Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C(C2SC=NN=2)[N:10]2[C:18]3[C:13](=[N:14][CH2:15][NH:16][CH:17]=3)[CH:12]=[C:11]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=C(C(F)(F)F)C=1.FC1C=CC=CC=1C1NC2C=NC=NC=2C=1.[F:51][C:52]([F:81])([F:80])[C:53]1[CH:58]=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:56]=[CH:55][C:54]=1[C:63]1[CH:67]=[C:66]([CH2:68]OS(C2C=CC(C)=CC=2)(=O)=O)[O:65][N:64]=1>>[F:81][C:52]([F:51])([F:80])[C:53]1[CH:58]=[C:57]([C:59]([F:62])([F:60])[F:61])[CH:56]=[CH:55][C:54]=1[C:63]1[CH:67]=[C:66]([CH2:68][N:16]2[CH:17]=[C:18]3[N:10]=[C:11]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH:12]=[C:13]3[N:14]=[CH:15]2)[O:65][N:64]=1
Reactant: Cc1ccc(S(=O)(=O)OCc2cc(-c3ccc(C(F)(F)F)cc3C(F)(F)F)no2)cc1
Reactant: COc1ccc(C(c2nncs2)n2c(-c3ccccc3F)cc3c2=CNCN=3)c(C(F)(F)F)c1
Agent: Fc1ccccc1-c1cc2ncncc2[nH]1
Product: Fc1ccccc1-c1cc2ncn(Cc3cc(-c4ccc(C(F)(F)F)cc4C(F)(F)F)no3)cc-2n1
Yield: 7 %

Procedure:
Prepared analogously to the method described for 3-[5[(4-methoxy-2-trifluoromethyl-phenyl)-[1,3,4]thiadiazol-2-ylmethyl]-6-(2-fluorophenyl)-3H-pyrrolo[3,2-d]pyrimidine beginning with 6-(2-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine (100 mg, 0.46 mmol) and toluene-4-sulfonic acid 3-(2,4-bis-trifluoromethylphenyl)-isoxazol-5-ylmethyl ester (322 mg, 0.7 mmol) to produce the desired product (16.1 mg, 7%). 1H-NMR: (d6-DMSO, 400 MHz) δ 9.58 (s, 1H), 9.40 (s, 1H), 8.26 (s, 1H), 8.24 (d, 1H), 8.16 (dt, 1H), 7.83 (d, 1H), 7.72 (m, 1H), 7.58 (s, 1H), 7.52 (d, 1H), 7.44 (d, 1H) 7.13 (d, 1H), 6.20 (s, 2H). LCMS calculated for C24H13F7N4O 506.4, found 507.09 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][C:12]2[C:13]([Cl:19])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH2:20]([NH2:22])[CH3:21].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][C:12]2[C:13]([Cl:19])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[O:10])[C:5]([NH:22][CH2:20][CH3:21])=[N:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)c2cc(Br)cnc2Cl)c(Cl)n1
Reactant: CCN
Solvent: O
Solvent: C1CCOC1
Product: CCNc1ncc(Br)cc1C(=O)Nc1ccc(C)nc1Cl
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A solution of 5-bromo-2-chloro-N-(2-chloro-6-methyl-3-pyridinyl)-3-pyridinecarboxamide (1.7 g, 4.8 mmol) and ethylamine (2M in THF, 10.5 mmol, 5.2 mL) in THF (5 mL) was stirred at 90 to 95° C. in a steel autoclave for 16 h. The resulting mixture was poured into water (100 mL), stirred for 15 min and filtered. The solid was washed with water followed by hexane to give the title compound as a yellow solid (1.58 g, 89% yield).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:27]([N:2]([CH3:1])[C@H:3]2[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:5][CH2:4]2)=[O:28])=[CH:31][CH:32]=1
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reaction time: 1 h

