Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[CH3:2][O:3][CH2:4][CH2:5][N:6]([CH2:16][CH2:17][O:18][CH3:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]=[C:14]=[S:15]>C(O)C>[CH3:19][O:18][CH2:17][CH2:16][N:6]([CH2:5][CH2:4][O:3][CH3:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([NH2:1])=[S:15]
Reactant: COCCN(CCOC)c1ccccc1N=C=S
Reactant: N
Solvent: CCO
Product: COCCN(CCOC)c1ccccc1NC(N)=S
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A saturated solution of ammonia in ethanol (40 ml) was added over 40 minutes to a mixture of 2-[bis(2-methoxyethyl)amino]phenyl isothiocyanate (7.5 g) and ethanol (10 ml) which had been cooled to 10° C. The mixture was stirred at 0° C. for 8 hours and then stirred without cooling for 16 hours. The solvent was then removed by evaporation and the residue purified by chromatography on a silica column eluted with a 1:4 mixture of ethyl acetate and hexane and then a 1:1 mixture of ethyl acetate and hexane to give 1-{2-[bis(2-methoxyethyl)amino]phenyl}thiourea (m.p. 118°-119° C.).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17].[S]>N1C=CC=CC=1.[Cl-].[Na+].O>[NH:17]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:18]=[C:1]1[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1ccccc1N
Reactant: Cc1nc2ccccc2s1
Agent: [Cl-]
Agent: [Na+]
Agent: [S]
Solvent: c1ccncc1
Solvent: O
Product: c1ccc2[nH]c(-c3nc4ccccc4s3)nc2c1
Yield: 13.7 %

Procedure:
The heterogeneous mixture consisting of methylbenzothiazole (59.6 g, 0.4 mol), ortho-phenylenediamine (43.2 g, 0.4 mol) and sulfur (38.4 g, 1.2 mol) in 300 ml of pyridine was heated at the reflux point of pyridine for 22 hours. The reaction mixture was cooled and poured into a solution of brine. After extraction with ethyl acetate, washing of the organic phase 3 times with water, drying over sodium sulfate and concentration of the solvent under vacuum, the solid obtained was washed with acetone. After drying, 2-(1H-benzimidazol-2-yl)benzothiazole (13.8 g, yield: 13%) was obtained in the form of a yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:24])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([CH2:20]Cl)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[NH2:25][C:26]([C:28]1([NH:41][CH3:42])[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=[O:27].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:25][C:26]([C:28]1([N:41]([CH2:20][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][C:16]=2[O:22][CH3:23])[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=2[F:24])[CH3:42])[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:32][CH2:33]1)=[O:27]
Reactant: CNC1(C(N)=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 78.8 %

Procedure:
N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine hydrochloride (0.30 g, 0.775 mmol) was added over a period of 40 minutes to a stirred solution of tert-butyl 4-(aminocarbonyl)-4-(methylamino)piperidine-1-carboxylate (0.498 g, 1.93 mmol) and DIPEA (0.50 g, 3.89 mmol) in DMF (1 ml) at 120° C. The reaction mixture was stirred for 1 hour, cooled, concentrated and purified by column chromatography on silica eluting with acetonitrile to afford tert-butyl 4-(aminocarbonyl)-4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-1-carboxylate (0.35 g, 79%) as a white foam; Mass Spectrum: (M+H)+ 573.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]([CH2:19]I)=[CH:17][C:16]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]5)=[N:25][CH:26]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:39])[CH3:2].[CH3:40][O:41][CH2:42][CH2:43][OH:44].[H-].[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]([CH2:19][O:44][CH2:43][CH2:42][O:41][CH3:40])=[CH:17][C:16]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]5)=[N:25][CH:26]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:39])[CH3:2]
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(CI)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(COCCOC)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
Ethyl 1-[5-[2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-7-(iodomethyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (160 mg, 0.241 mmol) and 2-methoxyethanol (95 μL, 1.21 mmol) were dissolved in THF (10 mL). Sodium hydride (96 mg, 2.41 mmol) was added portion-wise and the mixture stirred under argon at rt for 1 h. The mixture was then diluted with EtOAc (50 mL), carefully quenched with saturated aqueous NH4Cl, washed with water, brine and separated. The organic fraction was dried (Na2SO4), concentrated under reduced pressure and the resulting solid residue purified by flash column chromatography (40 g GraceResolv, silica cartridge) eluting with 50-100% EtOAc/heptane to afford the desired compound (86 mg, 58%) as a colourless resin. MS: 612.16 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11](=[O:12])[N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:27])([F:26])[F:28])=[N:20][C:21]([C:22]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:24])=[C:15]2[CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCCC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 73.6 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), pyrrolidine (38.4 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-3-[1-(pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 12a (120 mg, yield 74%) as a white solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4][C:5]1[S:6][C:7]([C:15]([O:17]CC)=[O:16])=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:9]=1>O.C(O)C.O>[CH2:13]([O:12][C:10]([C:8]1[N:9]=[C:5]([S:4][CH3:3])[S:6][C:7]=1[C:15]([OH:17])=[O:16])=[O:11])[CH3:14]
Reactant: CCOC(=O)c1nc(SC)sc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nc(SC)sc1C(=O)O
Reaction time: 1 h

