Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1.C(N(CC)CC)C.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>O1CCCC1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2([CH3:14])[O:10][CH2:11][CH2:12][O:13]2)=[C:2]([O:1][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC1(c2ccc(Br)cc2O)OCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(c2ccc(Br)cc2O[Si](C)(C)C)OCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
Under ice-cooling, to a solutin of 3.11 g (12 mmol) of 2-(2-hydroxy-4-bromophenyl)-2-methyl-1,3-dioxolane in 24 ml of tetrahydrofuran were added dropwise successively, 1.84 ml (13.2 mmol) of triethylamine and 1.68 ml (13.2 mmol) of trimethylsilyl chloride with stirring. The mixture was stirred at room temperature for 3 hours and filtered. The filtrate was concentrated under reduced pressure to give 4.0 g of the crude product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([NH:26]C=O)[CH:6]=[C:7]([CH2:15][P:16]([O:22]C(C)C)([O:18]C(C)C)=[O:17])[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2].C[Si](C)(C)Br.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([NH2:26])[CH:6]=[C:7]([CH2:15][P:16]([OH:22])([OH:18])=[O:17])[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2]
Reactant: CCOC(=O)C(C=C(CCN(C)C(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(N)C=C(CCN(C)C(C)=O)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
8.2 g (18.9 mmol) of 6-(N-acetyl-N-methylamino)-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 40 ml of dichloromethane, and 9.8 ml (75.6 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 24 hours, 40 ml of ethanol are added dropwise, the mixture is left to stand for a further 24 hours and is concentrated by evaporation, the residue is dissolved in 40 ml of ethanol, and a mixture of 40 ml of propylene oxide and 40 ml of ethanol is added dropwise. A suspension forms, which is stirred for a further one hour at room temperature and for one hour at 0° and is then filtered with suction. Drying yields 6-(N-acetyl-N-methylamino)-2-amino-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 222°-223° C. (decomp.).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Cn1ccnc1S
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nccn3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 2-mercapto-1-methylimidazole was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.48-1.65 (m, 8H) 1.86 (m, 2H) 3.72 (s, 3H) 3.80 (s, 3H) 7.04 (m, 2H) 7.19 (d, J=1.7 Hz, 1H) 7.46 (s, 1H) 7.58 (s, 1H). MS (APCI) calcd for C23H27ClN2O4S: 462.99; found 463.1.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CNc2ncc(I)cc2N1
Product: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Yield: 38 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.623 g) was reacted with benzyl bromide as in General Procedure 1 to give the title compound as a light yellow solid (38% yield). M.p. 225° C., LCMS: m/z=366.03 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.14 (s, 2H), 5.10 (s, 2H), 7.13 (s, 1H), 7.7.22-7.29 (m, 4H), 7.31-7.38 (m, 2H), 7.78 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=O)[NH:8][CH:7]=[C:6]2[C:16]#[N:17].P(Br)(Br)([Br:20])=O.C(Cl)Cl>C1(OC)C=CC=CC=1>[Br:20][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[C:6]([C:16]#[N:17])=[CH:7][N:8]=1
Reactant: COc1cc2c(C#N)c[nH]c(=O)c2cc1OC
Reactant: O=P(Br)(Br)Br
Solvent: ClCCl
Solvent: COc1ccccc1
Product: COc1cc2c(C#N)cnc(Br)c2cc1OC
Temperature: 80 °C
Yield: 73.1 %