Procedure:
To a solution of 245 mg (0.53 mmol) trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.trifluoroacetic acid salt and 143.5 mg (0.75 mmol) 4-chlorophenyl chloroformate in 4 ml dioxane, was added at RT 1.54 ml (3.12 mmol) Hünig's base. The mixture was stirred for 1 h, then extracted with EtOAc/1N HCl and water. The organic phases were concentrated under reduced pressure and purified by chromatography on silica gel with EtOAc/hexane 1:3 to yield 167 mg (73%, 2 steps) of pure trans-Methanesulfonic acid 5-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexyl}-pentyl ester, MS: 432 (MH+, 1Cl).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]([CH2:19][C@H:20]([NH:32]C(OC(C)(C)C)=O)[C:21]([O:23][C@H:24]([CH3:31])[C@H:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])=[O:22])[CH:10]=[CH:11][C:12]=1[O:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].[ClH:40]>O1CCOCC1>[ClH:40].[NH2:32][C@@H:20]([CH2:19][C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]([O:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:8]=1)[C:21]([O:23][C@H:24]([CH3:31])[C@H:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])=[O:22]
Reactant: CCOC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H](C)[C@@H](C)OC(C)=O)cc1OC(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Oc1ccc(C[C@H](N)C(=O)O[C@H](C)[C@@H](C)OC(C)=O)cc1OC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
(1R,2R)-2-Acetyloxy-1-methylpropyl (2S)-3-[3,4-bis(ethoxycarbonyloxy)phenyl]-2-[(tert-butoxy)carbonylamino]propanoate (35) (0.6 g, 1.1 mmol) was dissolved in 10 mL of 4M HCl in 1,4-dioxane. The mixture was stirred at room temperature for 60 min. Dioxane was evaporated under reduced pressure. The colorless oil was further dried under vacuum to give 0.6 g (96% yield) of the title compound (31). 1H NMR (400 MHz, CD3OD): δ 1.16 (d, J=7.8 Hz, 3H), 1.18 (d, J=7.8 Hz, 3H), 1.35 (t, J=7.2 Hz, 3H), 1.36 (t, J=7.2 Hz, 3H), 2.03 (s, 3H), 3.23 (dd, J=14.0, 6.8 Hz, 1H), 3.27 (dd, J=14.0, 6.8 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 4.30 (q, J=7.2 Hz, 2H), 4.40 (t, J=6.8 Hz, 1H), 4.94 (m, 1H), 5.05 (m, 1H), 7.26 (dd, J=8.0, 2.0 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H). MS (ESI) m/z 456.2 (M+H)+ and 454.0 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][C:13]=2Br)=[CH:8][CH:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC#N>[CH3:1][O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][C:13]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)C=Cc1ccc(C2=C(Br)CCc3ccccc32)cc1
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(C2=C(c3ccccc3)CCc3ccccc32)cc1
Yield: 50 %

Procedure:
Prepared from the coupling of 2k and benzene boronic acid, (R6—Ph)B(OH)2 where R6=H, by the general method described for example 2d. Yield 50%; APcI m/z: 408 (M+H+CH3CN+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH:16]1([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=2)[CH2:18][CH2:17]1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH:16]4[CH2:18][CH2:17]4)=[CH:24][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C2CC2)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(C3CC3)nc2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-cyclopropyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[C:11]([NH2:12])[C:2]1=2.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[C:17]([Cl:29])=[CH:16][N:15]=1>>[Cl:29][C:17]1[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[N:19][C:14]([NH:12][C:11]2[C:2]3[O:1][CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[CH:8]=[CH:9][CH:10]=2)=[N:15][CH:16]=1
Reactant: COc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1cccc2c1OCCCC2
Product: COc1ccccc1Nc1nc(Nc2cccc3c2OCCCC3)ncc1Cl

Procedure:
The title compound was prepared from 2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-phenyl)-amine in analogous manner to Example 179. Product was isolated as a light pink solid (20 mg, 30%). LCMS (m/e) 397 (M+H); 1H NMR (DMSO-d6, 400 MHz) δ 8.27 (s, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.86 (d, 1H, J=7.3 Hz), 7.72 (d, 1H, J=7.8 Hz), 7.19 (dd, 1H, J=7.3, 8.3 Hz), 7.12 (d, 1H, J=8.3 Hz), 6.94 (td, 1H, J=7.6 Hz), 6.76 (m, 2H), 3.94 (m, 2H), 3.82 (s, 3H), 2.72 (m, 2H), 1.88 (m, 2H), 1.62 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([O:10][CH3:11])[CH:4]=1)#[N:2].Cl[S:13]([OH:16])(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:13](=[O:15])(=[O:14])[OH:16])=[C:5]([O:10][CH3:11])[CH:4]=1)#[N:2]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cc(C#N)ccc1N
Solvent: ClC(Cl)Cl
Product: COc1cc(C#N)ccc1NS(=O)(=O)O

