Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=[CH2:26])[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:40]>C(Cl)Cl.C(=O)(O)[O-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]([CH:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]3[O:40][CH2:26]3)[C:20]([O:22][CH3:23])=[O:21])(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: C=CC(OCc1ccccc1)C(NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)C(=O)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)C(OCc1ccccc1)C1CO1
Reaction time: 2 h

Procedure:
The methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-3-phenylmethoxy-4-pentenoate 63d (1.23 g, 2.48 mmol) is dissolved in methylene chloride (9 mL) and sodium bicarbonate (252 mg), in water (4 mL), then the reaction is cooled to 0° C. 3-Chloroperoxybenzoic acid is added slowly and the reaction is stirred for two hours. The substrate is still present so additional 3-chloroperoxybenzoic acid is added (1 g) along with 175 mg sodium bicarbonate and the reaction is stirred overnight. The mixture is diluted with aqueous sodium bicarbonate solution and methylene chloride and the layers are separated. The aqueous layer is washed with ethyl acetate (3 times) and the organic layers are combined and dried under reduced pressure. The resulting material is redissolved in ethyl acetate and washed with dilute sodium bicarbonate solution and then with brine, dried over magnesium sulfate and concentrated in vacuo to a light brown oil (2 g). The crude material is adsorbed onto silica gel and purified over a silica column eluting with hexane:ethyl acetate (8:2) followed with hexane:ethyl acetate (1:1). Product fractions are combined and dried to give the desired product.
Reaction SMILES: [CH:1]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:17])=[C:12](F)[C:13]=3[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23]>C(#N)C>[CH:1]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:17])=[C:12]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:22][CH3:23])[CH2:27]4)[C:13]=3[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CCC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCNCC1CCNC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CCC4)c3c2F)C1
Yield: 67.6 %

Procedure:
To 0.76 g (2.7 mmol) of the 1-cyclobutyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 0.4 g (2.7 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.36 g (2.7 mmol and 0.36 g (2.7 mmol) of 3-[(ethylamino)methyl]pyrrolidine. The mixture was refluxed for 3.5 hours, cooled, filtered, and washed with ether to give 0.74 g of 1-cyclobutyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 223°-225° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I.Cl>O.CO>[I:15][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([OH:8])=[CH:6][CH:5]=1
Reactant: Cc1ncccc1O
Reactant: II
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nc(I)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
2-Methylpyridin-3-ol (3.00 g, 27.5 mmol) was dissolved in a solution of Na2CO3 (5.83 g, 55.0 mmol) in water (48 mL) and MeOH (30 mL). Iodine (6.98 g, 27.5 mmol) was added and the reaction mixture was stirred for 1 h at RT. The mixture was treated with 2 M HCl solution (14 mL) and the resultant suspension was extracted with EtOAc (2×65 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was slurried with DCM (20 mL) and the resultant solid was collected to afford 6-iodo-2-methylpyridin-3-ol (3.6 g, 55.7% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.41 (d, J=8.26 Hz, 1H), 6.78 (d, J=8.26 Hz, 1H), 5.03 (br s, 1H), 2.47 (s, 3H); MS (ESI) m/z: 236.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[CH2:13]([O:15]C(=O)COC1C([N+]([O-])=O)=NC(Br)=CC=1)C>C(O)(=O)C.CCOC(C)=O.[Fe]>[O:12]=[C:8]1[CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([CH:13]=[O:15])=[N:11][C:10]=2[NH:9]1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Reactant: O=C1COc2ccc(Br)nc2N1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=Cc1ccc2c(n1)NC(=O)CO2
Temperature: 90 °C
Reaction time: 6 h
Yield: 57 %