Procedure:
The mixture of 6,7-Dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carbonitrile (8 g, 35 mmol) and phosphorus oxybromide (70 g, 244 mmol) in anisole (30 mL) was heated to 80° C. for 12 h. The solvent and excess POBr3 were removed by rotary evaporator. The resulting solid was washed with hexane and dried. The solid was slowly added to ice and the product was extracted with chloroform. The organic layer was washed with saturated aqueous sodium carbonate solution, saturated aqueous sodium chloride solution (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford a brown solid. Flash chromatography (Merck Silica gel 60, 70–230 mesh, methylenechloride) afforded 1-Bromo-6,7-dimethoxy-isoquinoline-4-carbonitrile (7.5 g, 75%) as a brown solid. LC-MS m/e calcd for C12H9BrN2O2 (MH+) 293, found 293.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[CH:27][C:28]=4[F:30])[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[C:5]([O:41][CH3:42])[CH:4]=1)#[N:2].[OH:43]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[CH:27][C:28]=4[F:30])[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[C:5]([O:41][CH3:42])[CH:4]=1)(=[O:43])[NH2:2]
Reactant: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)cc(F)c32)C1c1cccc(Cl)c1F
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)cc(F)c32)C1c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide (0.3 g, 0.49 mmol) prepared in Example 75 in DMSO (15 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (1.1 g, 9.7 mmol), then aqueous solution (1N) of NaOH (4.9 mL, 4.9 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in dichloromethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as a white solid (Yield 0.2 g, 64%)
Reaction SMILES: Br[C:2]([CH:9]=[O:10])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:11]=[N+:12]=[N-:13].[Na+]>C(COC)OC.O>[N:11]([C:2]([CH:9]=[O:10])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(C)(Br)C=O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(C)(C=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl α-bromo-α-formylpropionate (20 g.) in dimethoxyethane (200 ml.) is added a solution of sodium azide (8 g.) in water (40 ml.) and the mixture is stirred at room temperature for 5 hours. The dimethoxy ethane is removed under reduced pressure and the residue is taken up in a mixture of ether and water. The ethereal phase is separated, washed with water, dried over anhydrous sodium sulfate and evaporated yielding ethyl α-azido-α-formylpropionate which is purified by vacuum distillation.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[Cl:11]Cl.N>CC(O)=O>[Cl:11][C:3]1[C:4]2[NH:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: ClCl
Reactant: Nc1ccc2nc[nH]c2c1
Agent: N
Solvent: CC(=O)O
Product: Nc1ccc2nc[nH]c2c1Cl

Procedure:
To a solution of 5-aminobenzimidazole (1.0 g, 7.5 mmol) in 20 ml of AcOH was added Cl2 saturated AcOH solution until it produced a precipitation. The reaction mixture was concentrated in vacuo, yielding a dark residue which was subjected to column chromatography (NH3 sat'd 30% MeOH/EtOAc) to yield 120 mg (0.72 mmol) of 4-chloro-5-aminobenzimidazole.
Reaction SMILES: [CH2:1]([C:5]1[CH2:9][CH2:8][C:7](=[N:10][OH:11])[C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([F:20])[CH:13]=1)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl.CCCCCC>[CH2:1]([C:5]1[CH2:9][CH2:8][C:7](=[N:10][OH:11])[C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:20])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=C(c2ccc(OC)c(F)c2)C(=NO)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCC1=C(c2ccc(O)c(F)c2)C(=NO)CC1
Reaction time: 2 h
Yield: 57.9 %

Procedure:
To a stirred solution of 20 mg 3-butyl-2-(3-fluoro-4-methoxyphenyl)-2-cyclopenten-1-one oxime (Example 40) in 5 ml dichloromethane, was added 0.5 ml 1.0 M boron tribromide in hexane at 0° C. under inert atmosphere. The reaction mixture was stirred for 2 hours, poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Then the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/ethyl acetate=2:1) to yield 11 mg 3-butyl-2-(3-fluoro-4-hydroxyphenyl)-2-cyclopenten-1-one oxime. Spectral data for Example 41 are provided along with the melting point in Table 4.
Reaction SMILES: [CH3:1][C:2]1[C:3]([Se:16][C:17]#[C:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:53][C:54]1[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=1>C1COCC1>[OH:60][C:57]1[CH:58]=[CH:59][C:54]([NH:53][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([C:18]#[C:17][Se:16][C:3]3[C:2]([CH3:1])=[CH:11][C:10]4[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=4[CH:4]=3)=[N:20][CH:21]=2)=[CH:55][CH:56]=1
Reactant: Cc1cc2c(cc1[Se]C#Cc1ccc(C(=O)O)cn1)C(C)(C)CCC2(C)C
Reactant: Nc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1cc2c(cc1[Se]C#Cc1ccc(C(=O)Nc3ccc(O)cc3)cn1)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to that of Example 10, by reaction of 300 mg (0.72 mmol) of the 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)nicotinic acid with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300 mg (1.45 mmol) of 1,3-dicyclohexylcarbodiimide and 95 mg (0.87 mmol) of 4-aminophenol in 20 ml of THF, and after purification on a column of silica (ethyl acetate 20/heptane 80), 20 mg (6%) of a yellow solid are obtained. m.p.=172° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-:3])=[O:2].[NH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1>>[C@H:16]1([NH:15][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[N:9]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: N[C@@H]1CCc2ccccc21
Product: O=[N+]([O-])c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12

