Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Br:12][Si](C)(C)C>C(#N)CC>[Br:12][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: C[Si](C)(C)Br
Solvent: CCC#N
Product: FC(F)(F)c1ccnc(Br)c1

Procedure:
A mixture of 2-chloro-4-(trifluoromethyl)pyridine (2.70 g, 14.9 mmol) and bromotrimethylsilane (3.90 mL, 29.6 mmol) in propanenitrile (15.0 mL) was heated under reflux for 22 h. The product (very volatile) was carefully rotary evaporated to give 4.07 g (propanenitrile contained) of thick light brown suspension w/o further purification. LC-MS calculated for C6H3BrF3N (M+H) 226.9; found 225.9/227.8.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)=[O:14])=O)C1C=CC=CC=1.[CH3:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>[Pd]>[CH2:26]([O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:43]([C:40]2[CH:41]=[CH:42][C:37]([CH3:36])=[CH:38][CH:39]=2)(=[O:45])=[O:44])[CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:21][CH:20]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NC(=O)OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Pd]
Product: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 51.9 %

Procedure:
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy) propanamide (1.0 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-methylbenzenesulfonyl chloride (778 mg) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-methylbenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (540 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(OCC)(=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc([N+](=O)[O-])c(Br)c1
Reaction time: 6 h

Procedure:
Combine 3-bromo-4-nitrophenol (1 eq.), triethylamine (1.1 eq.) and tert-butyldimethylsilyl chloride (1.1 eq.) in methylene chloride at 0° C. After about 6 hours, pour the reaction mixture into ethyl acetate, wash with brine, dry the organic layer over Na2SO4 and then concentrate. Purify to give 3-bromo-4-nitro-1-tert-butyldimethylsilyloxybenzene.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7]3[S:21][C:20]([CH2:22][CH3:23])=[CH:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.S(=O)(=O)(O)O.C(=O)([O-])[OH:30].[Na+].[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[Cl:44])[C:38](Cl)=[O:39]>C(Cl)(Cl)Cl>[Br:1][C:2]1[N:6]([C:7]2[S:21][C:20]([CH2:22][CH3:23])=[CH:19][C:8]=2[C:9](=[O:30])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:5]([CH2:11][NH:10][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][C:43]([Cl:44])=[C:35]([Cl:34])[CH:36]=2)=[N:4][N:3]=1
Reactant: O=C([O-])O
Reactant: CCc1cc2c(s1)-n1c(Br)nnc1CN=C2c1ccccc1Cl
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(Br)nnc2CNC(=O)c2ccc(Cl)c(Cl)c2)s1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
9-Bromo-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine is added to 2M sulfuric acid, and the mixture is stirred at 80° C. overnight. Sodium hydrogencarbonate is added to the reaction mixture to make the mixture alkaline. Chloroform and 3,4-dichlorobenzoyl chloride are added, and the mixture is stirred at room temperature for 2 hours to give N-(3-bromo-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazol-5-ylmethyl)-3,4-dichlorobenzamide.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][N:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[C:18]([CH:19]3[CH2:24][O:23][CH2:22][CH2:21][O:20]3)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=2[N:14]=1)=[O:8].[F:30][C:31]([F:35])([F:34])[CH2:32][OH:33].C(Cl)(Cl)Cl>O1CCOCC1.CN(C=O)C>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:27]=[CH:28][N:29]=[C:4]([O:33][CH2:32][C:31]([F:35])([F:34])[F:30])[CH:5]=3)=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(OCC(F)(F)F)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide sodium hydride and 2,2,2-trifluoroethanol in dioxane and DMF. [α]D20=+11.3° (c=0.11, CHCl3), ES-MS m/e (%): 470 (M+H+, 100).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][C:31]([NH:33][CH3:34])=[O:32])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][C:31]([NH:33][CH3:34])=[O:32])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OC(F)F)ccc21
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(methylamino)-2-oxoethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (69.0 mg, 115 μmol) in dichloromethane (3.00 mL) under Ar, trifluoroacetic acid (372 mg, 0.25 mL, 3.26 mmol) was added at 25° C. After 18 h, the solvent was removed and the residue was dissolved in a mix of dichloromethane/methanol/NH3OH (3:2:0.25, 5.25 mL) and stirred. After 2.5 h, the reaction was concentrated and dried in vacuo (200 mTorr, 25° C.). The solid residue was triturated with water (50 mL) and isolated by filtration. The solid was washed with water and hexanes and dried in vacuo (200 mTorr, 40° C.) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(methylamino)-2-oxoethyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45.6 mg, 91.9 μmol, 80%) as a light brown solid. MS (M)'=472; 1H NMR (DMSO-d6) δ: 12.83 (br. s, 1H), 9.04 (s, 1H), 8.39 (d, J=2.8 Hz, 1H), 8.21 (m, 2H), 7.89 (s, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.40 (dd, J=2.0, 9.0 Hz, 1H), 7.20 (t, J=74.3 Hz, 1H), 5.24 (s 2H), 2.65 (m, 3H), 1.51 (s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([N+:43]([O-:45])=[O:44])[CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([N+:43]([O-:45])=[O:44])[CH:38]=2)=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc([N+](=O)[O-])c2)cc1

