Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[CH3:13][CH:14]([NH2:19])[CH2:15][CH2:16][S:17][CH3:18]>C(#N)C>[I:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[C:8]([NH:19][CH:14]([CH3:13])[CH2:15][CH2:16][S:17][CH3:18])=[O:9]
Reactant: CSCCC(C)N
Reactant: O=C1OC(=O)c2c(I)cccc21
Solvent: CC#N
Product: CSCCC(C)NC(=O)c1c(I)cccc1C(=O)O
Reaction time: 3 h
Yield: 89.2 %

Procedure:
To a suspension of 2.74 g of 3-iodophthalic anhydride in 8 ml of acetonitrile cooled with ice was slowly added dropwise a solution of 1.19 g of 1-methyl-3-methylthiopropylamine in 3 ml of acetonitrile. After completion of the dropping, a reaction was carried out at room temperature for 3 hours with stirring. After completion of the reaction, the deposited crystal was collected by filtration and washed with a small quantity of acetonitrile. Thus, 3.5 g of the objective compound was obtained.
Reaction SMILES: [CH2:1]([O:3][Si:4](OCC)([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].FC(F)(F)C([O:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])=O>>[F:23][C:20]([F:21])([F:22])[C:19]([O:18][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[O:24]
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCO[Si](OCC)(OCC)OC(=O)C(F)(F)F
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Tetraethylorthosilicate (TEOS), 104 g, is loaded into a dried 1.3 L stainless steel pressure reaction vessel. A stoichiometric amount of trifluoroacetic anhydride, 105 g, is added. The reactor is sealed and the contents are heated at 80-100° C. for at least 12 hours. Preferably, the reaction is run at 80° C. for 16 hours. After sufficient time is permitted for conversion into the desired product, the reaction mixture is cooled and transferred to a vacuum distillation apparatus.
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([NH:11][C:12](=[NH:33])[C:13](=[NH:32])[NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:20]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)Cl.[S:37](N1C(=O)C2=CC=CC=C2C1=O)N1C(=O)C2=CC=CC=C2C1=O>C(N(CC)CC)C>[CH2:4]([NH:11][C:12]1[C:13]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:20]=2)=[N:32][S:37][N:33]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N=C(NCCCOc1cccc(CN2CCCCC2)c1)C(=N)NCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1SN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(CNc2nsnc2NCCCOc2cccc(CN3CCCCC3)c2)cc1
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A mixture of N-benzyl-N'-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride (4.73 g; 9.16 mmoles) [prepared in Step A], 45 ml of CH2Cl2 and 3.8 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (3.64 g; 9.16 mmoles) and stirred for one hour. The mixture was washed with 44 ml of 10% KOH, dried (MgSO4), filtered, diluted with toluene and concentrated. The residue was chromatographed by flash chromatography on 110 g of silica gel (230-400 mesh) using ethyl acetate as the eluent to give 3.1 g (77%) of the title compound. Treatment of the product with an equivalent amount of aqueous HCl in 2-propanol gave the hydrochloride salt of the title compound, mp 138°-141° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:11]([NH:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NCc1ccccc1
Temperature: 80 °C
Yield: 105.3 %

Procedure:
According to a modification of a procedure by Goker, H. et. al. (II Farmaco 1998, 53, 415-420) a mixture of 1-fluoro-2-nitro-benzene (1067) (1.1 mL, 10.4 mmol) and benzylamine (2.35 mL, 21.5 mmol) in DMF (5 mL) was heated overnight at 80° C. The reaction mixture was concentrated to give an orange solid which was filtered, washed with water and dried to afford benzyl-(2-nitro-phenyl)-amine (1068) (2.5 g, 100%). 1H NMR 6 (400 MHz, CDCl3) 8.44 (b, 1H, NH), 8.22-8.19 (dd, 1H), 7.41-7.27 (m, 6H), 6.84-6.81 (dd, 1H), 6.70-6.66 (m, 1H), 4.58-4.57 (d, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][NH:7]1)=[O:5])[CH3:2].[C:16]([N:19]([CH2:21][C:22](O)=[O:23])[CH3:20])(=[O:18])[CH3:17]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][N:7]1[C:22](=[O:23])[CH2:21][N:19]([C:16](=[O:18])[CH3:17])[CH3:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2ccccc2CN1
Reactant: CC(=O)N(C)CC(=O)O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: CCOC(=O)C1Cc2ccccc2CN1C(=O)CN(C)C(C)=O