Procedure:
5-Nitro-2-chloroquinoline (CAS 13067-94-2, 2.4 g, 11.5 mmol) and (R)-1-aminoindane (3.13 g, 23 mmol) were stirred in a sealed tube at 120° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0→50:50 gradient). (R)-Indan-1-yl-(5-nitro-quinolin-2-yl)-amine was obtained as a brown solid (2.67 g, 76%), MS: m/e=306.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH2:8][C:9]#[N:10].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH:8]([C:20](=[O:21])[NH:19][C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[C:9]#[N:10]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cn1cccc1C(=O)CC#N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccc(F)cc1
Reaction time: 8 h

Procedure:
To the suspension of 4.0 g of 1-methyl-β-oxo-2-pyrrolpropionitrile in 70 ml of toluene and 3.2 g of triethylamine, 3.7 g of p-fluorophenylisocyanate are added while stirring. The mixture is warmed on the steam cone until dissolution and the red-brown solution is allowed to stand overnight at room temperature. It is evaporated on the steam cone, the residue taken up in methanol and the solution poured into the mixture of 8 ml of 5 N hydrochloric acid and 300 ml of water. The precipitated crystals are collected, washed with water, dried, triturated with methanol and recrystalllized from ethyl acetate, to yield the 1-methyl-β-oxo-α-(p-fluorophenylcarbamoyl)-2-pyrrolpropionitrile melting at 198°-199°.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>C1COCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:35](=[O:36])[CH2:34][O:33][CH3:32])=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (1.30 g) in THF (18 mL) were added triethylamine (0.757 ml) and methoxyacetyl chloride (472 mg), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.11 g).
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[N:4]([CH3:6])C.N1CCCC1.CO[C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([N+:23]([O-])=O)=CN=1>CN(C)C=O.[Pd]>[CH3:1][O:2][C:3]1[CH:22]=[C:20]2[CH:21]=[CH:16][NH:23][C:19]2=[CH:6][N:4]=1
Reactant: COc1cc(C)c([N+](=O)[O-])cn1
Reactant: COC(OC)N(C)C
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: COc1cc2cc[nH]c2cn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
10.76 g of N,N-dimethylformamide dimethyl acetal and 2.45 ml of pyrrolidine are added, in succession, to a solution of 5 g of the product obtained in Step 1 in 60 ml of dimethylformamide. The mixture obtained is first heated at 100° C. for 8 hours and then at 150° C. for 1 hour. Concentration is carried out under a vacuum of 10−1 mbar and the residue is taken up in 150 ml of tetrahydrofuran. The solution obtained is hydrogenated under a pressure of 10 bars for 4 hours in the presence of 10% Pd/C. After filtration and concentration, the residue is chromatographed over silica (eluant CH2Cl2/EtOH: 95/5) to yield the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][N:6]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:4].[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:28]=[N+:29]=[N-:30])[CH2:7][N:6]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of (2S,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (14.4 g, 36.09 mmol) in dry N,N-dimethylformamide (50 mL) was added sodium azide (4.7 g, 72.18 mmol) and the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water, brine, and dried over anhydrous sodium sulfate. Filtration and concentration gave a crude which was purified by column chromatography (15% ethyl acetate in hexane as eluent) to give (2S,4S)-4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (7.8 g, 80% yield) as a light brown liquid. MS calcd. for C11H19N4O4 [(M+H)+] 271.0, obsd. 271.0.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=2[CH3:25])=[CH:9][CH:8]=1)C.[OH-].[K+]>C(O)C.O1CCCC1>[C:21]([C:19]1[CH:18]=[CH:17][C:16]([CH3:25])=[C:15]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7]([CH:6]=[CH:5][C:4]([OH:26])=[O:3])=[CH:8][CH:9]=2)[CH:20]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)C=Cc1ccc(C#Cc2cc(C(C)(C)C)ccc2C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)C)cc1C#Cc1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A solution of 3-[4-(5-tert-butyl-2-methyl-phenylethynyl)-phenyl]-acrylic acid ethyl ester (Intermediate 111, 0.09 g, 0.26 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with 3M potassium hydroxide solution (1 mL, 3 mmol) and the resulting reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo slightly, the residue was neutralized with dilute hydrochloric acid, and the solid that was formed was filtered and washed with water and acetonitrile and dried to afford title product (0.064 g, 77%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[NH2:7])(=[O:3])[CH3:2].Cl[C:15]1[N:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[N:16]=1.Cl.Cl.C(C1C=C(NC(NC(N)=N)=N)C=C(C(=O)C)C=1)(=O)C>O>[C:1]([C:4]1[CH:5]=[C:6]([NH:7][C:15]2[N:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[N:16]=2)[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Reactant: Nc1nc(N)nc(Cl)n1
Agent: CC(=O)c1cc(NC(=N)NC(=N)N)cc(C(C)=O)c1
Agent: Cl
Solvent: O
Product: CC(=O)c1cc(Nc2nc(N)nc(N)n2)cc(C(C)=O)c1
Yield: 62.5 %

