Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Br:14])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].CN([CH:27]=[O:28])C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([CH:27]=[O:28])[C:8]=1[Br:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(F)c(C=O)c1Br
Reaction time: 1.25 h
Yield: 62 %

Procedure:
To a solution of 2-bromo-4-fluoro-benzoic acid tert-butyl ester (10.0 g, 36 mmol) in THF (100 mL) at −78° C. under an atmosphere of nitrogen was added lithium diisopropylamide (1.8M solution, 20 mL, 36 mmol) dropwise. The reaction mixture was stirred for 1.25 hours before adding DMF (10 mL) then stirred for a further 10 minutes before quenching with acetic acid (3 mL). The products were partitioned between ethyl acetate and water, the organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a yellow oil which crystallized on standing. The crude product was triturated in cyclohexane to give the title compound as a yellow solid (6.8 g, 62%). 1H NMR (CDCl3, 400 MHz) 10.38 (1H, s), 7.80-7.73 (1H, m), 7.17 (1H, t, J=9.09 Hz), 1.62 (9H, s).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:14]([O:16][CH3:17])=[O:15])#[N:2].C(=O)([O-])[O-:19].[Na+].[Na+].OO.S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[C:1]([CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:14]([O:16][CH3:17])=[O:15])(=[O:19])[NH2:2]
Reactant: COC(=O)c1cc2ccccc2n1CCC#N
Reactant: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1cc2ccccc2n1CCC(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
A mixture of 3.12 g (13.7 mmol) of methyl 1-(2-cyanoethyl)-2-indolecarboxylate, 30 ml of 10% sodium carbonate solution, 30 ml of 30% hydrogen peroxide and 100 ml of acetone was stirred at room temperature for 4 hours. Next, the reaction mixture was cooled to 0° C. and 10% sodium sulfite solution was added dropwise to decompose an excess of the peroxide. The most of acetone in the reaction mixture was then distilled off and the concentrate was extracted three times with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2.30 g (68%) of methyl 1-(2-carbamoylethyl)-2-indolecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@H:25]3[CH2:28][C@H:27]([CH2:29]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:41]12([NH2:51])[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2>CN(C)C=O>[C:41]12([NH:51][CH2:29][C@H:27]3[CH2:26][C@H:25]([N:8]4[C:4]5[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=5[C:10]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]6[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=6)[CH:12]=5)=[CH:9]4)[CH2:28]3)[CH2:48][CH:47]3[CH2:46][CH:45]([CH2:44][CH:43]([CH2:49]3)[CH2:42]1)[CH2:50]2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](n3cc(-c4cccc(OCc5ccccc5)c4)c4c(N)ncnc43)C2)cc1
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CNC23CC4CC(CC(C4)C2)C3)C1
Reaction time: 24 h