Procedure:
Analogously to Method D, 1.0 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.417 g of 1-chloromethyl-3-nitrobenzene are used to obtain the title compound as a slightly yellowish oil. Rf=0.37 (1:2 EtOAc-heptane); Rt=6.05.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10](Cl)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](C)=[N:7]2.[CH3:15]C1C=C2C(C=CC=N2)=CC=1O>>[Br:1][C:2]1[C:11]([OH:12])=[C:10]([CH3:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1ccc2c(Br)c(O)c(Cl)cc2n1
Reactant: Cc1cc2ncccc2cc1O
Product: Cc1cc2ncccc2c(Br)c1O

Procedure:
Compound 3D was prepared following the procedure used to prepare compound 1D of Example 1, except that 7-methylquinolin-6-ol (3C) was used instead of compound 1C. LCMS-ESI+ (m/z): 238.1, 240.1 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].[N+]([O-])(O)=O.[C:9]([O:12][CH2:13][CH3:14])(=[O:11])C.CCOCC>C(OCC)(=O)C>[N+:1]([O-:4])([OH:3])=[O:2].[O:11]1[CH2:14][CH2:13][O:12][CH2:9]1
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])[O-]
Solvent: O=[N+]([O-])O
Solvent: CCOCC
Product: C1COCO1

Procedure:
analysis: C28H23Cl2N3O4 (MW 536.43) calc. C 62.69, H 4.32, N 7.83; found C 62.4, H 4.4, N 7.6. Nitrate formation: 1.93 g (3.6 mmol) of base were dissolved in 15 ml of ethyl acetate, and 3.6 ml of 1M HNO3 /ethyl acetate were added with stirring. Ether was subsequently added until no further precipitate was produced, and the precipitate was filtered off under suction. 2.05 g (yield of nitrate, 95.3% of theory) of cis-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-4-[4-(benzoxazol-2-yl)benzyl)oxymethyl]-1,3-dioxolane nitrate were obtained; melting point 121°-2° C.,
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]/[C:12](=[C:19]2\[C:20](=[O:38])[NH:21][C:22]3[C:27]\2=[CH:26][C:25]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:24][CH:23]=3)/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(O)=[O:2].[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH2:39]([NH:46][C:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11]/[C:12](=[C:19]2\[C:20](=[O:38])[NH:21][C:22]3[C:27]\2=[CH:26][C:25]([NH:28][S:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])=[CH:24][CH:23]=3)/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)=[O:2])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)Cc1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1)NCc1ccccc1

Procedure:
A solution of 315 mg (0.6 mmol) of (Z)-3-[1-(4-carboxymethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone, 85 mg (0.8 mmol) of benzylamine, 212 mg (0.66 mmol) of TBTU and 1 ml of N-ethyl-N,N-diisopropyl-amine in 5 ml of DMF is stirred for 3 hours at ambient temperature. Then 50 ml of water are added. The yellow precipitate formed is suction filtered, washed with water, a little isopropanol and ether, then dried in vacuo.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](OC)=O)=[C:6]([CH3:12])[CH:5]=[C:4]([CH2:13][CH2:14][C:15]([OH:33])([CH3:32])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:31])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]=1[C:34](OC)=O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1.C1C=CC=CC=1>[CH3:8][C:7]1[C:6]([CH3:12])=[CH:5][C:4]([CH2:13][CH2:14][C:15]([OH:33])([CH3:32])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:31])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])=[C:3]([CH3:34])[C:2]=1[OH:1]
Reactant: COC(=O)c1c(C)cc(CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C)c(C(=O)OC)c1O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1cc(CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C)c(C)c(O)c1C
Yield: 99.9 %

