Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]=[CH2:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl.O.[OH-].[NH4+]>C(Cl)(Cl)Cl>[CH3:24][C:4]1[C:5]2([C:20]([O:22][CH3:23])=[O:21])[CH:6]3[CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]([CH3:1])([CH2:19][CH:18]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=2)[N:3]=1
Reactant: C=Cc1ccccc1C1C(C(=O)OC)=C(C)NC(C)=C1C(=O)OC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)C1C2c3ccccc3C3CC1(C)N=C(C)C32C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Into a solution of the Compound 2b (0.3 mmol) in dry chloroform (5 ml) was bubbled anhydrous hydrogen chloride. The resulting solution was stirred for 2.5 hours at ambient temperature. The reaction mixture was diluted chloroform (10 ml) and water (5 ml) and then neutralized with concentrated aqueous ammonium hydroxide. The organic phase was separated and the aqueous phase extracted with chloroform (2×20 ml). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the resulting yellow oil purified by flash chromatography on silica gel eluted with hexane:diethyl ether (1:2). The β-isomer had an Rf =0.4 and the α-isomer had an Rf =0.3.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8]>ClC(Cl)(Cl)Cl>[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][Br:1])[C:7]([O:9][CH3:10])=[O:8]
Reactant: CON=C(C(=O)OC)c1ccccc1C
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CON=C(C(=O)OC)c1ccccc1CBr
Yield: 45.7 %

Procedure:
21.4 g (0.133 mol) of bromine are added to a stirred solution of 27.5 g (0.133 mol) of methyl 2-methylphenylglyoxylate O-methyloxime in 400 ml of tetrachloromethane. The mixture is then refluxed while irradiating with a 300 W Hg vapor lamp for four hours. It is then concentrated, the residue is taken up in ethyl acetate/water, and the organic phase is washed with H2O, dried with sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel with cyclohexane/ethyl acetate (9/1). 17.4 g (46%) of the abovementioned compound are obtained as an oil.
Reaction SMILES: [CH:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=2)[CH2:4]1)=O.COC(OC)OC.[CH2:29]([NH2:34])[CH2:30][CH:31]([CH3:33])[CH3:32]>CO>[CH3:32][CH:31]([CH3:33])[CH2:30][CH2:29][NH:34][CH2:1][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=2)[CH2:4]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CC(C=O)C3)nc1
Reactant: CC(C)CCN
Solvent: COC(OC)OC
Solvent: CO
Product: CC(C)CCNCC1Cc2ccc(Oc3ccc(C(N)=O)cn3)cc2C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 25 %

Procedure:
Combine 6-(2-Formyl-indan-5-yloxy)-nicotinamide (Intermediate 32, 25.3 mg, 0.09 mmol), MeOH (2.4 mL), trimethylorthoformate (1.6 mL), and isopentyl amine (9 uL, 0.08 mmol). After the reaction stirs at room temperature under a nitrogen atmosphere for 4.5 hours, add NaBH (4.1 mg, 0.11 mmol), then stir at room temperature for another 12 hours. After that time, concentrate under reduced pressure then add ethyl acetate. Wash the organic phase with water, brine, and dry over Na2SO4. After concentration under reduced pressure the mixture, add to a 2 g SCX column, wash with MeOH and elute with 1N NH3-MeOH. After concentration, flash chromatograph using 2% 1N NH3-MeOH, 20% THF, 38% DCM to afford 7.0 mg, 0.02 mmol (25% yield) of the title compound: 1H NMR (500 MHz, d-Methanol); 0.9 (6H, d), 1.4-1.5 (2H, m), 1.6-1.7 (1H, m), 2.6-2.8 (6H, m), 3.1-3.2 (2H, m), 3.3-3.4 (1H, m), 6.8 (1H, d), 6.9 (1H, s), 7.1 (1H, d), 7.2 (1H, d), 8.1 (1H, d), 8.5 (1H, s); TLC 2% 1N NH3-MeOH:20% THF:78% CH2Cl2:Rf:=0.27.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[C:10](Cl)=[N:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:15])[C:6]1=[O:16])[C:2]#[C:3][CH3:4].C(OC([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=O)(C)(C)C>>[CH2:1]([N:5]1[C:9]2[C:10]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:15])[C:6]1=[O:16])[C:2]#[C:3][CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC#CCn1c(=O)n(C)c2ccnc(Cl)c21
Product: CC#CCn1c(=O)n(C)c2ccnc(N3CCNCC3)c21
Temperature: 175 °C
Yield: 64.5 %

