Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([OH:12])=O.C(C#N)(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OC([N:45]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([CH:55]([NH2:57])[CH3:56])[CH:53]=2)[CH2:48][CH2:47][CH2:46]1)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:57][CH:55]([C:52]1[CH:53]=[C:54]2[C:49]([CH2:48][CH2:47][CH2:46][NH:45]2)=[CH:50][CH:51]=1)[CH3:56])=[O:12]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: CC(N)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C=Cc1ccccc1F)c1ccc2c(c1)NCCC2
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of 3-(2-fluoro-phenyl)-acrylic acid (166 mg, 1 mmol), CCl3CN (289 mg, 2 mmol) and PPh3 (52 mg, 2 mmol) in CH2Cl2 (10 mL) was stirred at 23° C. for 1.5 hours. Then 7-(1-amino-ethyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester, Preparation 29 (276 mg, 1 mmol) was introduced followed by triethylamine (304 mg, 3 mmol). After stirring for 1 hour, the solvent was evaporated, the residue was re-dissolved in a mixture of MeOH (5 mL) and 1M HCl in Et2O (5 mL), and stirred at 23° C. for 24 hours. The solvent was evaporated and the residual material was partitioned between EtOAc and aqueous NaHCO3. The organic phase was washed with water, dried (MgSO4) and evaporated. The crude product was purified by chromatography (SiO2, 10-50% EtOAc in hexane) to give 267 mg (82%) of the title compound as a tan solid.
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:12]=[C:13]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)[CH:14]=[CH:15][C:16]=1[Cl:17].CN(C(ON1N=NC2[CH:38]=[CH:39][CH:40]=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(OC(N1CCNCC1)=O)(C)(C)C>>[NH:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]=[C:3]1[C:11]1[CH:12]=[C:13]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([N:41]3[CH2:40][CH2:39][CH2:38][CH2:36]3)=[O:25])[CH2:19]2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)[C@@H]1CCCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)C1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: O=C([C@@H]1CCCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)C1)N1CCCC1
Temperature: 35 °C
Yield: 52.4 %

Procedure:
Method B—Step a To a vial with (R)-1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-piperidine-3-carboxylic acid hydrochloride (obtained as described in general method 2, step e) (0.10 g, 0.28 mmol) (obtained as described in general method 2), HATU (0.11 g, 0.30 mmol), triethylamine (TEA) (0.09 mL, 0.66 mmol) and tert-Butyl-1-piperazinecarboxylate (0.08 g, 0.62 mmol) dichloromethane (2 L) was added and the reaction mixture was heated at 35° C. overnight. Reaction was cooled to room temperature, solvent removed and the crude purified by preparative HPLC and NH2 column filtration, to obtain 0.06 g of the title compound (55%).
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.[C:31]([O-:34])(=[S:33])[CH3:32].[K+].P(O)(O)([O-])=O.[Na+].O>C(O)=O>[C:31]([S:33][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:34])[CH3:32]
Reactant: CC([O-])=S
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(C)=O)CS[C@H]12)c1csc(N)n1
Reaction time: 0.08 h

Procedure:
A solution of the syn isomer of 4.55 g of 3-acetoxymethyl-7-[{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl}amino]-ceph-3-eme-4-carboxylic acid, 1.7 g of potassium thioacetate, 2 g of deshydrated monosodium phosphate 1.05 g sodium acid carbonate and 20 ml of distilled water was heated at 70° C. for 90 minutes and the mixture was acidified with 2 ml of formic acid and was extracted 4 times with 60 ml of methyl acetate (insolubles vacuum filtered). The organic solution was washed with water and evaporated to dryness. The residue was dissolved in 20 ml of acetone containing 10% of water and 0.5 g of activated carbon were added thereto. The mixture was stirred for 5 minutes and was vacuum filtered and the filter was washed with acetone containing 10% of water. The filter was evaporated to dryness and the residue was treated with absolute ethanol and was vacuum filtered. The product was washed with alcohol and then with ether to obtain 1.9 g of the pure syn isomer of 3-acetylthiomethyl-7-[{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl}amino]-ceph-3-eme-4-carboxylic acid which was identical to the product of Example 6.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH2:23].C(N(CC)CC)C>C1COCC1>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH:23][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CNCc1ccc(Cl)cc1Cl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-1-(3-nitrophenyl)ethanone (10.0 g, 41.15 mmol, 1.00 equiv) in THF (150 mL), (2,4-dichlorophenyl)methanamine (7.16 g, 40.91 mmol, 1.00 equiv) and triethylamine (5.96 g, 59.01 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 25° C. The solids were filtered out. The filtrate was concentrated to dryness and used for next step, assuming theoretical yield.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[S-:11][C:12]#[N:13].[NH4+].[CH3:15][NH:16][C:17]1[S:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[CH:18]=1>CC(C)=O>[S:21]1[C:17]([N:16]([C:12]2[S:11][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:5])[N:13]=2)[CH3:15])=[CH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]1=2
Reactant: CNc1cc2ccccc2s1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [NH4+]
Solvent: CC(C)=O
Product: CN(c1cc2ccccc2s1)c1nc(=O)c2cccnc2s1

Procedure:
The reaction procedure of Example 102 was followed except that 278 mg of 2-chloronicotinoyl chloride, 120 mg of ammonium thiocyanate, 258 mg of -2-(methylamino)benzo[b]thiophene and 6 ml of acetone were used. The product was then recrystallized from a mixture of ethanol and ethyl acetate to obtain 143 mg of 2-[N-(benzo[b]thiophen-2-yl)-N-methylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]([S:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=1)=O.[Cl:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31]([CH3:35])=[N:32]2)=[CH:27][CH:26]=1>C(OC(=O)C)(=O)C>[Cl:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31]([CH:35]=[CH:1][C:3]3[CH:4]=[C:5]([CH:9]([S:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=3)=[N:32]2)=[CH:27][CH:26]=1
Reactant: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=O)c1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1

Procedure:
A solution of aldehyde (Step 1) (5.2 g) and 7-chloroquinaldine were heated in 45 ml acetic anhydride for 48 hours. The reaction mixture was evaporated. Flash chromatography of the residue using 5% ethylacetate in hexane afforded the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:13][NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][C:17]=1[F:23].Cl>CS(C)=O.C(O)(C)C>[CH3:13][NH:14][C:15]([C:16]1[CH:21]=[CH:20][C:19]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[CH:18][C:17]=1[F:23])=[O:24].[CH3:13][NH:14][C:15]([C:16]1[CH:21]=[CH:20][C:19]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[CH:18][C:17]=1[F:23])=[O:24]
Reactant: C[C@H](N)C(=O)O
Reactant: CNC(=O)c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CC(C)O
Product: CNC(=O)c1ccc(N[C@@H](C)C(=O)O)cc1F
Product: CNC(=O)c1ccc(N[C@H](C)C(=O)O)cc1F
Temperature: 90 °C
Reaction time: 18 h

Procedure:
(D,L)-, (D)- or (L)-Alanine (347 mg, 7.8 mmol) and Cs2CO3 (2.54 g, 7.8 mmol) were added to the solution of N-methyl-2,4-difluorobenzamide (667 mg, 3.9 mmol) in DMSO (3 ml). The reaction mixture was stirred in closed vial at 90° C. for 18 h. Cooled mixture was diluted with isopropanol, neutralized with HCl (1.36 ml, 15.6 mmol), filtered, evaporated in vacuo, and by HPLC method N-(4-methylcarbamoyl-3-fluorophenyl)alanine 4.2(2) (R1=CH3, R4=H, R5=CH3), (S)—N-(4-methylcarbamoyl-3-fluorophenyl)alanine (S)-4.2(2) or (R)—N-(4-methylcarbamoyl-3-fluorophenyl)alanine (R)-4.2(2) were isolated. LCMS (M+H)+ 241. 1H NMR (DMSO-d6, 400 MHz): 12.66 (br. s, 1H), 7.62 (m, 1H), 7.45 (t, J=8.8 Hz, 1H), 6.67 (br. d, J=7.2 Hz, 1H), 6.42 (dd, J1=8.4 Hz, J2=2.0 Hz, 1H), 6.29 (dd, J1=14.8 Hz, J2=2.0 Hz, 1H), 4.03 (m, 1H), 2.73 (d, J=4.4 Hz, 3H), 1.37 (d, J=7.2 Hz, 3H). Solution of amine 4.2(2), (S)-4.2(2) or (R)-4.2(2) (110 mg, 0.46 mmol) and 4-isothiocyanato-2-(trifluoromethyl)-benzonitrile 3.2 (144 mg, 0.55 mmol) in DMF (2 ml) was stirred at 90° C. for 12 h in microwave oven, then additional portion of 4-isothiocyanato-2-(trifluoromethyl)-benzonitrile 3.2 (50 mg, 0.19 mmol) was added and stirring was continued for another 12 h. The reaction mixture was evaporated in vacuo, and by HPLC method N-methyl-4-{5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl}-2-fluorobenzamide 1.2(2), or N-methyl-4-{(S)-5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl}-2-fluorobenzamide (S)-1.2(2) or N-methyl-4-{(R)-5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl}-2-fluorobenzamide (R)-1.2(2) were isolated, respectively. The apparent inhibition constant of androgen receptors (Ki) for these compounds are: Ki1.2(2)=140.2 nM, Ki(S)-1.2(2)=106.7 nM Ki(R)-1.2(2)=73.6 nM, respectively. LCMS (M+H)+ 451. 1H NMR (CDCl3, 400 MHz): 8.28 (t, J=8.6 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.94 (d, J=1.2 Hz, 1H), 7.81 (dd, J1=8.0 Hz, J2=1.2 Hz, 1H), 7.48 (dd, J1=12.4 Hz, J2=1.6 Hz, 1H), 7.36 (dd, J1=8.4 Hz, J2=1.6 Hz, 1H), 6.72 (br. m, 1H), 4.83 (q, J=7.2 Hz, 1H), 3.08 (d, J=4.8 Hz, 3H), 1.60 (d, J=7.2 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][CH:9]1[N:14]=[C:13]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[C:12]([C:27]([O:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])=[O:28])=[C:11]([CH3:35])[NH:10]1.C(N(CC)C1C=CC=CC=1)C.C(O)C#CCCCC.[Cl:55][C:56]([O:58][CH:59]([CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH3:60])=[O:57]>O1CCCC1.ClC(OC(Cl)(Cl)Cl)=O>[Cl:55][C:56]([O:58][CH:59]([CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH3:60])=[O:57].[CH3:60][CH:59]([O:58][C:56]([N:14]1[CH:13]([C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)[C:12]([C:27]([O:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])=[O:28])=[C:11]([CH3:35])[N:10]=[C:9]1[CH3:8])=[O:57])[CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]
Reactant: COc1cc(C2=NC(C)NC(C)=C2C(=O)OCC=C(C)C)cc(OC)c1OC
Agent: CCCCC#CCO
Agent: CCCCCC(C)OC(=O)Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCN(CC)c1ccccc1
Product: CCCCCC(C)OC(=O)N1C(C)=NC(C)=C(C(=O)OCC=C(C)C)C1c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
0.5 ml of Triethylamine was added to a solution of 200 mg of 2,6-dimethyl-5-(3-methyl-2-butenyloxycarbonyl)-4-(3,4,5-trimethoxyphenyl)-dihydropyrimidine in 5 ml of tetrahydrofuran (THF) and 2-heptyl chloroformate dissolved in 6 ml of THF was added dropwise. The 2-heptyl chloroformate was prepared by adding 0.25 ml of N,N-diethylaniline dissolved in 2 ml of THF to a solution of 0.15 g of 2-heptyn-1-ol and 0.1 mg of trichloromethyl chloroformate in 4 ml of THF in a separate reaction vessel. After stirring at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure. The residue was purified on silica gel by column chromatography (silica gel 20 g, eluant:benzene/ethyl acetate 9:1) to obtain 187 mg (69% yield) of title product.