Procedure:
This compound can be prepared by condensing 1,2,3,4-tetrahydroisoquinoline-3-carboxylic ethyl ester with N-acetylsarcosine according to the above-described methods; the corresponding acid can be prepared via catalytic hydrogenation of the product ester using Lindlar's catalyst or via base hydrolysis.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(O)C>[CH2:12]([N:9]1[CH2:10][CH:11]=[C:6]([C:4]2[CH:5]=[N:1][NH:2][CH:3]=2)[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1cc(-c2cn[nH]c2)ccn1
Reactant: BrCc1ccccc1
Solvent: CC(C)O
Product: C1=C(c2cn[nH]c2)CCN(Cc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
To a hot (80° C.) solution of 4-(1H-pyrazol-4-yl)pyridine (4.8 g) in 2-propanol was added benzyl bromide (10 mL, 2.5 equiv.) and the resulting mixture heated at reflux for 10 minutes. After cooling in an ice bath, the precipitate was filtered and washed with more 2-propanol and air dried. The solid was suspended in ethanol at 0° C. and sodium borohydride (6.5 g) was added in several portions over 30 minutes, and the mixture was stirred for an additional 30 minutes. The reaction was quenched by carefully addition of water, and the ethanol was removed by evaporation, and the residue was partitioned between dichloromethane and water. The organic layer was dried over MgSO4, and filtrated and evaporation gives 1-benzyl-4-(1H-pyrazol-4-yl)-1,2,3,6-tetrahydropyridine (7.5 g)
Reaction SMILES: C([N:8]([CH2:22][C@H:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19](=[O:21])[NH2:20])[CH:13]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:19]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[OH:18])[O:11][CH2:10][CH2:9][NH:8][CH2:22][C@H:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:21])[NH2:20]
Reactant: [H][H]
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)C[C@H](O)c2ccccc2)ccc1O
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc(OCCNC[C@H](O)c2ccccc2)ccc1O

Procedure:
A solution of 23 g of crude (R)-α-[N-benzyl-N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-benzyl alcohol in 230 ml of methanol is hydrogenated, with the addition of 5 g of palladium-charcoal catalyst (5%), under normal conditions until 1 mol-equivalent of hydrogen has been absorbed. The catalyst is subsequently filtered off, is washed with methanol, and the combined methanolic solutions are concentrated under reduced pressure. The crystalline residue is recrystallised from methanol and yields (R)-(-)-α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-benzyl alcohol, m.p. 166°-172°; [α]D =-23°±1° (C=0.6% in methanol).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O.[Cl:33]CCl>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:33])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4]
Reactant: ClCCl
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1

Procedure:
In analogy to the procedure described in example 253a, (2S,4R)-4-benzenesulfonyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester was treated with trifluoroacetic acid in dichloromethane to give the title compound as yellow oil. MS (ESI): m/z=270.2 [M+H]+.
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][NH2:25])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH:13]1[C:9]2[CH:10]=[CH:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[C:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:26])[CH2:24][NH:25][C:40]([N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:41])[CH2:21][CH2:22]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)N1CCCCC1)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
200 mg (0.545 mmol) of 2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride was suspended in 2 ml of dichloromethane. 0.19 ml of triethylamine was added to the obtained suspension. A solution of 96.5 mg (0.654 mmol) of 1-piperidinecarbonyl chloride in 3 ml of dichloromethane was added dropwise to the resultant mixture under cooling with ice, and they were stirred at room temperature for 30 minutes. Dichloromethane was concentrated under reduced pressure. Ethyl acetate was added to the residue. The resultant mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the basic silica gel chromatography (hexane:ethyl acetate=4:1 to 1:4) to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH3:19].[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH3:19])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: CC(C)C(=O)Cl
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)C(C)C
Yield: 43.6 %