Procedure:
To a solution of 4-cyano-2-methoxyaniline (1 mmol) in chloroform (1 mL) at −78° C. is added chlorosulfonic acid. Upon reaction completion, the crude material is concentrated and may be purified by recrystalization to give N-(4-cyano-2-methoxyphenyl)-sulfamic acid.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:13])[CH:4]=1)#[N:2].[C:14]1([CH2:20][C:21]([NH:23][NH2:24])=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](O)[CH2:32]CC>>[CH2:20]([C:21]1[NH:23][N:24]=[C:1]([C:3]2[S:7][C:6]([C:8]([O:10][CH2:11][CH2:12][CH2:31][CH3:32])=[O:9])=[C:5]([CH3:13])[CH:4]=2)[N:2]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1sc(C#N)cc1C
Reactant: NNC(=O)Cc1ccccc1
Reactant: CCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOC(=O)c1sc(-c2n[nH]c(Cc3ccccc3)n2)cc1C
Temperature: 150 °C
Reaction time: 20 h
Yield: 42 %

Procedure:
A mixture of ethyl 5-cyano-3-methylthiophene-2-carboxylate (0.37 g, 1.90 mmol), phenylacetic hydrazide (0.29 g, 1.90 mmol) and potassium carbonate (0.26 g, 1.90 mmol) in 1-butanol (5 mL) was stirred in a sealed tube at 150° C. for 20 h. The reaction mixture was cooled to ambient temperature and concentrated. The residue was purified by column chromatography eluted with 0-30% ethyl acetate in hexanes to afford the title compound as a colorless solid (0.28 g, 42%). 1H NMR (300 MHz, CDCl3) δ 10.49 (br s, 1H), 7.46 (s, 1H), 7.41-7.27 (m, 5H), 4.28 (t, J=6.5 Hz, 2H), 4.21 (s, 2H), 2.56 (s, 3H), 1.77-1.66 (m, 2H), 1.54-1.40 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); MS (ES+) m/z 356.3 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][C:11]2[NH:12][C:13]3[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[CH3:22][S:19]([C:14]1[C:13]2[NH:12][C:11]3[CH2:23][CH2:24][NH:8][CH2:9][C:10]=3[C:18]=2[CH:17]=[CH:16][CH:15]=1)(=[O:20])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(S(C)(=O)=O)cccc3c2C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc2c3c([nH]c12)CCNC3
Reaction time: 2.5 h

Procedure:
6-methanesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (214 mg, 0.61 mmol) was dissolved in DCM (1 mL) and the 4M HCl in dioxane (1 mL) added. Evolution of gas commenced immediately and the reaction was stirred for 2.5 h when no further evolution was observed but a black solid had separated from the reaction.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][C@@H:11]([NH2:24])[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:31]=[CH:30][C:29]([CH:32]2[CH2:36][CH:35](OC)O[CH:33]2OC)=[CH:28][CH:27]=1.FC(F)(F)C(O)=O>ClCCCl>[CH2:1]([O:8][C:9](=[O:25])[CH2:10][C@@H:11]([N:24]1[CH:35]=[CH:36][C:32]([C:29]2[CH:30]=[CH:31][C:26]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:27][CH:28]=2)=[CH:33]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:18])([CH3:19])[CH3:17])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)[C@@H](NC(=O)[C@H](N)CC(=O)OCc1ccccc1)C(C)(C)C
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)C(C)(C)C
Yield: 35 %

Procedure:
According to the procedure described in Example 1(c) for the preparation of N-(8-oxo-4oxa-1,7-diaza-tricyclo-[9.6.1.012,17]-octa-deca-11(18),12,14,16-tetraen-9S-yl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-amino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester (prepared as described in Example 1(b))was condensed with 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) in 1,2-dichloroethane with trifluoroacetic acid to provide in 35% yield 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester as an amorphous solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C:35]([O-])([O-])=O.[K+].[K+].IC[CH2:43][C:44]([CH3:49])([CH3:48])[C:45]([O-:47])=[O:46].Cl>CN(C=O)C.O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([CH2:35][O:47][C:45](=[O:46])[C:44]([CH3:49])([CH3:48])[CH3:43])[N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CC(C)(CCI)C(=O)[O-]
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2COC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 23.6 %