Reaction SMILES: [BrH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[C:5]([CH3:11])[CH:4]=1>C(O)(=O)C.O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Br:1])=[C:5]([CH3:11])[CH:4]=1
Reactant: Br
Reactant: Cc1cc(Br)ccc1CO
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Br)ccc1CBr
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Hydrobromic acid (conc., 2 eq.) was added to a stirred solution of the alcohol from step 1 (1 eq.) in acetic acid (0.22M). The mixture was stirred at 50° C. for 12 h, cooled down to room temperature, poured in water and extracted with Et2O. The organic extract was washed with water, aqueous sodium hydrogen carbonate (3×), brine, dried over MgSO4, filtered and concentrated to afford the desired benzyl bromide as a light yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.Cl[C:32]([C@@H:34]([O:36]C(=O)C)[CH3:35])=[O:33]>>[OH:36][C@@H:34]([CH3:35])[C:32]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)=[O:33]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)[C@H](C)O)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A178) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(C(F)(F)F)c2)n1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccc(C(F)(F)F)c2)n1
Yield: 34.7 %

Procedure:
Following the procedure in Example 118A, 3-tert-butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (344 mg, 1.21 mmol) and phenyl chloroformate (0.25 mL, 1.82 mmol) were reacted to give phenyl 3-tert-butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-ylcarbamate (119 mg, 0.42 mmol, 35%). 1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 7.62-7.50 (m, 3H), 7.58-7.43 (m, 3H), 7.23 (t, 1H), 7.12 (br s, 2H), 6.39 (s, 1H), 1.29 (s, 9H); LC-MS (ESI) m/z 404 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]([OH:21])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15].C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[C:12]([OH:21])=[O:20])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
To a cooled (−78° C.) solution of 2,4-dichloro-5-nitropyrimidine (0.53 g, 2.75 mmol) in THF (2 mL) was added a solution of anthranilic acid (0.37 g, 2.50 mmol) and N,N-diisopropylethylamine (0.5 mL, 3.0 mmol) in THF (2.0 mL). The reaction was stirred for 2.0 hours. The reaction was then poured onto ice and allowed to warm to room temperature then was filtered. The isolated solid was dried under vacuum, then recrystallized from hot ethyl acetate and cold hexane to give 2-[(2-chloro-5-nitropyrimidin-4-yl)amino]benzoic acid (307 mg, 42%) as a yellow solid. 1H NMR (DMSO-d6/D2O): δ 9.20 (s, 1H), 8.36 (d, 1H), 8.07 (d, 1 H), 7.70 (t, 1 H), 7.37 (t, 1 H). MS m/z 294 (M+1).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[NH:14]2)=[O:12])[CH:7]=[CH:8][CH:9]=1.CCN(CC)CC.[CH2:29]([O:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>C(Cl)Cl>[CH2:29]([O:36][C:37]([N:14]1[C@H:13]([C:11](=[O:12])[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:20])([F:1])[F:21])[CH:5]=2)[CH2:17][CH2:16][C@@H:15]1[CH2:18][OH:19])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CC[C@H](CO)N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CC[C@H](CO)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-5-hydroxymethyl-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl)-amide (797 mg, 2.62 mmol) (prepared as described in Scheme B3) in CH2Cl2 (10 mL) was added under nitrogen atmosphere Et3N (440 μl, 3.14 mmol) and benzylchloroformate (406 μl, 2.88 mmol) and the mixture was further stirred at RT overnight. CH2Cl2 and HCl 0.1N were added, the layers were separated and the aqueous one re-extracted with CH2Cl2. The crude organic extracts were washed with brine dried over Na2SO4, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 1:1) to give the title compound. MS (LC-MS): 439 [M+H]+; tR (HPLC conditions b) 4.88 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]([F:29])([F:28])C([O-])=O.[Na+].C(OCC)(=O)C.O>CN1CCCC1=O.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C:24]([F:29])([F:28])[F:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])C(F)(F)F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Agent: I[Cu]I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C(F)(F)F)nc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.7 %