Procedure:
Using the general method of Example 205, 1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 7.83 mmol) was reacted with isobutyryl chloride (835 mg, 7.83 mmol). The product was recrystallized from methyl acetate to provide 1.11 g of N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-2-methylpropanamide as an off white powder, m.p. 239.0-240.1° C. Analysis: Calculated for C18H23N5O.0.20 C3H6O2: % C, 65.66; % H, 7.17; % N, 20.58. Found: % C, 65.51. % H, 7.05; % N, 20.71.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:36])[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][C:31]1[N:36]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:30]=1
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 300 mg (0.720 mmol) of the compound from Example 45A and 93.6 mg (0.792 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted Yield: 231 mg (63% of theory, approx. 15% trans isomer)
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:10])=[C:4]2[CH:3]=[N:2]1.[I:11]NC(=O)CCC(N)=O>>[I:11][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:10])[NH:1][N:2]=1
Reactant: NC(=O)CCC(=O)NI
Reactant: Nc1ncnc2[nH]ncc12
Product: Nc1ncnc2[nH]nc(I)c12

Procedure:
Halogenation of commercially available 1H-pyrazolo[3,4-d]pyrimidin-4-amine provides an entry into the synthesis of compounds of Formula (A), (B), (C) and/or (D). In one embodiment, 1H-pyrazolo[3,4-d]pyrimidin-4-amine is treated with N-iodosuccinamide to give 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. Metal catalyzed cross coupling reactions are then carried out on 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. In one embodiment, palladium mediated cross-coupling of a suitably substituted phenyl boronic acid under basic conditions constructs intermediate 2. Intermediate 2 is coupled with N-Boc-3-hydroxypiperidine (as non-limiting example) via Mitsunobu reaction to give the Boc (tert-butyloxycarbonyl) protected intermediate 3. After deprotection with acid, coupling with, but not limited to, an acid chloride, such as, but not limited to, acryloyl chloride, completes the synthesis to give compound 4.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:28][CH3:29]>>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH2:18][O:19][CH2:28][CH3:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccc(N(Cc2ccccc2)Cc2ccccc2)c1CO
Reactant: CCI
Product: CCOCc1c(N(Cc2ccccc2)Cc2ccccc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 46B and iodoethane were processed as described in Example 46C to provide the title compound.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([S:35]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=4)(=[O:37])=[O:36])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:44][C:40]1[CH:39]=[C:38]([S:35]([CH:32]2[CH2:33][CH2:34][N:29]([C:19]3[N:18]=[C:17]4[CH2:16][NH:15][CH2:24][CH2:23][C:22]4=[N:21][C:20]=3[NH:25][CH:26]([CH3:28])[CH3:27])[CH2:30][CH2:31]2)(=[O:36])=[O:37])[CH:43]=[CH:42][CH:41]=1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(S(=O)(=O)c3cccc(F)c3)CC1)CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)Nc1nc2c(nc1N1CCC(S(=O)(=O)c3cccc(F)c3)CC1)CNCC2
Reaction time: 2 h

Procedure:
To a solution of 6-benzyl-3-(4-((3-fluorophenyl)sulfonyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (68 mg, 0.107 mmol) in THF (1333 μL) was added Pd(OH)2 (20 wt %, 22.5 mg, 0.032 mmol). The flask was purged with nitrogen then allowed to stir under an atmosphere of hydrogen (balloon) for 2 h. The reaction mixture was filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR) and washed with EtOAc. The crude material was concentrated in vacuo to give 3-(4-((3-fluorophenyl)sulfonyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine as a TFA salt (58 mg) as a yellow film.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([N+:7]([O-:9])=[O:8])[NH:4][N:3]=1.[OH-].[Na+].S(OC)(O[CH3:16])(=O)=O>CC(C)=O>[Br:1][C:2]1[N:3]([CH3:16])[N:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1nc(Br)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cn1nc([N+](=O)[O-])nc1Br
Reaction time: 18 h
Yield: 42.7 %

