Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[N:8]=[C:7]([C@H:9]([CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[O:6][N:5]=1)=[O:3].FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]([C:4]1[N:8]=[C:7]([C@H:9]([CH2:18][CH2:19][CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:10][C:11]([OH:13])=[O:12])[O:6][N:5]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)c1nc(C(N)=O)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of tert-butyl (3R)-3-[3-(aminocarbonyl)-1,2,4-oxadiazol-5-yl]-6-phenylhexanoate (Preparation 5) (250 mg, 0.68 mmol) in dichloromethane (10 ml) was cooled to 0° C. and treated with trifluoroacetic acid (5 ml). The mixture was stirred for 2 hours, being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue was azeotroped with toluene (×2) then hexane to afford the title compound as a white solid (204 mg).
Reaction SMILES: [CH:1](=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:11](=[O:15])[CH:12]([CH3:14])[CH3:13].N1CCC[C@H]1C(O)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([C@@H:2]([C@@H:11]([OH:15])[CH:12]([CH3:14])[CH3:13])[CH:1]=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C=O
Reactant: O=CCCc1ccccc1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](O)[C@@H](C=O)Cc1ccccc1
Reaction time: 26 h
Yield: 75 %

Procedure:
A solution of freshly distilled hydrocinnamaldehyde (132 μL, 1.0 mmol) in 500 μL dimethylformamide was added slowly over the course of 24 h to a stirring suspension of isobutyraldehyde (272 μL, 3.0 mmol), L-proline (11.5 mg, 0.10 mmol) and 500 μL dimethylformamide at room temperature. After 26 h, the resulting solution was diluted with ethyl acetate and washed successively with water and brine. The combined aqueous layers were back-extracted with 3 portions dichloromethane. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated in vacuo. Flash chromatography (3:1 hexanes:ethyl acetate) afforded the title compound as a clear, colorless oil in 75% yield (155 mg, 0.75 mmol), 91% ee and 95:5 anti:syn. IR (film) 3466, 3086, 3063, 3028, 2962, 2932, 2834, 2733, 1950, 1875, 1806, 1722, 1604, 1496, 1454, 1390, 1368, 1244, 1180, 1136, 1049, 1031, 993.0, 964.3, 849.7, 800.6, 739.8, 700.2 cm−1; 1H NMR (300 MHz, CDCl3) δ9.83 (d, 1H, J=2.1 Hz, CHO); 7.27 (m, 5H, Ar—H); 3.43 (ddd, 1 H, J=6.6, 6.6, 4.5 Hz, CHOH); 3.06 (dd, 1H, J=13.2, 7.8 Hz, PhCH2); 2.92 (dd, 1H, J=13.2, 6.9 Hz, PhCH2); 2.81 (m, 1H, CHCH2); 2.15 (d, 1H, J=6.0 Hz, OH); 1.90 (m, 1H, CH(CH3)2); 0.96 (d, 3H, J=6.6 Hz, CH(CH3)2); 0.92 (d, 3H, J=7.2 Hz, CH(CH3)2); 13C NMR (75 MHz, CDCl3) δ205.6, 129.2, 128.9, 128.6, 126.8, 76.9, 55.8, 33.4, 32.0, 19.7, 18.2; HRMS (CI) exact mass calcd for [M+H]+ (C13H19O2) requires m/z 207.1385, found m/z 207.1386; [α]D=−7.9 (c=1.0, CHCl3). The product ratios were determined by HPLC analysis of the corresponding alcohol (obtained by NaBH4 reduction) using a Chiracel OJ and OJ guard column (1.0% ethanol/hexanes, 1 mL/min); (2S, 3S) anti isomer tr=7.5 min, (2R, 3R) anti isomer tr=9.4 min, (2R, 3S) and (2S, 3R) syn isomers tr=6.3, 6.9 min.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27]N)=[CH:23][CH:22]=1>CC(O)=O.CC(=O)OCC>[F:20][C:21]1[CH:22]=[C:23]2[C:24](=[CH:25][CH:26]=1)[NH:27][C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:4][C:3]2=1
Reactant: NNc1ccc(F)cc1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(NC1CCc2[nH]c3ccc(F)cc3c2C1)OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of benzyl (4-oxocyclohexyl)carbamate (21.7 g, 87.8 mmol) and 4-fluorophenylhydrazine hydrochloride (14.3 g, 87.8 mmol) in glacial AcOH (148 ml) was stirred at reflux for 1 h30. After cooling to rt, the reaction mixture was diluted with EA and washed with sat.aq. NaHCO3 solution. The aqueous phase was extracted twice with EA, the combined organic extracts were washed with sat. aq. NaHCO3 solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a light brown foam which was used for the next step without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH:13]=[CH:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[F:24][C:21]1[CH:22]=[CH:23][C:18]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)=[CH:19][CH:20]=1
Reactant: Fc1ccc(-n2ccc3cc(OCc4ccccc4)ccc32)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc2c(ccn2-c2ccc(F)cc2)c1
Yield: 70 %