Procedure:
To a solution of 0.8 g (2.17 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) in 12 ml 1-methyl-2-pyrrolidone, 2.36 g (17.4 mmol) sodium trifluoroacetate was added. After a solution had formed, 1.65 g (8.7 mmol) copper iodide was added and the reaction mixture was heated to 180 deg C. for 2 h. The mixture was cooled to room temperature, ethyl acetate and water were added and the suspension was filtered through a bed of dicalite speed plus. The phases were separated, the aqueous layer was washed with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel (0.032–0.063 mm) with tert-butyl methyl ether:n-hexane (1:5) as eluant to afford the desired compound as a colorless oil (27.7%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.C[O:27][C:28](=[O:40])[C@@H:29]([NH2:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1>>[Cl:38][C:33]1[CH:32]=[C:31]([CH2:30][C@H:29]([NH:39][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][C:4]=2[NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[C:28]([OH:27])=[O:40])[CH:36]=[CH:35][C:34]=1[Cl:37]
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
4-Iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid was coupled with (S)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as in Example 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.05 min. MS (ESI−): mass calcd. for C24H17Cl2IN4O5S, 671.29; m/z found, 669/671 [M−H]−. 1H NMR (500 MHz, CDCl3): 10.86 (s, 1H), 9.01 (d, J=1.6, 1H), 8.92 (d, J=1.6, 1H), 8.55 (dd, J=7.3,1.0, 1H), 8.32 (dd, J=8.5, 1.0, 1H), 8.08 (d, J=1.3, 1H), 7.91-7.88 (m, 1H), 7.34 (d, J=8.2, 1H), 7.30-7.24 (m, 2H), 6.98 (dd, J=8.2, 1.9, 1H), 6.88 (d, J=8.2, 1H), 6.38 (d, J=7.3, 1H), 4.90 (q, J=5.9, 1H), 3.28-3.12 (m, 2H).
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[N:38]=[C:37]([C:39]([O:41]C)=O)[C:36]([C:43]([O:45]C)=O)=[N:35]1)(=O)C1C=CC=CC=1.[NH3:47].CO.[NH3:50]>>[C@H:11]1([N:34]2[N:35]=[C:36]([C:43]([NH2:47])=[O:45])[C:37]([C:39]([NH2:50])=[O:41])=[N:38]2)[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: N
Reactant: COC(=O)c1nn([C@H]2O[C@@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)nc1C(=O)OC
Solvent: CO
Product: NC(=O)c1nn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)nc1C(N)=O
Temperature: 95 °C
Yield: 89 %

Procedure:
Compound 31 (6.0 g, 9.5 mmol) was dissolved in MeOH/NH3 (dry MeOH sat. with anhydrous NH3 at 0° C., 60 mL) were placed in a steel reaction vessel. The vessel was heated at 95° C. for 16 h. The reaction vessel was cooled, opened carefully and the NH3 was allowed to evaporate at room temperature. The MeOH was evaporated to dryness and the residue was triturated with hot toluene (3×50 mL) and filtered. The brown residue was crystallized from aqueous EtOH (95%) to furnish 2.40 g (89%) of 32: mp 210-212° C.; 1H NMR (Me2SO-d6) δ3.45-3.59 (m, 2H, C5′H), 3.98 (m, 1H, C4′H), 4.25 (m, 1H, C3′H), 4.54 (m, 1H, C2′H), 4.78 (t, 1H, C5′OH, D2O exchangeable), 5.27 and 5.67 (2d, 2H, C2′,3′, OH, D2O exchangeable), 589 (d, 1H, J1′,2′=3.85 Hz, C1′H), 8.05 and 9.05 (2br s, 4H, 2 CONH2). Anal. calc. for C9H13N5O6 (287.23): C, 37.63; H, 4.56; N, 24.38. Found: C, 37.52; H, 4.19; N, 24.59.