Procedure:
A stirred solution of 3-bromo-5-nitro-1H-1,2,4-triazole (13.1 g) in acetone (100 ml) was cooled to 0° and treated with 10% sodium hydroxide solution (30 ml), followed by dimethyl sulphate (9.5 g). After 18 h at room temperature, the mixture was evaporated in vacuo; the residue was diluted with water and extracted with ethyl acetate. The combined extracts were washed with 2N sodium hydroxide solution, water, and evaporated in vacuo. The resulting solid was recrystallized from a mixture of ethyl acetate and cyclohexane to yield the title compound (6.0 g), m.p. 90.5°-91.5°.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].Br[C:14]1[N:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=2[CH2:32][CH2:33][CH3:34])[CH:17]=[CH:16][CH:15]=1.C(OCC)C>CN(C)C=O>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:18]2[N:19]=[C:14]([S:1][C:2]3[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=3)[C:5]([OH:7])=[O:6])[CH:15]=[CH:16][CH:17]=2)=[C:23]([CH2:32][CH2:33][CH3:34])[C:24]=1[OH:31])(=[O:30])[CH3:29]
Reactant: O=C(O)c1cccc(S)c1
Reactant: CCCc1c(OCc2cccc(Br)n2)ccc(C(C)=O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCc1c(OCc2cccc(Sc3cccc(C(=O)O)c3)n2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.1 %

Procedure:
To a solution of 3-mercaptobenzoic acid (361 mg, 2.35 mmol) in dimethylformamide (15 mL) add sodium hydride (23 mg, 9.38 mmol) at 0° C., stir 10 min. Add 1-[4-(6-bromo-pyridin-2-ylmethoxy)-2-hydroxy-3-propyl-phenyl]-ethanone (854 mg, 2.35 mmol), heat to 100° C. for 6 hours. Cool to ambient temperature and add diethyl ether, collect the resulting red precipitate by filtration (290 mg). Purify by the residue by preparative LC (inject 110 mg) to yield the title compound as a white solid (50 mg, 0.12 mmol): 1H NMR (DMSO-d6) δ 0.88 (t, 3H), 1.50 (q, 2H), 2.55 (s, 3H), 2.61 (m, 2H), 5.25 (s, 2H), 6.65 (d, 1H), 6.97 (d, 1H), 7.26 (d, 1H), 7.62 (t, 1H), 7.76 (m, 1H), 7.83 (m, 1H), 8.02 (m, 1H), 8.07 (m, 1H), 12.85 (s, 1H), 13.25 (br s, 1H); MS (m/z): 436 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[OH:14].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14]
Reactant: COc1ccccc1C1CCCC1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: COc1ccccc1C1CCCC1=O
Yield: 73.6 %