Procedure:
13.2 g (41.5 mmol) 5-Benzyloxy-1-(4-fluoro-phenyl)-1H-indole in 150 ml ethanol were hydrogenated in the presence of 200 mg 5%Pd/C to yield 6.6 g (70%) 1-(4-Fluoro-phenyl) -1H-indol-5-ol as white solid, MS: 227 (M).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[NH2:25][C:26]1[C:27]([CH3:33])=[N:28][N:29]([CH3:32])[C:30]=1[CH3:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:25][C:26]3[C:27]([CH3:33])=[N:28][N:29]([CH3:32])[C:30]=3[CH3:31])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: Cc1nn(C)c(C)c1N
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1c(Nc2c(C)nn(C)c2C)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 150 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 371 mg, 1.00 mmol), 4-amino-1,3,5-trimethylpyrazole (375 mg, 3.00 mmol) and p-toluenesulfonic acid monohydrate (190 mg, 1.00 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was stirred at 150° C. for 16 hr. After cooling, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 0-5% methanol/ethyl acetate gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (340 mg, 0.74 mmol, 74%) as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][CH3:11])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([N:10]([CH3:11])[C:8]1[O:7][N:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:9]=1)=[O:15]
Reactant: CN=C=O
Reactant: CNc1cc(C(C)(C)C)no1
Product: CNC(=O)N(C)c1cc(C(C)(C)C)no1
Temperature: 80 °C
Yield: 86.5 %

Procedure:
A mixture of 3-t-butyl-5-methylaminoisoxazole (2.16 g) and methyl isocyanate (1.04 g) is heated at 80° C. in a sealed tube for 13 hours. Then, methyl isocyanate (0.40 g) is added thereto, and the resultant mixture is heated at 80° C. for 9 hours. The reaction mixture is chromatographed on a column of silica gel, whereby 1,3-dimethyl-3-(3-t-butyl-5-isoxazolyl)-urea (2.56 g) is obtained. The yield is 86.3%. IR: 1700, 1598 cm-1 (CC14).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:27]([O:38][CH3:39])[CH:26]=1>CN(C=O)C>[C:32]([NH:31][C:29](=[O:30])[C:28]1[CH:36]=[CH:37][C:25]([CH2:24][N:11]2[C:10](=[O:13])[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:12]2)=[CH:26][C:27]=1[O:38][CH3:39])([CH3:35])([CH3:34])[CH3:33]
Reactant: COc1cc(CBr)ccc1C(=O)NC(C)(C)C
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)ccc1C(=O)NC(C)(C)C
Temperature: 70 °C
Reaction time: 16 h

Procedure:
An amount of 70 mg (0.30 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one (preparation as per WO 2007/134862 Example 36A) was dissolved in 3 ml of DMF and admixed with 194 mg (0.59 mmol) of caesium carbonate and also 98 mg (0.33 mmol) of the compound from Example 23A. The mixture was stirred at 70° C. for 16 h. After cooling to RT, the crude mixture was freed from insoluble constituents by filtration and subjected directly to chromatographic purification [Method 8]. This gave 89 mg (66% of theory) of the target compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 64 %

Procedure:
As described for Example 12, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (97 mg, 64%) which was obtained as an off-white solid. MS: m/e=347.3 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([N:11]=[N+:12]=[N-:13])[CH2:9][C:8]([P:14]([O:19][CH2:20][CH3:21])(=[O:18])[O:15][CH2:16][CH3:17])=[CH:7][C@H:6]1[OH:22])(=[O:3])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29].C(S(O)(=O)=O)(F)(F)F>>[C:1]([NH:4][C@@H:5]1[C@@H:10]([N:11]=[N+:12]=[N-:13])[CH2:9][C:8]([P:14]([O:15][CH2:16][CH3:17])(=[O:18])[O:19][CH2:20][CH3:21])=[CH:7][C@H:6]1[O:22][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])(=[O:3])[CH3:2]
Reactant: CCC(CC)OC(=N)C(Cl)(Cl)Cl
Reactant: CCOP(=O)(OCC)C1=C[C@@H](O)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1
Agent: O=S(=O)(O)C(F)(F)F
Product: CCOP(=O)(OCC)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1
Yield: 82 %