Procedure:
Compound No. 13: A suspension of 3,5-diacetylaniline (1.95 g) in water (10 mL) was treated with 2-chloro-4,6-diamino-1,3,5-triazine (1.455 g) and concentrated HCl (0.1 mL) and heated at reflux for 20 min. After cooling the hydrochloride of Compound No. 13 separated as a white powder. This was filtered out, dissolved in 60 mL of boiling aqueous 75% methanol and treated with triethylamine (1.5 mL). On cooling, off-white flakes separated. Filtration and drying gave 1.79 g of 2-(3,5-diacetylphenyl)amino-4,6-diamino-1,3,5-triazine, mp 271°-2° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][S:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CNCCNC.[Na+].[I-:28]>O1CCOCC1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][S:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([I:28])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCSC(c2ccc(Br)cc2)C1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCSC(c2ccc(I)cc2)C1
Temperature: 130 °C
Yield: 41.3 %

Procedure:
To a degassed solution of 2-(4-bromo-phenyl)-thiomorpholine-4-carboxylic acid tert-butyl ester (0.75 g; 2.09 mmol) and N,N′-dimethylethylenediamine (0.11 mL; 1.05 mmol) in 1,4-dioxane (10 mL) was added CuI (39.9 mg; 0.21 mmol) and NaI (0.78 g; 5.23 mmol). The resulting mixture was heated in a closed vessel, at 130° C., for 3 days. After cooling to room temperature the mixture was concentrated in vacuo, and the residue was purified by column chromatography (SiO2, CH2Cl2/hexanes 1:1) to afford 2-(4-iodo-phenyl)-thiomorpholine-4-carboxylic acid tert-butyl ester (0.35 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:32][CH:33]1[CH:40]2[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:42][CH:34]1[CH2:35]3)[CH2:39]2.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:32][CH:33]2[CH:34]3[CH2:42][CH:38]4[CH2:37][CH:36]([CH2:41][CH:40]2[CH2:39]4)[CH2:35]3)=[O:8])=[CH:9][CH:10]=1
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of 4-fluorobenzoic acid (15.0 g, 0.11 mol) in DMF (400 mL) was added HOBt (24.59 g, 0.16 mol) and EDAC (20.53 g, 0.11 mol). The resulting mixture was stirred for 1 hr at room temperature at which time a solution of 2-amino-adamantane.HCl (20.1 g, 0.11 mol) and DIPEA (20.52 mL) in DMF (100 mL) was added dropwise. The mixture was stirred at room temperature for 16 hrs and the volatiles evaporated in vacuo. The residue was dissolved in AcOEt and washed with aq. NaHCO3, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo affording 28.66 g, (98%) of 4-fluoro-N-adamantan-2-yl-benzamide as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cu][C:23]#[N:24].O>CN(C)C=O>[CH2:15]([O:14][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:7][C:2]=1[C:23]#[N:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#C[Cu]
Reactant: COCOCCc1ccc(OCc2ccccc2)c(Br)c1
Solvent: CN(C)C=O
Solvent: O
Product: COCOCCc1ccc(OCc2ccccc2)c(C#N)c1
Temperature: 120 °C
Reaction time: 48 h
Yield: 104.5 %

Procedure:
To a stirred solution of the obtained 4′-benzyloxy-3′-bromophenethyl alcohol (782 mg) in dichloromethane (8 ml) were added N,N-diisopropylethylamine (665 μl) and chloromethyl methyl ether (232 μl) under ice-cooling, and the mixture was stirred for 6 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. After the extract was washed with brine, removal of the solvent under reduced pressure gave benzyl 2-bromo-4-(2-methoxymethoxyethyl)phenyl ether (804 mg). To a solution of benzyl 2-bromo-4-(2-methoxymethoxyethyl)phenyl ether (804 mg) in N,N-dimethylformamide (5 ml) was added copper(I) cyanide (458 mg) and the mixture was stirred for 2 days at 120° C. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, and removal of the solvent under reduced pressure gave 2-benzyloxy-5-(2-methoxymethoxyethyl)benzonitrile (711 mg).