Procedure:
At room temperature, a solution of 1.10 g (27.5 mmol) of sodium hydroxide in 10 ml of water was added over a period of one hour to a solution of 7.00 g (25 mmol) of diethyl 2-methylthiothiazole-4,5-dicarboxylate in 100 ml of ethanol/water (2:1). The mixture was stirred for one hour, the solvent mixture was then removed under reduced pressure, the residue was taken up in 100 ml of water, the solution was extracted once with 50 ml of diethyl ether, and the aqueous phase was acidified with concentrated hydrochloric acid. The precipitated product was filtered off and dried.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1>C(OCC)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[O:26][C:22]=3[CH:21]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 6-amino-3H-benzoxazol-2-one according to the method described in Example 1c. Melting Point: 190-193° C. (diethylether)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].O>CN(C)C=O>[C:21]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Oc1ccc2c(=O)c(-c3ccccc3)coc2c1
Reaction time: 0.17 h

Procedure:
To a solution of 7 g of 7-hydroxyisoflavone in 190 ml of N,N-dimethylformamide, 2 g of sodium hydride (80% in paraffin oil) were added. The mixture was stirred for 10 minutes, then 4.2 g of pivaloyl chloride were dropped in 1 minute, under vigorous stirring. After 20 minutes at r.t. the mixture was poured into water (400 ml), the precipitate was filtered, washed with water (1000 ml) and dissolved in chloroform (800 ml). The organic solution was dried over sodium sulphate and evaporated to dryness.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15](Cl)=O>>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][N:9]=1
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)c1ccco1
Product: c1coc(C2=NCCc3ccccc32)c1

Procedure:
1-(Furan-2-yl)-3,4-dihydroisoquinoline was prepared by reacting phenethylamine with 2-furanoyl chloride followed by reflux with polyphosphoric acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2([CH2:28][NH:29][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[O:12])[CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CNC(=O)c3n[nH]c4ccccc34)CCCC2)cc1OC
Reaction time: 16 h
Yield: 9.9 %

Procedure:
1H-Indazole-3-carboxylic acid (32.4 mg, 0.200 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (47.1 g, 0.200 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (83.6 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (76.0 mg, 0.200 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (7.47 mg, 0.0197 mmol, 9.84%) ESI-MS m/z calc. 379.2, found 380.4 (M+1)+. Retention time of 3.02 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:15][C@@:7]3([OH:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:21]([O:24][CH2:25]CO)([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][CH2:19][CH2:25][O:24][CH:21]([CH3:23])[CH3:22])=[O:17])[CH2:15][C@@:7]3([OH:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reactant: CC(C)OCCO
Solvent: Cc1ccccc1
Product: CC(C)OCCOC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1