Procedure:
3-(2-butynyl)-4-chloro-1-methyl-1,3-dihydroimidazo[4.5-c]pyridin-2-one (0.041 g) and piperazine-1-carboxylic acid t-butyl ester (0.200 g) were heated at 175° C. for four hours under nitrogen atmosphere. Additional piperazine-1-carboxylic acid t-butyl ester (0.200 g) was then added, and this was heated at 175° C. for 16 hours. The residue was purified by reverse phase high performance liquid chromatography to give the title compound (0.032 g).
Reaction SMILES: [CH3:1][SiH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:1][Si:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCC[SiH2]C
Reactant: C=CCCCCCCCC
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCCC[Si](C)(CCCCCCCC)CCCCCCCCCC
Yield: 86 %

Procedure:
A mixture of 72.6 grams methyloctylsilane and 200 grams of 1-decene was reacted in the presence of 0.0042 gram of chlorotris(triphenylphosphine)rhodium(I) for one hour at 87°-100° C. After stripping off unreacted decene under high vacuum, followed by hydrogenation of the residue, and distillation, resulted in an 86 percent yield of methyldidecyloctylsilane having a boiling point of 200°-206° C. (0.25 mm).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]3[N:18]([N:28]=[C:29]([C:31]([OH:33])=O)[CH:30]=3)[C:19](=[O:27])[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[NH2:41][C:42]1[NH:46][N:45]=[N:44][N:43]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH:43]1[C:42]([NH:41][C:31]([C:29]2[CH:30]=[C:17]3[NH:16][C:15]([C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:10][CH:11]=4)=[C:20]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[C:19](=[O:27])[N:18]3[N:28]=2)=[O:33])=[N:46][N:45]=[N:44]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Temperature: 25 °C
Reaction time: 41 h
Yield: 35.5 %

Procedure:
To a solution of 71 mg (0.16 mmol) of 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid in 4 mL of dimethylformamide (DMF) was added 0.053 mL (0.48 mmol) of 4-methyl-morpholine, 14 mg (0.164 mmol) of 5-aminotetrazole, followed by 100 mg (0.192 mmol) of PYBOP when the solution turned yellow, and the resulting mixture was stirred at rt for 41 h. The reaction mixture was concentrated to give a residue which was purified via reverse-phase chromatography to afford 29 mg (35% yield) of desired 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (1H-tetrazol-5-yl)-amide (540) as a solid as indicated by 1H-NMR; LC-MS calcd. for C27H26N8O3 [M++H]+: 511.21; found: 511.1.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20]([O:22]CC)=O)[CH:12]=[N:11][C:10]1=2.C(#N)C>CO>[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20]([NH:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[O:22])[CH:12]=[N:11][C:10]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: CC(=O)NCCN
Solvent: CC#N
Solvent: CO
Product: CC(=O)NCCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 120 °C
Yield: 76.5 %