Procedure:
6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one. To a solution of (6-bromo-2-nitro-pyridin-3-yloxy)-acetic acid ethyl ester (3.14 g, 10.3 mmol) in glacial acetic acid (12.4 mL) was added iron powder (1.67 g, 29.9 mmol). The suspension was heated to 90° C. and stirred for 6 h, after which it was cooled to RT and diluted with EtOAc (50 mL). The mixture was filtered through a pad of SiO2 and the filtrate was concentrated. Recrystallization from CH3OH provided 1.32 g (57%) of the title compound as a solid. MS (ESI): exact mass calculated for C7H5BrN2O2, 227.95; m/z found, 228.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.98 (d, J=5.3, 1H), 7.16-7.09 (m, 1H), 6.98 (dd, J=8.0, 4.9, 1H), 4.68 (d, J=1.4, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]#[N:11])(=[O:3])[CH3:2].[Br:12]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([Br:12])=[CH:8][C:9]=1[C:10]#[N:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1sccc1C#N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(=O)Nc1sc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Acetylamino-3-cyanothiophene (13.5 g) was dissolved in dimethylformamide (110 ml) and cooled in an ice/water bath. N-Bromosuccinimide (15.9 g) was added portion wise over 20 minutes and then the mixture warmed to room temperature and stirred for 3 h. The mixture was concentrated to approximately half the volume and water added to precipitate the product. This was filtered off and dried at 60° C. under vacuum (18.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([NH:16][NH2:17])=[O:15])=[C:12]([C:18]2[CH:19]=[N:20][N:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:22]=2[C:23]([F:26])([F:25])[F:24])[O:11][N:10]=1.[C:34](Cl)(=[O:36])[CH3:35]>O1CCOCC1>[C:34]([NH:17][NH:16][C:14]([C:13]1[C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:10][O:11][C:12]=1[C:18]1[CH:19]=[N:20][N:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:22]=1[C:23]([F:25])([F:26])[F:24])=[O:15])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: NNC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccccc2F)c1C(F)(F)F
Solvent: C1COCCO1
Product: CC(=O)NNC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccccc2F)c1C(F)(F)F
Yield: 84.7 %

Procedure:
To a solution of 190 mg (0.393 mmol) 3-(2-chloro-6-fluorophenyl)-5-(1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carbohydrazide (which was synthesized in analogy to the procedure described for example I-133) in 5.8 ml absolute dioxane, 148 mg (1.885 mmol) acetyl chloride were added. The conversion is complete within minutes. Volatiles were evaporated, residue was re-evaporated with ethanol. Residue was crystallized from EtOAc-heptane to give 175 mg (85%) of compound I-142 as a pale yellow powder. Result of LC/MS MH+: 526.06; 1H-NMR (400 MHz, methanol-d4) δ ppm: 1.98 (3H, s, CH3), 7.25-7.32 (1H, m, CH-arom.), 7.41-7.48 (3H, m, CH-arom.), 7.54-7.61 (1H, m, CH-arom), 7.64-7.74 (1H, m, CH-arom.), 8.63 (1H, s, CH-pyraz.)
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]2[S:22][C:12]3=[N:13][C:14](O)=[C:15]([N+:18]([O-:20])=[O:19])[C:16](=[O:17])[N:11]3[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CCC)CCC)CC.P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:14]1[N:13]=[C:12]2[S:22][C:9]([CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:10][N:11]2[C:16](=[O:17])[C:15]=1[N+:18]([O-:20])=[O:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c([N+](=O)[O-])c(O)nc2sc(CCC3CCCCC3)nn12
Agent: CCCN(CCC)CCC
Product: O=c1c([N+](=O)[O-])c(Cl)nc2sc(CCC3CCCCC3)nn12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In 30 ml of phosphorous oxychloride was suspended 10.2 g of 2-(2-cyclohexylethyl)-7-hydroxy-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one, and 4 ml of tripropylamine was added dropwise to the suspension at room temperature while stirring. The stirring was continued at 80° to 85° C. for an additional 3 hours. After cooling, the reaction mixture was poured into ice-water, and the precipitate formed was collected by filtration and washed with water to obtain 10.4 g of 7-chloro-2-(2-cyclohexylethyl)-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as a crystalline powder.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[N:15]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[S:16]([CH3:19])(=[O:18])=[O:17])[C:9]([O-:11])=[O:10])[CH2:3][CH2:2]1.[Li+].C(Cl)CCl.O[CH2:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[N:15]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)[S:16]([CH3:19])(=[O:17])=[O:18])[C:9]([O:11][CH2:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=[O:10])[CH2:3][CH2:2]1
Reactant: CN1CCN(CCN(c2ccc(C(=O)[O-])cc2OCC2CC2)S(C)(=O)=O)CC1
Reactant: O=C(CO)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCN(CCN(c2ccc(C(=O)OCC(=O)OCc3ccccc3)cc2OCC2CC2)S(C)(=O)=O)CC1
Yield: 76 %