Procedure:
To methyl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a-,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 118, 0.20 g, 0.67 mmol) was added toluene (10 ml) titanium (IV) ethoxide (0.07 ml) and 2-isopropoxy ethanol. The reactants were stirred together and then heated under reflux for 1 h, before concentrating in vacuo. The crude residue was purified using a Sep Pak cartridge eluting with hexane and then hexane:ethyl acetate (50:50). Further purification by preparative HPLC was performed using a Magellan column 212×150 mm, flow rate 20 ml/min, eluting with a gradient of water:acetonitrile (55:45 to 90:10) over 8 min to yield the title compound (63.9 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([CH3:28])=[CH:26][S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[N:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:27]([CH3:28])=[CH:26][S:25][C:15]=3[N:16]=2)=[CH:24][CH:23]=1
Reactant: Cc1csc2nc(-c3ccncc3)nc(Cl)c12
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1csc2nc(-c3ccncc3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-4-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3-nitrobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][OH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(O)C>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[C:7]3[CH:6]=[C:5]4[O:1][CH2:2][O:3][C:4]4=[CH:9][C:8]=3[CH2:10][CH2:11][O:12]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: OCCc1ccc2c(c1)OCO2
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C2OCCc3cc4c(cc32)OCO4)cc1
Yield: 81 %

Procedure:
36.0 g (0.21 mmol) of 2-(1,3-benzodioxol-5-yl)-ethanol is reacted with an equivalent amount of 4-nitrobenzaldehyde analogously to C.A. 105, 1986, 226357, and 50.7 g (81%) of the title compound, melting point 149-150° C. (ethanol), is obtained.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C:13]([CH2:15][C@:16]4([CH3:22])[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:14].C(N(CC)CC)C.FC(F)(F)S(O[Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])(=O)=O>ClCCl>[O:6]([C:5]1[CH2:4][CH2:3][C@@:2]2([CH3:1])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:12]2[C:13](=[O:14])[CH2:15][C@@:16]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C:20]2=[O:21])[CH:7]=1)[Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1=CC2=CC[C@@H]3[C@H](C(=O)C[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of adrenosterone (6.0 g, 20 mmol) in dry dichloromethane (120 ml) was added triethylamine (8.4 ml, 60 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (5.0 ml, 22 mmol) and the mixture stirred at room temperature for 3 h. The dichloromethane was evaporated and the residue redissolved in diethyl ether (100 ml), then allowed to stand for 30 min, after which time an oil separated. The ether phase was decanted off the oil and the solvent evaporated to give the title compound which was used directly in step (b). IR νmax 1705, 1747 cm-1 ; 1H-NMR(CDCl3) inter alia δ0.12 (6H,s,Me2Si), 0.85 (3H,s,18-CH3), 0.92 (9H,s,tBuSi) 1.17(3H,s,19-CH3), 4.73 (1H,dm, J 6.9 Hz, 6-H), 5.36 (1H,m,4-H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:11])[CH3:10]>CN(C=O)C.C(Cl)Cl>[C:9]([C:12]1[C:13]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:16]([Br:1])[CH:17]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(C(C)=O)c(OCc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(OCc2ccccc2)c(C(C)=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
N-Bromosuccinimide (0.756 g, 4.27 mmol) was added portionwise to a solution of N-(4-acetyl-3-benzyloxy-phenyl)-acetamide (1.2 g, 4.24 mmol) in DMF (24 ml) and the reaction stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed with water and dried over MgSO4 to afford a white solid (1.03 g, 67%). LC/MS: RT=2.609 min. 362/364 (MH+).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:26](O)=[O:27])[N:16]([CH3:25])[C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1>>[C:1]([NH:5][C:26]([C:15]1[N:16]([CH3:25])[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=2)[N:14]=1)=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: Cn1c(C(=O)O)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Product: Cn1c(C(=O)NC(C)(C)C)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1

Procedure:
Using essentially the same procedure as Example 20, Step B, but using t-butylamine (0.020 mL, 0.12 mmol), 4,5-di-(4-chlorophenyl)-1-methylimidazole-2-carboxylic acid (20 mg, 0.060 mmol) from Example 20, Step A was converted to the title compound.
Reaction SMILES: [C:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][N:13]1[C:17]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:16]([CH:27]([CH3:29])[CH3:28])[N:15]=[C:14]1[CH3:30])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[C:31]([O:37][CH2:38]I)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>>[C:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][N:13]1[C:17]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:16]([CH:27]([CH3:28])[CH3:29])[N:15]=[C:14]1[CH3:30])(=[O:7])[CH2:2][CH2:3][C:4]([O:6][CH2:38][O:37][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[O:5]
Reactant: CC(C)(C)C(=O)OCI
Reactant: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCOC(=O)CCC(=O)[O-]
Product: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCOC(=O)CCC(=O)OCOC(=O)C(C)(C)C
Yield: 84.5 %