Procedure:
By a procedure similar to that for 11a, the reaction of alcohol 10b (498 mg, 1.5 mmol) with 3-pentyl trichloroacetimidate (420 mg, 1.8 mmol) in the presence of CF3SO3H (15.6 μL, 0.18 mmol), followed by another batches of the imidate and CF3SO3H, gave the alkylation product 11b (495 mg, 82% yield). Colorless oil; TLC (EtOAc/hexane, 1:1) Rf=0.2; [α]D20=−61.3 (c=0.65, CDCl3); IR (neat) 2100, 1756, 1634, 1246 cm−1; 1H NMR (600 MHz, CDCl3) δ 6.56 (1 H, d, JP-2=21.6 Hz), 5.71 (1 H, d, J=6.9 Hz), 4.52 (1 H, d, J=7.8 Hz), 4.34-4.30 (1 H, m), 4.11-4.01 (4 H, m), 3.31-3.23 (2 H, m), 2.69-2.64 (1 H, m), 2.12-2.08 (1 H, m), 2.01 (3 H, s), 1.51-1.43 (4 H, m), 1.39-1.31 (6 H, m), 0.90-0.81 (6 H, m); 13C NMR (150 MHz, CDCl3) δ 171.0, 141.7, 126.3 (C-1, d, JP-1=182 Hz), 810.9, 73.7, 62.14, 62.10, 54.3, 57.1, 31.0, 26.2, 25.4, 23.6, 16.4, 16.3, 9.6, 9.2; 31P NMR (162 MHz, CDCl3) δ 16.99; HRMS calcd for C17H32N4O5P (M++H): 403.2110, found: m/z 403.2111.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[NH:19][C:18]1=[O:30]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[NH:19][C:18]1=[O:30])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: COc1ccc2c(c1)NC(=O)C(N)CC2
Product: COc1ccc2c(c1)NC(=O)C(NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CC2

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step D by the procedure described in Example 1, Step F. 1H NMR (200MHz, CDCl3): 1.44 (s,6H), 1.50 (s,9H), 1.80 (m,1H), 2.80 (m,5H), 3.86 (2,3H), 4.62 (m,1H), 6.62 (d,2Hz,1H), 6.76 (dd;2,8Hz;1H), 7.20 (d,8Hz,1H). FAB-MS: calculated for C21H31N3O5 405; found 406 (M+H,42%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Br)=[CH:4][CH:3]=1.[Li]CCCC.[I:18]I.OS([O-])=O.[Na+]>C1COCC1>[I:18][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: II
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc(I)c2ccccc12
Temperature: -70 °C
Reaction time: 1 h

Procedure:
100 g (350 mmol) of 1,4-dibromonaphthalene are initially introduced in 1 l of THF, cooled to −70° C., and 235 ml of n-BuLi (1.6 M in hexane, 370 mmol) are added dropwise. After 1 h, 103 g of I2 (406 mmol) in 250 ml of THF are added dropwise, the mixture is stirred at −70° C. for a further 2 h, warmed to 0° C. and quenched by the addition of 50 ml (644 mmol) of aqueous NaHSO3 solution (w=39%). The phases are separated, and the aqueous phase is extracted once with MTB. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated in a rotary evaporator. The residue is purified by column chromatography (SiO2, heptane), and the further purification is carried out by recrystallisation from isopropanol, giving 1-iodo-4-bromonaphthalene as a yellow solid.
Reaction SMILES: [NH:1]([C:3]([C:5]1[C:14]([C:15]([NH:17]N)=[O:16])=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([CH2:21][CH3:22])=[CH:10][C:11]=2[Br:20])[N:6]=1)=[O:4])N>C(O)(=O)C>[Br:20][C:11]1[C:12]2[C:13]([OH:19])=[C:14]3[C:15](=[O:16])[NH:17][NH:1][C:3](=[O:4])[C:5]3=[N:6][C:7]=2[CH:8]=[C:9]([CH2:21][CH3:22])[CH:10]=1
Reactant: CCc1cc(Br)c2c(O)c(C(=O)NN)c(C(=O)NN)nc2c1
Solvent: CC(=O)O
Product: CCc1cc(Br)c2c(O)c3c(=O)[nH][nH]c(=O)c3nc2c1
Temperature: 81 °C
Yield: 68.5 %

