 8.34 (dd, 1H), 8.18 (s, 1H), 7.77 (m, 3H), 7.67 (m, 3H), 7.60 (m, 1H), 7.40 (m, 2H), 3.69 (s, 2H). MS (ESI) 336 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][Si](C)(C)C)=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[N:4][CH:5]=1)#[CH:10]
Reactant: CNc1ccc(C#C[Si](C)(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(NC)nc1

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 1.5 g (7.3 mmol) methyl-(5-trimethylsilanylethynyl-pyridin-2-yl)-amine (A6) and 507 mg (3.7 mmol) K2CO3 in 10 mL MeOH. Yield: 698 mg (56%) after chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([Cl:12])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([Cl:12])[C:3]=1[CH2:4][OH:5]
Reactant: COc1ccc(Cl)c(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cl)c(CO)c1Cl
Temperature: 25 °C
Yield: 93.3 %

Procedure:
Dissolve 2,6-dichloro-3-methoxy-benzaldehyde (10 g, 48.8 mmol) in ethanol (330 ml) add sodiumborohydride (1.8 g, 48.8 mmol) and stir at room temperature over night. Partition reaction mixture between water and ethyl acetate separate layers wash organic with brine, dry over sodium sulfate, filter and concentrate to yield 9.43 g (93%) of (2,6-Dichloro-3-methoxy-phenyl)-methanol.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([NH:16][S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH2:11][CH2:10]2>C(Cl)Cl>[Cl:3][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([NH:16][S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH2:11][CH2:10]2
Reactant: O=S(Cl)Cl
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(CO)ccc21
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1CCc2cc(CCl)ccc21
Reaction time: 1 h
Yield: 51.1 %

Procedure:
Thionyl chloride (0.355 mL, 4.90 mmol) was added to a solution of N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (660 mg, 2.450 mmol) in DCM (10 mL). The whole was stirred for 1 h before the reaction mixture was evaporated to dryness and the crude material was purified by silica flash column chromatography (EtOAc/heptane: from 0% to 60% of EtOAc) to afford the title compound as a white solid (360 mg, 51%). MS (ESI): m/z [M−H]− 286.0
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1>C(Cl)CCl>[CH2:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCCc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 13 °C

Procedure:
Aluminum chloride (0.23 moles) was added in portions over 7 minutes to a mixture of butylbenzene (0.10 moles) and succinic anhydride (0.11 moles) in ethylene chloride (100 ml), cooled to about 13° C. Thirty minutes later the reaction mixture was poured into ice cold 3N hydrochloric acid (250 ml) and then extracted with ethyl acetate (2×100 ml). The extract was washed with saturated sodium chloride (100 ml), dried over magnesium sulfate and evaporated to give 4-(4-butylphenyl)-4-oxobutanoic acid (mp 107°-111.5° C.). A mixture of this acid (31.63 mmoles), sulfuric acid (0.5 ml) and 10% palladium on charcoal (755 mg) in ethyl acetate (150 ml) was shaken under 50 psi hydrogen for about 15 minutes to yield the reduced product, 4-(4-butylphenyl)butanoic acid (mp 56°-58° C.). A solution of this acid (27.05 mmoles) in sieve dried tetrahydrofuran (25 ml) was reduced with ice cold diborane in tetrahydrofuran (30 mmoles) for about 1.5 hours to give 4-(4-butylphenyl)butanol as an oil. To an ice cold solution of the butanol (27 mmoles) and carbon tetrabromide (32.56 mmoles) in methylene chloride (50 ml) was added triphenylphosophine (32.75 mmoles) in methylene chloride (50 ml) over 15 minutes. The reaction mixture was stirred for 45 minutes and then the volatiles were evaporated. The resulting oil was triturated with hexane (2×100 ml), filtered, and the filtrate evaporated and chromatographed to leave 4-(4-butylphenyl)butyl bromide as an oil.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH2:18][CH2:19][CH2:20][N:21]1[CH2:34][CH2:33][C:24]2([O:28][C:27](=[O:29])[N:26]([CH2:30][CH3:31])[C:25]2=[CH2:32])[CH2:23][CH2:22]1.[Cl-].[NH4+]>CN(C)C=O>[CH2:30]([N:26]1[C:25](=[CH2:32])[C:24]2([CH2:33][CH2:34][N:21]([CH2:20][CH2:19][CH2:18][N:15]3[C:16]4[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=4[S:8][C:9]4[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH2:22][CH2:23]2)[O:28][C:27]1=[O:29])[CH3:31]
Reactant: C=C1N(CC)C(=O)OC12CCN(CCCCl)CC2
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=C1N(CC)C(=O)OC12CCN(CCCN1c3ccccc3Sc3ccccc31)CC2
Reaction time: 2 h
Yield: 57.6 %