Procedure:
0.516 g (5.05 mmol) of N-acetylethylenediamine was placed into a 10 ml round bottom flask. The flask was heated to 120° C. and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added to the stirring solution. The solution was heated at 120° C. for one hour. 8 ml of acetonitrile was added to the viscous oil and stirred. Approximately 1 ml of methanol was added and the solution was stirred vigorously for 30 minutes. The resulting white precipitate was collected by vacuum filtration and was washed with acetonitrile and ether to yield 237 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-[(1-oxoethyl)amino]ethyl]propanamide (AIT-0051) as a white solid upon drying. Yield: 76%
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:16])[C:4]([N:6]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5].[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.CCOCC>[C:17]1([NH:23][C:24]([S:1][CH2:2][CH:3]([CH3:16])[C:4]([N:6]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][C:8]([OH:10])=[O:9])=[O:5])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(CS)C(=O)N(CC(=O)O)C1CCCC1
Reactant: O=C=Nc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(CSC(=O)Nc1ccccc1)C(=O)N(CC(=O)O)C1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4.9 g (0.02M) of N-(3-mercapto-2-methyl propanoyl)-N-cyclopentyl glycine and 8 ml of phenyl isocyanate in 5 ml methylene chloride was stirred at room temperature for 72 hours. The mixture was diluted with ether and filtered. The ether solution was washed with water, dried over MgSO4 and evaporated to dryness. The crude residue was dissolved in acetonitrile, treated with charcoal and crystallized by addition of ether, m.p. 170°-172° C.
Reaction SMILES: [NH3:1].C(O[C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[N:15]4[C:19]([C:20](=[O:21])[C:8]([C:9]=23)=[CH:7][N:6]=1)=[CH:18][CH:17]=[C:16]4[N+:22]([O-:24])=[O:23])C.O>N1C=CC=CC=1>[NH2:1][C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[N:15]4[C:19]([C:20](=[O:21])[C:8]([C:9]=23)=[CH:7][N:6]=1)=[CH:18][CH:17]=[C:16]4[N+:22]([O-:24])=[O:23]
Reactant: CCOc1ncc2c(=O)c3ccc([N+](=O)[O-])n3c3cccc1c23
Reactant: N
Solvent: c1ccncc1
Solvent: O
Product: Nc1ncc2c(=O)c3ccc([N+](=O)[O-])n3c3cccc1c23
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A stream of ammonia is passed into a solution of 4-ethoxy-10-nitro-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (5 g) in pyridine (200 cc) until the solution is saturated. The solution obtained is then stirred at a temperature of about 20° C. for 16 hours. The resulting suspension of red crystals is poured into iced water (600 cc). The crystalline precipitate is filtered off and then washed successively with water (5 × 10 cc), ethanol (3 × 10 cc) and then diethyl ether (2 × 20 cc). After drying under reduced pressure (1 mm Hg) at 25° C., 4-amino-10-nitro-7-oxo-7H-indolizino[7,6,5-de]-isoquinoline (4.18 g) is obtained in the form of orange-red crystals.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH2:21])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH:21][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([OH:9])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:17]
Reactant: CCOC(=O)CN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Product: CCOC(=O)CNC(c1ccccc1)C(O)c1ccccc1
Yield: 69.1 %

Procedure:
A stirred mixture of trans-stilbene oxide (6.48 g, 0.033 mol), and glycine ethyl ester (6.15 g, 0.0598 mol) was heated at 120° for 22 hours. The mixture was triturated with ether and filtered to remove some insoluble materials. The filtrate was concentrated to yield 6.83 g (69.1%) of oil which solidified into a waxy solid upon cooling. The compound was purified and characterized as the hydrochloride salt, mp 185°-187° C. (absolute ethanolisopropyl ether) [reported mp 167°, Can. J. Chem. 45, 2865 (1967)].
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[CH3:19][N:20]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([N:20]([CH3:19])[CH:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=3)[CH2:30][CH2:29]2)=[CH:26][CH:25]=1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CN(c1ccc(N)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(c1ccc(N)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Yield: 28.9 %