Procedure:
To a solution of the dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate (5.17 g) in xylene (25 ml) at 10° was added sodium dihydrobis(2-methoxyethoxy)aluminate (20 ml of a 70% by weight solution in benzene) over 20 min with occasional cooling to keep the temperature at 10°. After 10 min the solution was heated to reflux for 1.5 hr, cooled to 10° and was poured cautiously into cold 20% by weight aqueous sulfuric acid (200 ml). The mixture was extracted with ether (3×100 ml) and the combined extracts were washed with aqueous sodium bicarbonate and brine and dried (Na2SO4) and concentrated on a rotary evaporator to give 4.29 g of crude 2,3,6-trimethyl-5-(3-hydroxy-3,7,11,15-tetramethylhexadecanyl)-phenol as a light yellow oil. Chromatography on silica gel eluting with ether in petroleum ether gave 3.19 g of pure 2,3,6-trimethyl-5-(3-hydroxy-3,7,11,15-tetramethylhexadecanyl)-phenol.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:40]3[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=3)[C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:71]([NH:73][C:74]4[CH:75]=[N:76][CH:77]=[CH:78][CH:79]=4)=[O:72])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1>>[OH:46][C:43]1[CH:44]=[CH:45][C:40]([CH:32]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:71]([NH:73][C:74]4[CH:75]=[N:76][CH:77]=[CH:78][CH:79]=4)=[O:72])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[CH:41][CH:42]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)Nc6cccnc6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](NC(=O)Nc6cccnc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-{2-((R)-3-amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-purin-9-yl}-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 106) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-3-yl-urea (Example 105). MS (ES+) m/e 748.41 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]([F:13])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Na+].[Na+].[H][H]>C(#N)C>[F:13][C:3]1[CH:2]=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:10])[F:11]
Reactant: [H][H]
Reactant: Fc1ccc(C(F)(F)F)c(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Fc1ccc(C(F)(F)F)c(F)c1
Yield: 66.6 %

Procedure:
100 g of 3-chloro-2,4-difluorobenzotrifluoride in 500 ml of acetonitrile and 60 g of pulverulent sodium carbonate were initially introduced into a hydrogenation apparatus equipped with a diffuser stone and a stirrer. 10 g of catalyst (5% by weight of metallic palladium on activated charcoal) were then added, and hydrogen was passed in at 80° C. for 10 hours. Subsequently, the batch was cooled and filtered, and the filtrate was distilled via a column packed with perforated rings made of stainless steel. 56 g of 2,4-difluorobenzotrifluoride having a boiling point of 105° to 106° C. at 1,030 mbar were obtained. The refractive index nD20 was 1.3968.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:34]([O:36][CH3:37])=[O:35]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:34]([O:36][CH3:37])=[O:35])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (1.05 g, ca. 2.6 mmol), Et3N (3.96 mL, 2.85 mmol), and DMAP (174 mg, 1.43 mmol) in anhydrous CH2Cl2 (20 mL) cooled to 0° C. was added a solution of methyl chloroformate (1.35 g, 14.25 mmol) in dichloromethane (20 mL) within 30 min. The reaction was stirred overnight, and evaporated under vacuum. The residue was purified by flash chromatography on silica gel to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (0.65 g). MS: 427 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+:23].[OH-:24].[Na+].Cl.[CH3:27][OH:28]>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH2:2][CH2:1][CH2:4][CH2:5][C:27]([O-:28])=[O:24])[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[Na+:23]
Reactant: [OH-]
Reactant: CC(C)c1ccc(-c2csc(NCc3cccs3)n2)cc1
Reactant: CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1ccc(-c2csc(N(CCCCC(=O)[O-])Cc3cccs3)n2)cc1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To the THF solution of [4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amine (150.0 mg, 0.5 mmol) and methyl 5-bromopentaoate (215 μL, 0.1.5 mmol) was added NaH (60 mg, 60%, 0.1.5 mmol) and the resulting mixture was heated at 60° C. for 5 h, after cooling to room temperature methanol (2.0 ml). NaOH (2.0 ml, 1.0 M) added and mix was stirred at room temperature for 15 h. HCl added dropwise to pH 7.0. The acid was extracted with EtOAc (2×20 ml), combined organic extracts dried (Na2SO4), filtered, concentrated, and purified on silica gel column. The sodium salt was made following procedure J to afford the sodium 5-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-pentanoate (110 mg). LCMS m/z: 416 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.Cl>[Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC=CC=1.N1C=CC=CC=1.C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:5].[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:5]
Reactant: C1CCNCC1
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Reactant: C1COCCN1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=C(c1cc(Cl)ccc1Cl)N1CCCCC1
Product: O=C(c1cc(Cl)ccc1Cl)N1CCOCC1