Procedure:
To a solution of 2-(2-methoxyphenyl)cyclopentanol (9.11 g, 47.4 mmol) in Acetone (Volume: 474 ml) was added Jones reagent (6.52 ml, 52.1 mmol) (8.0 M). After the addition was complete (the conversion of red reagent to green solid, and the supernatant solution took on the color of unreacted reagent), isopropanol was added to quench the excess reagent. The green solid was filtered off through ceilite and rinsed with acetone. The filtrate was concentrated and purified by flash chromatography to get 2-(2-methoxyphenyl)cyclopentanone (6.64 g, 34.9 mmol, 73.6% yield). LC-MS (M+H)+=191.0. 1H NMR (500 MHz, CD3OD) δ 7.24 (td, J=7.8, 1.8 Hz, 1H), 7.09 (dd, J=7.5, 1.7 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 3.77 (s, 3H), 3.43-3.37 (m, 1H), 2.48-2.30 (m, 3H), 2.23-2.11 (m, 2H), 2.00-1.88 (m, 1H).
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1)(C1C=CC(C)=CC=1)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+].O>CS(C)=O>[N:29]([CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCOc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-[4-(2-Tosyloxyethoxy)Benzyl]-2,4-Thiazolidinedione (12.5 g) in dry Dimethylsulphoxide (80 ml) was added sodium azide (2 g) in one portion. The mixture was stirred at ambient temperature for 18 hours and the resulting solution added to water (250 ml). The aqueous solution was extracted with dichloromethane (2×300 ml) and the combined organic phases were washed with water (3×300 ml), dried (MgSO4), filtered and evaporated to give the title compound as an oil which was used in the next stage without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[CH2:14][NH:15][CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1)[CH2:6][NH:7][C:8](=[O:10])[CH3:9].[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:36]2[C:37]([CH:42]=O)=[N:38][CH:39]=[CH:40][CH:41]=2)([CH3:35])[CH3:34])=[CH:29][CH:28]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([C:36]2[C:37]([CH2:42][N:15]([CH2:14][C:13]3[CH:12]=[CH:11][C:5]([CH2:6][NH:7][C:8](=[O:10])[CH3:9])=[CH:4][C:3]=3[CH2:2][OH:1])[CH:16]3[C:25]4[N:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH2:19][CH2:18][CH2:17]3)=[N:38][CH:39]=[CH:40][CH:41]=2)([CH3:35])[CH3:34])=[CH:31][CH:32]=1
Reactant: CC(C)(c1ccc(F)cc1)c1cccnc1C=O
Reactant: CC(=O)NCc1ccc(CNC2CCCc3cccnc32)c(CO)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCc1ccc(CN(Cc2ncccc2C(C)(C)c2ccc(F)cc2)C2CCCc3cccnc32)c(CO)c1

Procedure:
Using General Procedure B: Reaction of N-{3-hydroxymethyl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzyl}-acetamide in CH2Cl2 with 3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridine-2-carbaldehyde and NaBH(OAc)3 gave N-(4-{[{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzyl)-acetamide as a white foam. 1H NMR (CDCl3) δ 1.45 (m, 1H), 1.55 (s, 3H), 1.63 (s, 3H), 1.72 (m, 1H), 1.83 (m, 1H), 2.00 (s, 3H), 2.10 (m, 1H), 2.57 (m, 2H), 2.79 (m, 1H), 3.48 (s, 2H), 3.72-3.90 (m, 4H), 4.35 (d, 2H, J=6.0 Hz), 4.60 (d, 1H, J=12.0 Hz), 4.72 (d, 1H, J=12.0 Hz), 5.67 (br s, 1H), 6.79 (t, 2H, J=6.0 Hz), 6.91 (d, 1H, J=6.0), 7.03 (br s, 3H), 7.21 (m, 2H), 7.27 (d, 1H, J=9.0 Hz), 7.79 (d, 1H, J=9.0 Hz), 8.41 (d, 1H, J=3.0 Hz), 8.53 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 22.4, 23.6, 27.2, 29.4, 29.6, 32.6, 42.3, 43.8, 54.8, 55.2, 59.0, 63.7, 115.2, 115.5, 121.6, 121.8, 127.1, 127.4, 127.5, 130.7, 132.4, 133.9, 134.6, 136.8, 138.0, 142.9, 145.7, 146.8, 146.9, 157.6, 158.1, 159.5, 162.7, 170.3. HPLC: 95%. ES-MS m/z 567 [M+H]+. Anal. Calcd. for C35H39N4O2F.0.3 CH2Cl2: C, 71.60; H, 6.74; N, 9.46. Found: C, 71.48; H, 6.81; N, 9.58.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14]OS(C)(=O)=O)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])=[CH:22][CH:21]=2)[N:9]=1.[CH3:36][O-:37].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:36][O:37][CH2:14][C:12]1[CH:13]=[C:8]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])[N:9]=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])=[CH:24][CH:25]=2)[N:11]=1
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-[4-[4-[(3S)-3-Methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl]-3-phenyl-urea (90 mg) dissolved in a solution of DCM (5 mL) and triethylamine (0.045 mL). Sodium methoxide (33% in methanol) (0.073 mL) was added to the reaction and the mixture stirred at RT for 18 h before being quenched with water and partitioned. The organic phase was dried over magnesium sulphate and evaporated to give a gum which was purified by prep-HPLC (basic) to give the desired compound (32 mg) as a white solid.