Procedure:
The compound 76 (250 mg, 0.526 mmol) was converted to the ester with pivaloyloxymethyl iodide (140 mg, 0.578 mmol) under potassium carbonate (50.9 mg, 0.368 mmol) in the same manner as the example 61 to give the compound 78 (262 mg, 84%) as oil. Rf 0.18 (1:1 EtOAc - hexane).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=1
Reactant: OCc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 96.3 %

Procedure:
4-(Chloromethyl)-5-methyl-2-phenyl-1,3-oxazole (5.00 g), parahydroxybenzyl alcohol (3.29 g) and potassium carbonate (6.66 g) were suspended in dimethylformamide (25 ml) and the suspension was stirred at 50° C. for 3.5 hr. The reaction mixture was cooled and water (25 ml) was added at not higher than 15° C. The mixture was stirred for about 5 min and at about 5° C. for 1 hr under ice-cooling. The crystals were collected by filtration, washed twice with water (15 ml) and dried under reduced pressure at 50° C. to give the objective product (6.85 g) in a yield of 96%.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:4]=1.[CH3:25][O:26][CH2:27][CH2:28][OH:29]>>[CH3:25][O:26][CH2:27][CH2:28][O:29][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:4]=1
Reactant: COCCO
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Agent: [Na]
Product: COCCOc1cc(C)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 100 °C
Yield: 37 %

Procedure:
Sodium (10 mg, 0.45 mmol) was dissolved under an atmosphere of nitrogen in 2-methoxyethanol (0.95 mL). (4-Chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (99 mg, 0.3 mmol) was added and the suspension was heated to 100° C. for 2 hours. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound as a yellow solid (41 mg, 37%). MS ISP (m/e): 370.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.74 (s, 1H), 7.63 (s, 1H), 7.18 (d, 1H), 7.05 (s, 1H), 7.03 (d, 1H), 6.87 (s, 1H), 6.18 (s, 1H), 4.51 (dd, 2H), 3.86 (s, 3H), 3.73 (dd, 2H), 3.45 (s, 3H), 2.35 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [C:1]([N:8]([CH3:17])[C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH2:25]([O:32][C:33](=[O:50])[C@H:34]([CH3:49])[NH:35][C:36](=[O:48])[C@H:37]([CH3:47])[N:38]([C:40](=[O:46])[C@H:41]([CH:43]([CH3:45])[CH3:44])[NH2:42])[CH3:39])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][C:33](=[O:50])[C@H:34]([CH3:49])[NH:35][C:36](=[O:48])[C@H:37]([CH3:47])[N:38]([C:40](=[O:46])[C@H:41]([CH:43]([CH3:45])[CH3:44])[NH:42][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:17])[CH3:39])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)[C@H](N)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@H](C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 3.17 g (0.0537 mole) of Boc-N-methyl-L-leucine in 370 ml of dry dichloromethane was stirred and cooled at 0° C. as one-half of 13.15 g. (0.130 mole) of dry triethylamine was added, followed by 15.05 g (0.0591 mole) of BOP-CCl. This was stirred at 0° C. for 3 hours. The remainder of the triethylamine was added, followed by a solution of 13 g (0.0358 mole) of L-valyl-N-methyl-L-alanyl-L-alanine benzyl ester in 50 ml of dry dichloromethane. The reaction was stirred at ice temperature for 22 hours, then washed with 125 ml of a 10% solution of potassium bisulfate. The organic layer was further washed with 2×100 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, concentrated to a small volume, and chromatographed on silica gel eluting with 1:1 ether/hexane gradually increasing the ether to 2:1. The product weighed 15.8 g (75% of theory), and the FAB m.s. showed a molecular ion peak at 591.