Procedure:
0.6 g of sodium hydride (60% oily dispersion) is added to a solution of 3.0 g of phenothiazine in 20 ml of anhydrous dimethylformamide under argon, then the reaction mixture is stirred at 50° to 60° C. for 2 hours. Thereafter, 3.9 g of 8-(3-chloropropyl)-3-ethyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane dissolved in 20 ml of dimethylformamide are dropwise added and the mixture is stirred at 40° to 50° C. for additional 6 to 7 hours. After cooling down saturated ammonium chloride solution is added to the reaction mixture under argon and the solvent is evaporated under reduced pressure. After taking up the evaporation residue in benzene and washing the benzene solution with water the solution is dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue is recrystallized from ethanol to give the title product in 57.6% yield, m.p.: 122°-123° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[S:11]([NH:14][C@H:15]([CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:13])=[O:12].[CH2:35](O)[C:36]1[CH:44]=[CH:43][C:42]2[O:41][CH2:40][O:39][C:38]=2[CH:37]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:40]1[O:41][C:42]2[CH:43]=[CH:44][C:36]([CH2:35][N:14]([S:11]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=3[CH3:10])(=[O:12])=[O:13])[C@H:15]([CH2:23][N:24]3[C:25](=[O:34])[C:26]4=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]4[C:28]3=[O:29])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:37][C:38]=2[O:39]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: COc1cc(C)c(S(=O)(=O)N[C@H](CN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)c(C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
To a cooled (ice bath) solution of tert-butyl 2(R)-(2,6-dimethyl-4-methoxybenzene sulfonylamino)-3-phthalimido-propionate (6.9 g, 14.12 mmol) in dry benzene (150 ml) with piperonyl alcohol (3.22 g, 21.2 mmol) and tributyl phosphine (5.3 ml, 21.2 mmol) was added 1,1′-(azodicarbonyl)-dipiperidine (5.35 g, 21.2 mmol). The mixture was allowed to warm to ambient temperature overnight. The material was loaded onto a flash silica gel column using ethyl acetate-hexanes (30%) as eluant, providing tert-butyl 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-phthalimido-propionate as a white solid (8.59 g).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:12](=[O:22])[N:11]([CH3:23])[C:10]=3[N:9]=[C:8]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH:18]([OH:21])[CH2:19][CH3:20])[C:12](=[O:22])[N:11]([CH3:23])[C:10]=3[N:9]=[C:8]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:33])[F:34])[CH:26]=2)=[CH:36][CH:37]=1
Reactant: CCC(=O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCC(O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Reaction time: 2 h
Yield: 72.4 %

Procedure:
7-(4-Chlorobenzyl)-3-methyl-1-(2-oxobutyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.44 g, 0.82 mmol, example 363) was dissolved in methanol (8 mL) and DCM (1 mL), then cooled to 0° C. Sodium borohydride (0.93 g, 2.46 mmol) was added portion wise over 20 min and reaction was stirred in the cold for 2 h. The reaction solvent was removed under reduced pressure then the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to give a clear oil. The oil was purified using an 40 g silica gel flash column eluted with 1% methanol/DCM to give 7-(4-chlorobenzyl)-1-(2-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.32 g, 73% yield) as a white solid. LCMS retention time=4.265 min and 97% purity, LCMS MH+ 539. 1H NMR (DMSO-d6) δ 7.59 (t, 1H, J=8 Hz), 7.45-7.48 (m, 1H), 7.38-7.45 (m, 5H), 7.30 (d, 1H, J=12 Hz), 5.43 (s, 2H), 4.56 (d, 1H, J=4 Hz), 3.92-4.00 (m, 1H), 3.65-3.76 (m, 2H), 3.28 (s, 3H), 1.23-1.41 (m, 2H).
Reaction SMILES: C([C:8]1([CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:32][CH2:31]1)[CH2:9][NH:10][NH:11][C:12](=[O:30])[CH:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[C:14]1=[S:27](=[O:29])=[O:28])(OC(C)(C)C)=O.[ClH:42]>C(Cl)Cl.C(OCC)C>[N:36]1([C:33]2[CH:32]=[CH:31][C:8]([CH2:9][NH:10][NH:11][C:12](=[O:30])[CH:13]3[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[C:15]([C:23]([F:24])([F:26])[F:25])[C:14]3=[S:27](=[O:29])=[O:28])=[CH:35][CH:34]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[ClH:42]
Reactant: CC(C)(C)OC(=O)C1(CNNC(=O)C2C=C(C(F)(F)F)C=C(C(F)(F)F)C2=S(=O)=O)C=CC(N2CCCCC2)=CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NNCc1ccc(N2CCCCC2)cc1)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C1=S(=O)=O
Reaction time: 12 h

Procedure:
A solution of 650 mg of N-(1-BOC-4-piperidinyl-benzylamino)-sulfonyl-3,5-bis-trifluoromethyl-benzamide in 5 ml of CH2Cl2 is treated with 60 ml of 3 N HCl (gas) in diethylether. The mixture obtained is stirred for ca. 12 hours and solvent is evaporated. N-(4-Piperidinyl-benzylamino)-sulfonyl-3,5-bis-trifluoromethyl-benzamide in the form of a hydrochloride is obtained. 1H-NMR (DMSO) δ:1.72-1.86 (m, 4H), 2.90 (m, 2H), 3.20-3.3 (m, 2H), 4.15 (m, 1H), 4.60 (s, 2H, CH2), 7.31 (t, 1H), 7.40 (t, 1H), 7.48 (d, 1H), 8.38 (s, 1H), 8.48 (s, 2H), 8.48 and 8.75 (broad, 2H, NH).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([OH:21])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:22][C:23]1([CH2:29][OH:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(N1C2=NC=C(C(N[C@H](C3C=CC=CC=3)CO)=O)C(NC3CCOCC3)=C2C=N1)C>>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:22][C:23]3([CH2:29][OH:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:21])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: NC1(CO)CCOCC1
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Agent: CCn1ncc2c(NC3CCOCC3)c(C(=O)N[C@@H](CO)c3ccccc3)cnc21
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)NC3(CO)CCOCC3)cnc21

Procedure:
Intermediate 139 was prepared from Intermediate 17 and (4-aminotetrahydro-2H-pyran-4-yl)methanol (commercially available from PharmaCore Inc., 4170 Mendenhall Oaks Pkwy, Suite 140, High point, N.C., USA) using an analogous method to that for Intermediate 42. LCMS showed MH+=404, TRET=2.19 min.