Procedure:
A stirred mixture of 2,3-bishydrazinocarbonyl-5-bromo-7-ethyl-4-hydroxyquinoline (0.40 g, 1.1 mM) in glacial acetic acid (12 mL) was heated at 81° C. for 1.5 hr. After cooling to room temperature, the reaction mixture was filtered and the collected solids washed with acetic acid and air dried to provide the title compound (0.25 g, 70%) as a light brown solid, mp >400° C.; MS(CI): 336 (M+H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C=O)C.O>[Si:14]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)[C@H](C)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of (S)-ethyl lactate (11.8 g, 100 mmol) in DMF (50 mL) was added imidazole (10.2 g, 150 mmol). The mixture was cooled in an ice bath and tert-butyldimethylsilyl chloride (15.8 g, 105 mmol) was added in three portions, at intervals of 30 min between each addition. The reaction mixture was stirred overnight. The reaction mixture was diluted with water (30 mL) and extracted with Et2O (50 mL×2). The combined extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was distilled under vacuum (bp 70-78° C., 0.5 mmHg) to afford 22.07 g (95%) of (S)-ethyl 2-(tert-butyldimethylsilyloxy)propanoate: 1H NMR (400 MHz, CHLOROFORM-d) δ 4.32 (q, J=6.6 Hz, 1H), 4.11-4.25 (m, 2H), 1.40 (d, J=6.6 Hz, 3H), 1.29 (t, J=7.1 Hz, 3H), 0.93 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([S:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([S:20][CH2:21][C:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: C1CCNC1
Reactant: O=C(O)CSc1nc(-c2ccc(Cl)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CSc1nc(-c2ccc(Cl)cc2)cs1)N1CCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.25 mmol) of [4-(4-chloro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid trifluoroacetic acid salt and 35.6 mg (0.5 mmol) of pyrrolidine. Yield: 51 mg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17]Br)[N:3]=1.[C-:19]#[N:20].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17][C:19]#[N:20])[N:3]=1
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(CBr)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared from 2,4-diamino-5-(2,4-dichlorophenyl)-6-bromomethyl-pyrimidine (Example 53) by reaction with sodium cyanide in DMF at room temperature, mp. 249°-251° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.[IH:11].[NH2:12][NH:13][C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[NH:15]>C(O)C>[IH:11].[CH2:17]([NH:16][C:14]([NH:13][N:12]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([CH3:1])[CH:3]=1)=[NH:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(C=O)cc1C
Reactant: N=C(NN)NCc1ccccc1
Agent: I
Solvent: CCO
Product: Cc1ccc(C=NNC(=N)NCc2ccccc2)cc1C

Procedure:
A mixture of 2.68 g. of 3,4-dimethylbenzaldehyde and 5.84 g. of 1-amino-3-benzylguanidine hydroiodide [W. J. Finnegan, R. A. Henry and E. Lieber, J. Org. Chem., 18, 779 (1953)] in 30 ml. of 66% aqueous ethanol is heated under reflux for 3 hours and then allowed to cool and crystallize. Filtration gives nearly colorless crystals which are recrystallized from aqueous ethanol, giving the desired product as cream-colored crystals, m.p. 183°-185° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]3[CH2:15][CH2:16][CH:11]2[CH2:12][CH2:13]3)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-])=O>[Pd]>[CH:11]12[N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([C:17]([F:20])([F:18])[F:19])[CH:6]=3)[CH:14]([CH2:13][CH2:12]1)[CH2:15][CH2:16]2
Reactant: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Agent: [Pd]
Product: Nc1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Reaction time: 12 h
Yield: 91 %