Procedure:
A mixture of 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (0.71 g), K2CO3 (0.21 g) and iodomethylpivalate (0.36 g) in DMF (2 ml) was stirred at room temperature for 17 hours. The reaction mixture was digested with water and made acidic (pH 3-4) with 1N-HCl. The mixture was extracted with ethyl acetate and the organic layer was washed with H2O, dried and evaporated to dryness to give a residue. The residue was purified by column chromatography on silica gel to afford colorless powder (0.2 g, 23%), m.p. 188°-191° C.(d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[NH:15]1[CH:19]=[CH:18][N:17]=[N:16]1.FC1C=C(F)C=CC=1[C@]1([C@H](N2N=CC=N2)C)CO1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1c[nH]nn1
Agent: C[C@@H](n1nccn1)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ccnn1)[C@@]1(c2ccc(F)cc2F)CO1

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (497 mg) and 1H-1,2,3-triazole, (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(2H-1,2,3-triazol-2-yl)ethyl]oxirane (150 mg) and (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(1H-1,2,3-triazol-1-yl)ethyl]oxirane (204 mg) were obtained by the same way as in Reference Example 2.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH3:17])[CH:16]=1>CN(C)C=O>[N+:18]([C:14]1[CH:13]=[CH:12][C:11]([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:16][C:15]=1[CH3:17])([O-:20])=[O:19]
Reactant: Cc1cc(Br)ccc1[N+](=O)[O-]
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (57% oil emulsion, 1.11 g) in dimethylformamide (30 ml) is added in small portions 2.48 ml (2.64 g, 24 mmoles) of thiophenol. The mixture is cooled in an ice bath while a solution of 5-bromo-2-nitrotoluene (4.32 g, 20 mmoles) in dimethylformamide (10 ml) is added dropwise. The mixture is stirred for an additional 30 minutes and then poured into ice water (200 ml). The partially crystalline product is extracted with dichloromethane and the combined extracts are washed with water and dried. The solvents are evaporated under high vacuum to remove DMF and the residue is covered with hexane. The resultant crystals are broken up and filtered to give pure product, 2-nitro-5-phenylthiotoluene, 3.78 g, m.p. 69°-75°.
Reaction SMILES: [SH2]=N.[CH2:3]([NH:7][C:8](C1C=CC=CC=1C(O)=O)=[O:9])[CH2:4][CH2:5][CH3:6].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.C(N(CC)CC)C.O>CC(C)=O>[C:23]1([CH3:26])[CH:24]=[CH:25][C:20]([NH:19][C:8]([NH:7][CH2:3][CH2:4][CH2:5][CH3:6])=[O:9])=[CH:21][CH:22]=1
Reactant: CCCCNC(=O)c1ccccc1C(=O)O
Reactant: Cc1ccc(N)cc1
Agent: N=[SH2]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCNC(=O)Nc1ccc(C)cc1
Yield: 79.6 %

Procedure:
5.64 g n-butylcarbamoyl-benzoic acid sulfimide was reacted with 2.14 g p-toluidine and 2.8 ml triethylamine in 20 ml of a 1:1 mixture of water and acetone, as described in example 1. 3.28 g 1-(p-tolyl)-3-(n-butyl)-urea was obtained, melting at 118°-119° C.
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH2:11])=[S:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C@@H:13]([CH3:17])[C:14](O)=[O:15]>>[CH:1]1([NH:8][C:9]2[S:10][C@@H:13]([CH3:17])[C:14](=[O:15])[N:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=S)NC1CCCCCC1
Reactant: C[C@H](Br)C(=O)O
Product: C[C@@H]1SC(NC2CCCCCC2)=NC1=O