Procedure:
50 mg (0.09 mmol) of trans-toluene-4-sulfonic acid 3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl ester and 34 mg (0.225 mmol) of adamantan-1-ylamine (Fluka, Buchs, Switzerland) in 1 ml N,N-dimethylformamide are stirred for 18 h at RT and for 24 h at 60° C. Additional adamantan-1-ylamine is added (34 mg) and stirring is continued for 24 h at 120° C. The solvent is evaporated to dryness and the residue is purified by flash-chromatography (ethylacetate:methanol:NH4OHaqu.=95:5:1) to provide trans-7-[3-(adamantan-1-ylaminomethyl)cyclobutyl]-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine. Analytical HPLC: tR=11.14 min (Grad 1); ES-MS: m/eo=533.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C:18]3([OH:32])[CH2:23][CH:22]4[CH2:24][CH2:25][CH:19]3[CH:20]=[C:21]4[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:41][O:42][C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45].C1COCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C@:18]3([O:32][C:44](=[O:45])[C:43]([O:42][CH3:41])([CH3:48])[CH3:47])[CH2:23][C@H:22]4[CH2:24][CH2:25][C@@H:19]3[CH:20]=[C:21]4[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(C)(C)C(=O)Cl
Reactant: COc1cccc2[nH]c(CCCN(C)CCC3(O)CC4CCC3C=C4c3ccccc3)nc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc2[nH]c(CCCN(C)CC[C@]3(OC(=O)C(C)(C)OC)C[C@H]4CC[C@@H]3C=C4c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 295 mg of rac-(1R*,2R*,4R*)-2-(2-{[3-(4-methoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol in 6.6 mL of DCM was added 1.4 mL of NEt3, 81 mg of DMAP and 0.8 mL of 2-methoxy-2-methyl propanoyl chloride (prepared as in JOC, 1976, 41, 19, 3182-3187) at 0° C. The reaction mixture was allowed to warm up to rt and stirred for 5 min at rt before 0.3 mL of anh. THF was added. The reaction mixture was stirred overnight at 50° C., extracted with DCM and washed with sat. NaHCO3. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The crude product was purified by CC using DCM/MeOH/DIPEA 95/5/1 to yield 214 mg of rac-2-methoxy-2-methyl-propionic acid (1R*,2R*,4R*)-2-(2-{[3-(4-methoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester as white foam.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:51])[NH:29][C@@H:30]([CH3:50])[CH2:31][O:32][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:51])[NH:29][C@@H:30]([CH3:50])[CH2:31][OH:32])[N:27]=2)[CH2:20]1
Reactant: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[(1S)-2-(t-butyldiphenylsilyloxy)-1-methylethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (2.77 g, 3.77 mmol) (obtained as described in Reference Example 35(2)) in anhydrous tetrahydrofuran (140 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (9.06 ml, 9.06 mmol) in an ice bath. The mixture was stirred in the ice bath for 3.5 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (9:1) as the eluant to afford 3-hydroxy-1-[4-((1S)-2-hydroxy-1-methylethylcarbamoyl)-1,3-thiazol-2-yl]azetidine (911 mg, yield 94%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[N:16]([CH3:22])[CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C.C1C(=O)N([Br:31])C(=O)C1.C(Cl)Cl.C([O-])(O)=O.[Na+].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[N:16]([CH3:22])[CH2:15]2)=[CH:10][C:9]=1[Br:31]
Reactant: CN1CC(c2ccc(NC(=O)OC(C)(C)C)cc2)CN(C)C1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2ccc(N)c(Br)c2)CN(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
[4-(1,3-Dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-carbamic acid tert-butyl ester (as prepared in the previous step, 106 mg, 0.333 mmol) was dissolved in TFA (2 mL). The resulting mixture was stirred at RT for 30 min and concentrated. The residue obtained was dried in vacuo for 30 min and redissolved in DCM (5 mL). The resulting solution was cooled to 0° C. and NBS (64 mg, 0.35 mmol) was added. The reaction mixture was stirred at RT for 30 min and treated with DCM (20 mL) and satd aq NaHCO3 (20 mL). The organic layer was separated, dried (Na2SO4) and concentrated to afford the title compound (92 mg, 92%), which was directly used in next step without further purification. Mass spectrum (ESI, m/z): Calcd. for C12H16BrN3O, 298.0 and 300.0 (M+H). found 298.2 and 300.2.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([C:15](O)=[O:16])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[BH4-].[Na+]>O1CCCC1>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([CH2:15][OH:16])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(CO)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.8 %

Procedure:
A mixture of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxylic acid (196 mg, 0.41 mmol), prepared using procedures similar to those in Example 1, triethylamine (58 μL, 0.41 mmol), PyBOP (213 mg, 0.41 mmol) and sodium borohydride (48 mg, 1.24 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the resultant residue was partitioned between 20% aqueous citric acid and ethyl acetate. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a colorless residue that was purified by column chromatography. Eluting with 60% ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 48 mg, 0.11 mmol (25%) of [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methanol as a white solid. 1H NMR (400 MHz, CDCl3): 7.44 (d, 1H), 7.34 (d, 1H), 7.28-7.23 (m, 1H), 7.04-6.97 (m, 1H), 4.26-4.18 (m, 1H), 4.02-3.94 (m, 2H), 3.78-3.72 (m, 1H), 3.03 (d, 2H), 3.34 (s, 1H), 2.80-2.71 (m, 1H). MS (EI) for C17H14F3IN2O: 463 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH:15]CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Reaction time: 3 h