Procedure:
2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.948 mmol, 0.657 g), N1-methyl-N1-(piperidin-4-yl)benzene-1,4-diamine (1.948 mmol, 0.4 g) and potassium carbonate (5.84 mmol, 0.808 g) were combined and stirred at room temperature for 1 hour in acetonitrile (50 mL). The reaction mixture was filtered and concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried and concentrated under vacuum. The residue was purified by silica column chromatography (eluent: dichloromethane to 8% methanol in dichloromethane) to afford the title compound (260 mg). MS (ESI) m/z 462.4 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH:18][S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3)c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.53 mmol) and benzenesulfonyl chloride (92 mg, 0.63 mmol) were dissolved in pyridine (5 mL). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified on column chromatography using petroleum ether/ethyl acetate=5:1 as eluent to afford N-[3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide (110 mg, yield: 44%) as yellow solid. MS (ESI+APCI) M+1=427.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([S:23][CH3:24])[C:4]=1[C:5]([NH:7][CH:8]1[C:13](=O)[CH2:12][CH2:11][O:10][CH2:9]1)=[O:6].C(O)(=O)C.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:18]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:16]=[C:15]([S:23][CH3:24])[C:4]=1[C:5]([NH:7][C@H:8]1[C@@H:13]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:12][CH2:11][O:10][CH2:9]1)=[O:6]
Reactant: C1CCNC1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1COCC[C@@H]1N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
2-Methoxy-6-methylsulfanyl-N-(4-oxo-tetrahydro-pyran-3-yl)-4-trifluoromethyl-benzamide (intermediate C, 300 mg, 0.83 mmol) was dissolved in 5 mL tetrahydrofurane. Acetic acid (86 mg, 1.4 mmol) and pyrrolidine (70 mg, 0.99 mmol) were added and the reaction mixture was stirred 1 h at room temperature. Sodium triacetoxyborohydride (209 mg, 0.99 mmol) was added and stirring was continued at room temperature overnight. The mixture was extracted with 2N sodium carbonate solution and ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0→140:10:1) yielded cis-2-methoxy-6-methylsulfanyl-N-((3RS,4RS)-4-pyrrolidin-1-yl-tetrahydro-pyran-3-yl)-4-trifluoromethyl-benzamide as a light brown solid (80 mg, 40%), MS: m/e=419.1 [(M+H)] and trans-2-methoxy-6-methylsulfanyl-N-((3RS,4SR)-4-pyrrolidin-1-yl-tetrahydro-pyran-3-yl)-4-trifluoromethyl-benzamide as a light brown solid (25 mg, 12%), MS: m/e=419.1 [(M+H)+].
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][C:3](Cl)=[O:4].[CH:8]([N:11]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)[C:12](=[O:28])[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:10])[CH3:9]>C1COCC1>[O:6]=[C:1]1[N:14]([CH2:13][C:12]([N:11]([CH:8]([CH3:10])[CH3:9])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)=[O:28])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:3](=[O:4])[CH2:2]1
Reactant: COc1cccc(N(C(=O)CNc2ccccc2Nc2ccccc2)C(C)C)c1
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1CCOC1
Product: COc1cccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)c1
Reaction time: 8 h

Procedure:
Malonyl dichloride (1.48 mL) in THF (50 mL) is added dropwise over 35 min to a 0° C. solution of N-Isopropyl-N-(3-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide, prepared as in Part C, (5.45 g, 14.1 mmol) in THF (140 mL) and the resultant mixture allowed to attain RT overnight. The solvents were removed in vacuo and the residue diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium hydrogen carbonate (100 mL), water (100 mL), brine (100 mL), dried (MgSO4), and concentrated in vacuo. The resulting oil is purified by silica gel flash column chromatography using 3% methanol in methylene chlorideas eluent to afford 2-(-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(3-methoxy-phenyl) acetamide (2.4 g) as an amber foam: 1H NMR (300 MHz, CDCl3) δ7.3-7.1 (m, 10H), 7.02 (t, 1H, J=7.2), 6.92 (dd 1H, J=8.6,2.4), 6.83 (d, 1H, J=7.2), 4.95 (m, 1H, J=6.8), 4.38 (m, 1H), 4.02 (m, 1H), 3.78 (s, 3H), 3.48 (dd, 2H, J=39.3, 11.9), 1.06 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH3:11][OH:12]>>[CH3:11][O:12][C:3](=[O:2])[CH2:4][CH2:5][NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: CO
Product: COC(=O)CCNCc1ccc(OC)cc1

Procedure:
A solution of p-methoxybenzyl amine (690 mg, 722 μL, 8.01 mmol) in dry methanol (5 ml), under nitrogen was cooled to 0° and treated dropwise with a solution of metacrylate (951 μL, 1.0 g, 7.28 mmol) in MeOH (1.0 ml) added over 2 min. After 15.5 h the clear solution was distilled at atmospheric pressure to remove MeOH. The high boiling residue (>170°) formed 3-(4-Methoxy-benzylamino)-propionic acid methyl ester (1.88 g, Quantitative) 1H (300 MHz, CDCl3) 1.78 (bs, 1H), 2.45 and 2.53 (t, J=3.0 Hz, 2H), 2.77 and 2.87 (t, J=3.0 Hz, 2H), 3.46 and 3.67 (s, 3H), 3.64 and 3.73 (s, 3H), 3.88 (m, 2H), 6.78 and 6.85 (m, 2H), 7.17 and 7.23 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH:9]=[O:10])[CH:6]=[C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1.S([CH2:32][N+:33]#[C-:34])(C1C=CC(C)=CC=1)(=O)=O.COCCOC>O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH:6]=[C:7]([C:9]2[O:10][CH:34]=[N:33][CH:32]=2)[N:8]=1
Reactant: COc1ccc(CCNc2cc(C=O)nc(OC)n2)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: COCCOC
Solvent: O
Product: COc1ccc(CCNc2cc(-c3cnco3)nc(OC)n2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 8.5 %