Procedure:
Synthesis was performed from N-cycloheptylthiourea and (2S)-2-bromopropanoic acid according to Method C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])[CH:17]=[CH:18][CH:19]=1>>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])[CH:17]=[CH:18][CH:19]=1
Reactant: CON(C)C(=O)C=Cc1cccc(Br)c1
Reactant: FC(F)(F)C(F)(F)I
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1cccc(Br)c1)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 85.3 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (102.0 mL, 85.5 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (57.0 mL, 85.5 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of 3-(3-bromo-phenyl)-N-methoxy-N-methylacrylamide (7.7 g, 28.5 mmol, in diethyl ether 50.0 mL) prepared in Step 1 of Preparation 4 was slowly added thereto at −78° C. The reaction mixture was stirred at room temperature for 1 hour, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with diethyl ether. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30) to give 8.0 g of the titled compound as a yellow liquid.
Reaction SMILES: C1(C(Cl)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Br:28])C1C=CC=CC=1.BrN1C(=O)CCC1=O.[CH3:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH:48]=[CH:47][CH:46]=[C:45]2[C:49]#[N:50])=[CH:40][CH:39]=1>>[CH3:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH:48]=[C:47]([Br:28])[CH:46]=[C:45]2[C:49]#[N:50])=[CH:40][CH:39]=1
Reactant: Cc1ccc(-n2cccc2C#N)cc1
Reactant: BrCc1ccccc1
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Product: Cc1ccc(-n2cc(Br)cc2C#N)cc1

Procedure:
4-(2-(2H-2-trityltetrazol-5-yl)-1-pyrrolyl)-benzyl bromide is prepared as described in EP 0 480 204 A1 preparation 1 and 8, and as described in EXAMPLE 10. To this end 1-(4-methylphenyl)-2-cyanopyrrole is reacted with tributyltin azide to give 4-(2-(1H-tetrazol-5-yl)-1-pyrrolyl)-methylbenzene, which is protected by reaction with triphenylmethyl chloride. The benzylic methyl group of (2-(2H-2-trityltetrazol-5-yl)-1-pyrrolyl)-methylbenzene is then converted to the benzyl bromide with N-bromosuccinimide. An analog with a bromo substituent in the pyrrole ring is prepared from the same starting material 1-(4-methylphenyl)-2-cyanopyrrole by reaction with N-bromosuccinimide at room temperature to give 1-(4-methylphenyl)-4-bromo-2-cyanopyrrole. This is further reacted by analogy to the unsubstituted compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22](N)=[N:23][C:24]=2[Cl:28])(=[O:3])[CH3:2].[I:30]CI.N(OCCCCC)=O>C(#N)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([I:30])=[N:23][C:24]=2[Cl:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: ICI
Agent: CCCCCON=O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
To a solution of (2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-(2-amino-6-chloropurin-9-yl)oxolan-3-yl acetate in acetonitrile was added diiodomethane and n-pentyl nitrite. The mixture was heated under nitrogen for 20 hours, then solvent removed under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexanes to hexanes/ethyl acetate 2:1, to provide (2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-(6-chloro-2-iodopurin-9-yl)oxolan-3-yl acetate, which may be recrystallized from ethanol.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH:10]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.BrC[C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:27]([NH:29][C:30](=[O:31])[C:25]=12)=[O:28].[CH2:35]1COCC1>>[O:31]=[C:30]1[C:25]2[C:26](=[CH:32][CH:33]=[CH:34][CH:24]=2)[C:27](=[O:28])[N:29]1[CH2:35][C:10]([CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: C1CCOC1
Reactant: O=C1NC(=O)c2c(CBr)cccc21
Reactant: CCOC(=O)CC(Cc1ccccc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(Cc1ccccc1)(CN1C(=O)c2ccccc2C1=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a suspension of NaH (2.2 g, 54 mmole) in THF (200 mL) was added diethyl 2-(phenylmethyl)butanedioate (12.5 g, 49.9 mmole). After 30 min at RT, bromomethyl phthalimide was added to the reaction mixture and the contents were stirred for 14 h at RT. The reaction was quenched with H2O (15 mL), diluted with Et2O (300 mL) and layers separated. The organic layer was concentrated under vacuum and the resulting residue recrystallized from EtOH)(0°) to give the title compound (13 g, 64%) as a white solid: LCMS (ES) m/z 410 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:13]1[CH:14]=[C:15]([C:18]([F:20])([F:21])[F:19])[CH:16]=[CH:17][C:12]=1[F:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1cc(C(F)(F)F)ccc1F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 29.6 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 0.50 g, 3.4 mmol), 2-fluoro-5-(trifluoromethyl)phenylboronic acid (Aldrich; 561 mg, 3.4 mmol), copper(II) acetate (621 mg, 3.4 mmol) and triethylamine (480 μL, 3.4 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(2-fluoro-5-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (310 mg, 31%) as a colorless oil that solidified.