Procedure:
To a solution of lithium 3-(cyclopropylmethoxy)-4-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)benzoate (theoric 0.869 mmol) and EDC (349 mg, 1.821 mmol) in dry DCM (3 ml), benzyl 2-hydroxyacetate (151 mg, 0.910 mmol) and DMAP (111 mg, 0.910 mmol) were added at RT. The final mixture was stirred for 2 days, then the solvent was evaporated, the residue was portioned between water and EtOAc, the organic layer was washed with NaHCO3 sat. sol. and brine, dried over Na2SO4 and evaporated. The crude was purified by flash chromatography on silica gel (eluent: DCM/MeOH/32% NH4OH 95/5/0.5) to give 2-(benzyloxy)-2-oxoethyl 3-(cyclopropylmethoxy)-4-(N-(2-(4-methylpiperazin-1-yl)ethyl)-methylsulfonamido)benzoate as a colorless oil (370 mg, 0.661 mmol, 76% yield over 2 steps, MS/ESI+ 560.1 [MH]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:19]([NH:21][CH:22]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]2[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=2[N:24]([CH3:39])[C:23]1=[O:40])=[O:20])[C:15]([CH3:18])([CH3:17])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:19]([NH:21][CH:22]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=3[N:24]([CH3:39])[C:23]2=[O:40])=[O:20])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(NC(=O)[C@@H](N)C(C)(C)C)N=C(c2ccccc2)c2ccccc21
Product: CN1C(=O)C(NC(=O)[C@@H](NC(=O)Cc2cc(F)cc(F)c2)C(C)(C)C)N=C(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-tert-leucinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-Z), the title compound was prepared as a solid (mp.=221-222° C.). The product was purified by slurrying in ether.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:33])[C:16]([C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)([CH3:18])[CH3:17].CI.[C:36](OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]([CH3:36])[C:15](=[O:33])[C:16]([C:19]1[CH:20]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=1)([CH3:18])[CH3:17]
Reactant: CCOC(C)=O
Reactant: CC(C)(C(=O)Nc1ccccc1-c1ccccc1N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1-c1ccccc1N
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 151 mg (0.32 mmol) N-(2′-amino-biphenyl-2-yl)-2-(3,5bis-trifluoromethyl-phenyl)-isobutyramide in 1 ml N,N-dimethylformamide under argon 130 mg (0.65 mmol) potassium hexamethyldisilazide were added at 0°. Stirring was continued for 1 h at room temperature and the reaction mixture was cooled to 0° again. At this temperature, 115 mg (0.81 mmol) methyl iodide were added. After stirring for 3 hrs at room temperature, ethyl acetate was added and the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/CH2Cl21:1) to give 56 mg (36%) N-(2′-amino-biphenyl-2-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as colorless oil, MS(ISP): 481.1(M+H)+.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(O)=[O:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CC(C)=O>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:1]([CH2:4][N:5]2[C:9]([SH:10])=[N:8][N:7]=[N:6]2)=[O:2])[CH2:28][CH2:27]1
Reactant: O=C(O)Cn1nnnc1S
Reactant: CN1CCNCC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)Cn2nnnc2S)CC1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 45.4 %