Procedure:
A flask charged with 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (26) (7.07 g, 24.70 mmol) and 10% Pd/C (0.71 g, 6.64 mmol) was evacuated and then flushed with nitrogen. Ethanol (22 ml) was added and the reaction flask was fitted with a hydrogen balloon. After stirring vigorously for 12 h, the reaction mixture was purged with nitrogen and Pd/C was removed by filtration. The filtrate was concentrated to a dark oil under reduced pressure and the residue purified by silica gel chromatography (0-15% ethyl acetate in hexanes) to provide 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline (3) as a purple solid (5.76 g, 91% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 6.95 (dd, J=2.3, 8.8 Hz, 1H), 6.79 (d, J=2.6 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 4.89 (s, 2H), 4.09 (s, 2H), 1.61-1.59 (m, 4H) and 1.35 (d, J=6.8 Hz, 4H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].Cl.[NH2:30][NH:31][C:32]([NH2:34])=[O:33]>C(O)C>[N:1]1[C:10]2[C:9](=[CH:8][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=[N:30][NH:31][C:32]([NH2:34])=[O:33])[CH3:22])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:6][CH:5]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NNC(N)=O)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.3 %

Procedure:
To a solution of example 208 (0.070 g, 0.230 mmol) in ethanol (2 ml), sodium acetate (0.018 g, 0.230 mmol) and semicarbazide hydrochloride (0.026 g, 0.230 mmol) were added and stirred at RT for 12 h. The reaction mixture was concentrated and the residue was washed with bicarbonate solution, dichloromethane and dried under vacuum to afford the title compound as a yellow solid (0.040 g, 48%). M.P.: 249-250° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.70 (s, 1H), 8.88 (d, J=2.8 Hz, 1H), 8.54 (d, J=8.9 Hz, 1H), 8.45 (d, J=8.9 Hz, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.01 (s, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.81 (dd, J=8.6, 1.3 Hz, 1H), 7.53 (dd, J=8.2, 4.1 Hz, 1H), 6.78 (br s, 2H), 6.14 (s, 2H), 2.35 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Br:13].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Br:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14])=[O:23]
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)Cc1ccc(N)c(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Br)c1
Reaction time: 21 h
Yield: 74.4 %

Procedure:
To a mixture of methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-chlorophenyl isocyanate (0.29 ml, 2.40 mmol) in THF (2 ml) was added Et3N (33 ml, 0.24 mmol) at room temperature. After 21 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-bromo-4-[N′-(2-chlorophenyl)ureido]phenylacetate (710 mg, 74%) as a pale brown powder. 1H-NMR (CDCl3) δ3.57 (s, 2H), 3.70 (s, 3H), 7.02-7.28 (m, 2H), 7.36 (d, J=6.8 Hz, 1H), 7.48 (s, 1H), 8.00-8.11 (m, 2H); MS (ESI) m/z 397 (M+), 399 (M++2), 401 (M++4).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22](S(C)(=O)=O)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:39]([O:43][C:44]([NH:46][C@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>O1CCOCC1>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22]([N:49]5[CH2:50][CH2:51][C@H:47]([NH:46][C:44](=[O:45])[O:43][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:48]5)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:30])=[O:31])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(N5CC[C@H](NC(=O)OC(C)(C)C)C5)s4)ccc32)cc1
Yield: 90.2 %

Procedure:
A yellow solution of 2-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (168.4 mg, 0.296 mmol) and (35)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (TCI America, Portland, Oreg.; 165 mg, 0.888 mmol) in dioxane (1.0 mL) was heated in an open microwave vial at 90° C. for 2 days. Chromatographic purification of the resulting dry residue (silica gel, 0-100% EtOAc/Hex) furnished (S)-tert-butyl 1-(5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-yl)pyrrolidin-3-ylcarbamate (180 mg, 0.267 mmol, 90%) as a light-yellow solid: MS (ESI, pos. ion) m/z: 675.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.80 (s, 1H), 8.07 (s, 2H), 7.94-7.99 (m, 1H), 7.82 (d, J=8.2 Hz, 2H), 7.62 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.22-7.25 (m, 2H), 6.63 (d, J=8.2 Hz, 1H), 5.57 (spt, J=6.2 Hz, 1H), 4.72 (br. s., 1H), 4.40 (br. s., 1H), 3.84 (dd, J=10.4, 5.9 Hz, 1H), 3.68-3.75 (m, 1H), 3.60-3.68 (m, 1H), 3.41-3.55 (m, 1H), 3.45 (m, J=10.4, 3.5 Hz, 1H), 2.35 (s, 3H), 1.46 (s, 9H), 1.45 (br. s., 6H).