Procedure:
Preparation of 2,5-Dichlorobenzoyl Compounds 2,5-dichlorobenzoyl-containing compounds (e.g. 2,5-dichlorobenzophenones and 2,5-dichlorobenzamides) can be readily prepared from 2,5-dichlorobenzoylchloride. Pure 2,5-dichlorobenzoylchloride is obtained by vacuum distillation of the mixture obtained from the reaction of commercially available 2,5-dichlorobenzoic acid with a slight excess of thionyl chloride in refluxing toluene. 2,5-dichlorobenzophenones (2,5-dichlorobenzophenone, 2,5-dichloro-4'-methylbenzophenone,2,5-dichloro-4'-methoxybenzophenone, and 2,5-dichloro-4'-phenoxy-benzophenone) are prepared by the Friedel-Crafts benzoylations of benzene and substituted benzenes (e.g. toluene, anisole, diphenyl ether), respectively, with 2,5-dichlorobenzoylchloride at 0°-5° C. using 2-3 mol equivalents of aluminum chloride as a catalyst. The solid products obtained upon quenching with water are purified by recrystallization from toluene/hexanes. 2,5-dichlorobenzoylmorpholine and 2,5-dichlorobenzoylpiperidine are prepared from the reaction of 2,5-dichlorobenzoylchloride and either morpholine or piperidine, respectively, in toluene with pyridine added to trap the HCl that is evolved. After washing away the pyridinium salt and any excess amine, the product is crystallized from the toluene solution.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:13]([O:17][C:18](=[O:22])[CH:19](Br)[CH3:20])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[N:6]=[CH:5][N:4]([CH:19]([CH3:20])[C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22])[N:3]=1
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: Cc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ncn(C(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of 3-methyl-1H-1,2,4-triazole (7.3 g, 88 mmol) in DMF (75 mL) was added K2CO3 (60.7 g, 439 mmol) and 2-bromopropionic acid tert-butyl ester (14.6 mL, 88 mmol). The reaction was stirred at room temperature overnight. The mixture was diluted with EtOAc (500 mL), washed with water (×3) then brine. Dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane (20 to 100%) to give 13 g of crude product as a 3:1 mixture of regioisomers. The mixture was purified by Chiralcel OD with a gradient from 4% to 30% IPA/Heptane. Then the first two peaks were separated with Chiracel OD column isocratically eluting with 4% IPA/Heptane. The second peak was collected as the desired single stereoisomer (R or S) (2-(3-methyl-1H-1,2,4-triazol-1-yl)propanoic acid tert-butyl ester) (3.5 g, 19%). 1H-NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 4.90 (q, J=7 Hz, 1H), 2.35 (s, 3H), 1.72 (d, J=7 Hz, 3H), 1.40 (s, 9H). ESI-MS calculated for C10H17N3O2: Exact Mass: 211.13. Found 156.05 (-tBu).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].[CH3:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[C:16]([Cl:22])[N:15]=1>C1COCC1>[Cl:22][C:16]1[C:17]([CH3:21])=[C:18]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[N:19]=[C:14]([CH3:13])[N:15]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Cc1nc(Cl)c(C)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(Oc2nc(C)nc(Cl)c2C)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
A solution of 2,4,6-trimethylphenol (2.720 g, 20 mmol) in 60 ml of dry THF was treated with NaH (60% in oil, 1.200 g, 30 mmol) at room temperature. After stirring at room temperature for 15 minutes, 2,5-dimethyl-4,6-dichloropyrimidine (3.34 g, 20 mmol) was added and the resulting mixture was heated at reflux for 15 hours. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried and concentrated to give 5.4528 g of beige solid. The solid was recrystallized from isopropanol to give 5.1345 g of pale yellow solid, mp 86-87° C.; high MS (C15H17CIN20) calc. 276.1025, found 276.10359. 1H NMR (CDCl3) δ6.87 (s, 2H), 2.37 (s, 6H), 2.28 (s, 3H), 2.01 (s, 6H) ppm.