Procedure:
To a solution of 1-carboxymethyl-1H-tetrazole-5-thiol (3.2 g) in dry acetone (60 ml) was added triethyl amine (4.2 g). After the addition of a solution of pivaloyl chloride (4.8 g) in dry acetone (10 ml) with stirring at -15° C. over a period of 5 minutes, the mixture was stirred for one hour and 15 minutes at the same temperature. A solution of 1-methylpiperazine (4.0 g) in dry acetone (10 ml) was dropwise added over a period of 5 minutes and the resulting mixture was stirred at -15° C. for 40 minutes and under ice-cooling for a further 2.5 hours. After the evaporation of the reaction mixture under reduced pressure, water was added to the residue, 4N aqueous solution of sodium hydroxide was added until the crystals were dissolved. The resulting solution was evaporated under reduced pressure and the residue was crystallized from water to give 1-(4-methyl-1-piperazinyl)carbonylmethyl-1H-tetrazole-5-thiol (2.2 g). mp>250° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[C:5]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:4]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.Cl>C1COCC1>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[C:5]([N:16]2[CH2:17][CH2:18][N:19]([S:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:30])=[O:29])[CH2:20][CH2:21]2)[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)COc1ccc(Cl)cc1N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(Cl)cc1N1CCN(S(=O)(=O)c2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
To a mixture of the product from step c) (0.34 g) and benzenesulfonyl chloride (0.11 ml) in THF (3 ml) was added triethylamine (0.42 ml) dropwise. After 5 min, further THF (3 ml) was added and the reaction stirred for 16 h. It was poured into 2M HCl and extracted with ethyl acetate. The organic layer was separated and washed with sat aqueous sodium bicarbonate solution, brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was stirred in THF (2 ml) and 4M NaOH (4 ml) for 16 h. After acidification to pH 3, the aqueous layer was extracted with ethyl acetate. The organic layer was separated and the solvent removed in vacuo. Purification by RPHPLC (symmetry column) gave the title product as a white foam (0.12 g).
Reaction SMILES: [OH:1][CH:2]([CH3:17])[CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1Cl)(=[O:6])=[O:5].[CH2:18]([NH2:21])[CH2:19][NH2:20]>C(O)(C)C.O>[OH:1][CH:2]([CH3:17])[CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[NH:20][CH2:19][CH2:18][NH2:21])(=[O:6])=[O:5]
Reactant: NCCN
Reactant: CC(O)CS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Solvent: O
Solvent: CC(C)O
Product: CC(O)CS(=O)(=O)c1cc([N+](=O)[O-])ccc1NCCN

Procedure:
28 g (0.1 mol) of 2-chloro-5-nitrophenyl 2-hydroxypropyl sulphone are refluxed in 100 ml of isopropanol. To this are added gradually 15 ml of ethylenediamine, and heating is continued with stirring for a further hour. The cold reaction solution is diluted with 300 ml of water and stirred at 20° C. for two hours. The precipitated yellowish crystals are filtered off with suction, washed with 100 ml of water and dried. This gives 28 g of uniform 2-(2-aminoethylamino)-5-nitrophenyl 2-hydroxypropyl sulphone.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[Cl:31][CH2:32][C:33](Cl)=[O:34].C(N(CC)CC)C>C(#N)C>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:33](=[O:34])[CH2:32][Cl:31])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)CCl
Reactant: NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CNC(=O)CCl)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 210 mg (0.53 mmol) of trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine in 10 ml of acetonitrile is added 49 μl (0.61 mmol) of chloro-acetyl chloride (Fluka, Buchs, Switzerland) and 85 μl (0.61 mmol) of triethylamine. The solution is stirred for 5 h at RT. trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-2-chloro-acetamide is obtained after purification of the crude mixture by medium-pressure liquid chromatography. Analytical HPLC: tR=6.94 min (Grad 2); ES-MS: m/eo=476.0.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[CH:22].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([C:22]#[C:21][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C#Cc1ccccc1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@H]1C(=O)N(C)c2cnc(C#Cc3ccccc3)nc2N1C1CCCC1