Procedure:
In a tube is combined 2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carbaldehyde [120 mg, 0.42 mmol, Intermediate (59)], tosylmethylisocyanide (90 mg, 0.46 mmol), Ambersep 900 OH resin (800 mg), ethylene glycol dimethyl ether (3.5 mL) and water (3.5 mL). The tube is sealed and the mixture is heated to 90° C. and stirred for 18 hours. The mixture is allowed to cool to ambient temperature and filtered to remove the resin, and the resin is washed with MeOH (10 mL). The combined filtrate and washings are concentrated by rotary evaporator and the residue is subjected to flash column chromatography on silica gel eluting with 0 to 40% EtOAc in heptane gradient) to afford (2-methoxy-6-oxazol-5-yl-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine [11.6 mg, 8.5%, Example 45]. LCMS: RT=2.57 minutes, MS: 327 (M+H). IC50=7.8 nM
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(C)=O.Cl[CH2:10][C:11]1[N:12]=[C:13]([NH:16][C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[O:18])[S:14][CH:15]=1>O>[N:1]([CH2:10][C:11]1[N:12]=[C:13]([NH:16][C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[O:18])[S:14][CH:15]=1)=[N+:2]=[N-:3]
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CCl)cs1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1csc(NC(=O)NCc2cccc(F)c2)n1
Reaction time: 4 h

Procedure:
Sodium azide (390 mg, 6.0 mmol) was added to a DMSO (5 mL) solution of Intermediate 4: 1-(4-(chloro-methyl)thiazol-2-yl)-3-(3-fluorobenzyl)urea (600 mg, 2 mmol). The mixture was stirred for 4 hours at 40 C. Upon completion of the reaction, water was added at 10 C and the mixture was extracted with EtOAc. Organics were washed with brine, dried and evaporated. Recrystallization from CH2Cl2/hexane afforded 1-(4-(azidomethyl)thiazol-2-yl)-3-(3-fluorobenzyl)urea. 1H NMR (400 MHz, CDCl3): δ 10.3 (1H, br), 7.27 (m, 1H), 7.1-6.9 (m, 3H), 6.74 (s, 1H), 4.50 (d, 2H), 4.27 (s, 2H). MS (ES+): M/Z 307 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[OH:19][C@@H:20]1[C:32]2[C:24](=[CH:25][C:26]3[O:30][CH2:29][O:28][C:27]=3[CH:31]=2)[C@@H:23]([C:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]([OH:41])=[C:35]([O:42][CH3:43])[CH:34]=2)[C@@H:22]2[C:44](=[O:47])[O:45][CH2:46][C@@H:21]12>ClCCl>[C:9](=[O:10])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:41][C:36]1[C:35]([O:42][CH3:43])=[CH:34][C:33]([C@H:23]2[C@@H:22]3[C:44](=[O:47])[O:45][CH2:46][C@H:21]3[C@H:20]([OH:19])[C:32]3[C:24]2=[CH:25][C:26]2[O:30][CH2:29][O:28][C:27]=2[CH:31]=3)=[CH:38][C:37]=1[O:39][CH3:40]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@@H](O)[C@@H]3COC(=O)[C@@H]23)OCO4)cc(OC)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](O)[C@@H]3COC(=O)[C@@H]23)OCO4)cc(OC)c1OC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
0.55 mmol of triethylamine and 0.37 mmol of benzyl chloroformate are added in succession to a solution of 0.25 mmol of (5R,5aS,8aS,9S)-9-hydroxy-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one in 10 ml of anhydrous dichloromethane at 0° C. and under argon. After stirring for 1 hour, the reaction mixture is washed with water. The organic phase is then dried, filtered and subsequently concentrated under reduced pressure. Chromatography on silica gel (cyclohexane/ethyl acetate: 60/40) enables the expected product to be isolated.