Procedure:
A solution of (1S,2S,5R)-2-(Benzylamino-methyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2.32 mmol) in EtOH (40 mL) is treated with Pd/C (5%, 460 mg) and stirred under a hydrogen atmosphere (1 bar) for 3 h. An additional amount of Pd/C (150 mg) is added and the mixture is stirred for further 2 h. After filtration through celite and removal of the solvents the desired product is obtained which is used without further purification.
Reaction SMILES: [CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][OH:7].[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1>ClCCl.C(=O)([O-])O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][O:7][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1
Reactant: C1=COCCC1
Reactant: CSC(=S)NCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CSC(=S)NCCOC1CCCCO1
Reaction time: 1 h
Yield: 101.5 %

Procedure:
To a solution of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester (81.7 g) in dichloromethane (300 ml) are added dihydropyran (54 g) and toluene-p-sulfonic acid monohydrate (1.0 g), and the mixture is stirred for 1 hour. The reaction mixture is poured in aqueous sodium hydrogen carbonate, shaken and the resulting organic layer is separated. The layer is concentrated under reduced pressure to give N-[2-(2-tetrahydropyranyl)oxyethyl]dithiocarbamic acid methyl ester (129 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:16](=[CH:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[BH4-].[Na+].Cl.O>C(O)C.C1COCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[CH:1]1([C:4]2[CH:5]=[C:6]([CH:16]([CH2:22][CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:11])=[O:12])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(=CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.1 %

Procedure:
To a solution of ethyl 2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)acrylate (2.62 g) in ethanol (24 mL) and THF (12 mL) was added nickel(II) chloride hexahydrate (154 mg) under ice-cooling. Subsequently, sodium borohydride (489 mg) was added thereto under ice-cooling, followed by stirring at room temperature overnight. To the reaction mixture were added 1 M hydrochloric acid and water under ice-cooling. The resulting black solid was removed by filtration through Celite and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, ethyl 2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)propionate (2.82 g) was obtained as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:9][C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:2]=1[C:14]1[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][C:15]=1[Cl:17]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
4-Bromo-3-chloroaniline (3.0 g, 14.5 mmol), (2,4-dichlorophenyl)boronic acid (3.6 g, 18.9 mmol), Pd(dppf)Cl2 (1.2 g, 1.5 mmol), and K2CO3 (4.0 g, 29.1 mmol) were dissolved in 1,4-dioxane (60 mL) and water (15 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:7]=2[N:8]=[CH:9][N:10]=1)=O.[NH2:24][C:25]([NH2:27])=[S:26]>CC(C)=O>[C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([S:14]([N:11]2[C:7]3[N:8]=[CH:9][N:10]=[C:5]([C:3]4[N:24]=[C:25]([NH2:27])[S:26][CH:2]=4)[C:6]=3[CH:13]=[CH:12]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: NC(N)=S
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)CBr)ncnc32)cc1
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4csc(N)n4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
Into 75 mL of acetone was successively added [4.2 g, 10.65 mmol] of 2-Bromo-1-[7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethanone followed by [0.81 g, 10.65 mmol] of thiourea. The reaction was then stirred for 4.0 hours at ambient temperature. The pale yellow precipitate was collected via suction filtration and washed with more acetone. The crude cake was suspended into 20 mL of triethylamine and stirred for one hour. The material was then diluted with water and suction filtered to isolate the solid. The damp cake was triturated with acetonitrile, the solid isolated again via suction filtration and airdried. The beige solid, 2.6 g, represents a 72% yield of the free base.
Reaction SMILES: [C:1]([N:5]1[CH2:9][CH2:8][O:7][P:6]1Cl)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][OH:22])[CH3:19]>C1COCC1>[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][O:22][P:6]1[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][CH2:8][O:7]1)[CH3:19]
Reactant: CCCCC(CC)CO
Reactant: CC(C)(C)N1CCOP1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(CC)COP1OCCN1C(C)(C)C
Yield: 81 %