Procedure:
To a solution of Intermediate B (1.0 eq) in DMF, ethynylbenzene (compound III-139, 3.0 eq), Pd(PPh3)2Cl2 (0.2 eq), CuI (0.25 eq) and Et3N (5.0 eq) were added. The mixture was refluxed for 18 h under argon, extracted with EtOAc and purified by silica gel column to give (R)-8-cyclopentyl-7-ethyl-5-methyl-2-(phenylethynyl)-7,8-dihydropteridin-6(5H)-one (compound IV-139).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]([C:23]#[N:24])([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].[BH4-].[Na+]>O.O.O.O.O.O.[Co](Cl)Cl.CO>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:7][C:8](=[O:9])[NH:24][CH2:23]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(OC)c(OC)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CC1(c2ccc(OC)c(OC)c2)CNC(=O)C1
Temperature: 25 °C

Procedure:
Combined 3-cyano-3-(3,4-dimethoxy-phenyl)-pentanedioic acid diethyl ester (16.8 g, 48.0 mmol), methanol (300 mL) and cobalt (II) chloride hexahydrate (22.8 g, 96.0 mmol). Cooled until the internal temperature reached 10 ° C. Added portionwise so as to maintain the reaction temperature below 20° C., sodium borohydride (44.2 g, 1.17 mol). After addition was complete, the reaction mixture was allowed to warm to ambient temperature and stirred over the weekend. Concentrated in vacuo to obtain a residue. Partitioned between 1N HCl (800 mL) and dichloromethane (800 mL). The organic layer was extracted with 1N HCl (2×200 mL). The combined aqueous layers were extracted with dichloromethane (3×100 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to obtain a residue. The residue was chromatographed on silica gel eluting with ethyl acetate/methanol (20:1) to obtain the title compound:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][C@@H:19]([CH2:23][OH:24])[NH:20][CH2:21][CH:22]=4)=[CH:16][C:9]=23)[CH:7]=1.C(N(C(C)C)C(C)C)C.Cl[CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][C@@H:19]([CH2:23][OH:24])[N:20]([CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN[C@H](CO)C3)cc12
Reactant: CN(C)C(=O)CCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(CC(=O)N(C)C)[C@H](CO)C3)cc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of Example 260H (150 mg, 0.352 mmol) in N,N-dimethylformamide (1.8 mL) was added N-ethyl-N-isopropylpropan-2-amine (227 mg, 1.759 mmol) and 2-chloro-N,N-dimethylacetamide (39.9 μL, 0.387 mmol). The mixture was stirred for 3 days at room temperature and for 2 hours at 70° C., and partitioned between water and ethyl acetate (three times). The extracts were dried over sodium sulfate, filtered, and concentrated, and the residue was purified by flash chromatography on silica gel, eluting with a gradient of 0-8% methanol/dichloromethane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.18 (d, J=5.0 Hz, 1H), 7.31-7.16 (m, 3H), 7.02 (d, J=5.0 Hz, 1H), 6.46 (s, 1H), 6.18 (d, J=1.8 Hz, 1H), 4.61 (t, J=5.3 Hz, 1H), 3.74 (s, 3H), 3.60-3.27 (m, 6H), 3.33 (s, 3H), 3.02 (s, 3H), 2.93 (dd, J=11.1, 5.7 Hz, 1H), 2.81 (s, 3H), 2.48-2.32 (m, 2H); MS (ESI+) m/z 439.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2[C@H:7]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@H:6]2[NH:5]1.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>C1COCC1>[CH3:33][O:32][C:30](=[O:31])[CH2:29][N:5]1[C@H:6]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@@H:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:14]([F:16])([F:17])[F:15])[C:13]=2[C:4]1=[O:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2NC(=O)c3c(cccc3C(F)(F)F)[C@H]2C1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a suspension of sodium hydride (17 mg of 60% dispersion in mineral oil, hexane-washed, 0.42 mmol) in 2 mL of THF was added (3aR,9bS)-tert-butyl 5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 13, Part A (101 mg, 0.28 mmol) in 2 mL of THF. The resulting mixture was stirred at ambient temperature for 30 min, at which time gas evolution has ceased. Then there was added methyl bromoacetate (0.053 mL, 0.56 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. The reaction was quenched with 10 mL of 1 N HCl and extracted with ethyl acetate. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 120 mg (99%) of the title compound which was sufficiently pure to be used without purification. LRMS (ESI): 429.22 (M+H)+.