Procedure:
The procedure of Example 3 is repeated using 18.16 g (0.10 mol) of 3-tert-butyl-2-chloro-1,3,2-oxazaphospholidine in 115 ml of THF and 13.16 ml (0.10 mol) of triethylamine and 13.2 g (0.10 mol) of 2-ethylhexanol in 115 ml of THF to give 22.3 g (81.0%) of a clear liquid: b.p. 89°-92° C. (0.05 mm Hg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[C:22](O)=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(Cl)(Cl)=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[C:22]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2c(C(=O)O)ccc3cc(Cl)ccc23)cc1OC
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2c(C(=O)N3CCOCC3)ccc3cc(Cl)ccc23)cc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6.9 g of 1-(3,4-dimethoxyphenyl)-6-chloro-2-naphthoic acid are introduced into 50 ml of toluene, and 2.4 g of thionyl chloride are added thereto. The reaction mixture is heated to boiling point and then stirred for 5 hours under reflux. Then, at ~50°, 4.0 g of morpholine are added dropwise, and the mixture is again heated to boiling point and stirred for a further 3 hours under reflux. After cooling to room temperature, the reaction mixture is diluted with 100 ml of toluene, and the organic phase is washed three times with 250 ml of water each time, dried over sodium sulfate and filtered, and the solvent is evaporated off in vacuo. For purification, the oily residue is chromatographed over a column of silica gel using ethyl acetate. The title compound is obtained in the form of beige crystals. M.p. 157°-159°.
Reaction SMILES: CCCCCCC.Cl[S:9]([N:12]=C=O)(=[O:11])=[O:10].C(O)=O.[C:18]([O:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][C:26]([OH:34])([CH2:27]3)[CH2:25]1)[CH2:31]2)(=[O:22])[C:19]([CH3:21])=[CH2:20]>COC1C=CC(O)=CC=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.O.C(OCC)(=O)C.CN1CCCC1=O>[C:18]([O:23][C:24]12[CH2:31][CH:30]3[CH2:29][CH:28]([CH2:27][C:26]([O:34][S:9](=[O:10])(=[O:11])[NH2:12])([CH2:32]3)[CH2:25]1)[CH2:33]2)(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C=C(C)C(=O)OC12CC3CC(CC(O)(C3)C1)C2
Agent: COc1ccc(O)cc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: C=C(C)C(=O)OC12CC3CC(C1)CC(OS(N)(=O)=O)(C3)C2
Temperature: 5 °C
Reaction time: 10 h
Yield: 64.6 %

Procedure:
A 5-liter four-necked flask equipped with a thermometer, a dropping funnel and a stirrer was purged with nitrogen, and 980 g of heptane and 334 g (2.4 mol) of chlorosulfonyl isocyanate were added thereto using the dropping funnel. The internal temperature was cooled to 5° C., and 110 g (2.4 mol) of formic acid was added dropwise from the dropping funnel at a rate that maintained the temperature inside the flask at 5 to 8° C. Following completion of the dropwise addition, the internal temperature was raised to 20° C., and the mixture was stirred for 10 hours. To the resulting mixed solution was added a solution containing 186.7 g (0.79 mol) of 3-hydroxyadamantyl methacrylate, 525 g of N-methylpyrrolidone, 2.1 g of 4-methoxyphenol and 2.1 g of phenothiazine, with the addition performed via the dropping funnel at a rate that maintained the temperature inside the flask at a temperature of not more than 20° C. Following stirring for 3 hours at an internal temperature of 20 to 25° C., the reaction mixture was transferred to a separating funnel, and the upper layer was discarded. To the thus obtained lower layer were added 890 g of ethyl acetate and 700 g of water, and the resulting mixture was stirred, and left to settle. Then, the resultant was subjected to liquid separation to extract the ethyl acetate phase and the aqueous phase. A further 890 g of ethyl acetate was then added to the water layer, and a second extraction was performed. Following mixing of the two ethyl acetate layers, the resulting solution was washed 5 times with 900 g of water. The washed solution was then washed with 400 g of a 7% by weight aqueous solution of sodium bicarbonate, and then 400 g of water. The this obtained washed organic layer was concentrated under reduced pressure to obtain a concentrated solution of 500 g, and 630 g of toluene was added. The resulting solution was then heated to an internal temperature of 55° C., and then cooled to 3° C. to effect a recrystallization. The suspension obtained by the recrystallization was filtered, thereby obtaining 159.5 g (0.51 mol) (yield=64%) of crystals of the objective compound (11).
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8](=[O:31])[NH:9][CH:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]CC3C=CC=CC=3)[CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1>CO.[Pd]>[NH2:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8](=[O:31])[NH:9][CH:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(OCc2ccccc2)c1)NC(=O)NCc1ccc(N)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(Cc1cccc(O)c1)NC(=O)NCc1ccc(N)cc1
Yield: 97.7 %

Procedure:
A solution of 162 (205 mg) in MeOH (20 ml) was stirred for 1 h under hydrogen atmosphere in the presence of 10% Pd/C. The resulting mixture was filtered through celite and the filtrate was evaporated under reduced pressure to give 163 as white solid (160 mg, 98%). 1H NMR (DMSO): δ 1.28 (t, 3H, J=6.4 Hz), 2.97 (m, 2H), 4.12 (m, 2H), 4.19 (q, 2H, J=6.4 Hz), 4.51 (m, 1H), 5.02 (s, 2H), 6.24 (d, 1H, J=8.3 Hz), 6.46 (m, 1H), 6.63 (d, 2H, J=7.5 Hz), 6.71 (s, 2H), 6.75 (d, 1H, J=7.5 Hz), 7.00 (d, 2H, J=7.5 Hz), 7.19 (t, 1H, J=7.5 Hz), 9.42 (s, 1H). HPLC method B tr=17.75 nm (96.3%). ESI-MS m/z: 358.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:20][C:21]([OH:23])=[O:22])([O-:3])=[O:2].OS(O)(=O)=O.[CH3:29][CH2:30]O>>[CH2:29]([O:22][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:4]=1[N+:1]([O-:3])=[O:2])[CH3:30]
Reactant: O=C(O)Cc1cccc(Nc2cccc([N+](=O)[O-])c2)c1[N+](=O)[O-]
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(Nc2cccc([N+](=O)[O-])c2)c1[N+](=O)[O-]

Procedure:
[2-Nitro-3-(3-nitro-phenylamino)-phenyl]-acetic acid (0.79 g, 2.5 mmol) is refluxed in EtOH (50 ml) in the presence of 0.5 ml concentrated H2SO4 for 2 hours. It is then concentrated and to the residue is added saturated NaHCO3. The mixture is extracted with ethyl acetate (30 ml×3). The organic layers are combined and dried with Na2SO4 to give the desired compound after concentration: 1H NMR (CDCl3) δ 1.29 (t, 3H, J=7.2 Hz), 3.92 (s, 2H), 4.20 (q, 2H, J=7.2 Hz), 6.89 (d, 1H, J=6.0 Hz), 7.34-7.41 (m, 2H), 7.44-7.52 (m, 2H), 7.92 (d, 1H, J=7.6 Hz), 8.03 (s, 1H), 8.17 (s, 1H); LC-MS: 346.0 (MH+).