Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][CH2:3][OH:4])(=[O:20])=[O:21])=[C:15]([F:23])[CH:14]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCCO)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.1 %

Procedure:
To a solution of 2-aminoethanol (0.24 mL, 4.0 mmol), and triethylamine (1.5 mL, 11 mmol) in anhydrous THF (15 mL) was added 4-bromo-2-fluorobenzene-1-sulfonyl chloride (1.0 g, 3.7 mmol) portion wise and the reaction mixture stirred at room temperature for 16 h. The reaction was filtered, the filtrate was concentrated and the residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to afford the desired product (850 mg, 77%): ESI MS m/z 298 [C8H9BrFNO3S+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C1(C2C=CC(C(O)=O)=NC=2OCC2CCCO2)CC1.[NH2:40][C@@H:41]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([NH:44][CH3:45])=[O:43]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:40][C@@H:41]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([NH:44][CH3:45])=[O:43])=[O:20])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCOCC2)n1
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Agent: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1ccc(C2CC2)c(OCC2CCOCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b)) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=418.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][C:5]=1[NH2:20].N1C=CC=CC=1.[Cl:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][C:5]=1[NH:20][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:30]([CH2:29][Cl:28])[CH:31]=1
Reactant: COC(=O)c1cc(OCCCN2CCCCC2)ccc1N
Reactant: O=C(O)c1cccc(CCl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(OCCCN2CCCCC2)ccc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
2-Amino-5-(3-piperidin-1-yl-propoxy)-benzoic acid methyl ester (compound A) (1.1 g) produced by the above process was dissolved in anhydrous methylene chloride (12 ml). Pyridine (600 μl) and 3-(chloromethyl)benzoyl chloride (compound B) (600 μl) were added dropwise to the solution at 0° C., and the mixture was stirred at room temperature for one hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was then subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 2-(3-chloromethyl-benzoylamino)-5-(3-piperidin-1-yl-propoxy)-benzoic acid methyl ester (1.5 g, yield 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[F:46][C:47]1[CH:62]=[CH:61][C:50]([CH2:51][CH:52]2[CH2:57][CH2:56][N:55]([CH2:58][CH2:59][NH2:60])[CH2:54][CH2:53]2)=[CH:49][CH:48]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6](/[CH:8]=[CH:9]/[C:10]([NH:60][CH2:59][CH2:58][N:55]2[CH2:56][CH2:57][CH:52]([CH2:51][C:50]3[CH:49]=[CH:48][C:47]([F:46])=[CH:62][CH:61]=3)[CH2:53][CH2:54]2)=[O:12])[CH:7]=1
Reactant: COc1ccc(Br)cc1/C=C/C(=O)O
Reactant: NCCN1CCC(Cc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1/C=C/C(=O)NCCN1CCC(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (E)-3-(5-bromo-2-methoxy-phenyl)-acrylic acid (0.072 g, 0.28 mmol) in DMF (10 ml) is treated with 2-(1H benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate (0.09 g, 0.28 mmol) and diisopropylethylamine (0.058 ml, 0.33 mmol). The resultant solution is added to 2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethylamine and the mixture stirred at RT for 18 hours. The solvents are evaporated and the crude residue purified by preparative HPLC to afford (E)-3-(5-bromo-2-methoxy-phenyl)-N-{2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethyl}-acrylamide [MH]+ 475.2
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.BrC1C=CC(I)=CC=1C(Cl)=O.[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[O:6]
Reactant: CCOP(OCC)OCC
Reactant: O=C(O)c1cc(I)ccc1Br
Agent: O=C(Cl)c1cc(I)ccc1Br
Product: CCOP(=O)(OCC)C(=O)c1cc(I)ccc1Br

Procedure:
2-Bromo-5-iodobenzoic acid was converted to 2-bromo-5-iodobenzoyl chloride following procedures similar to those in Example 82A. The 2-bromo-5-iodobenzoyl chloride was reacted with triethyl phosphite following procedures similar to those in Example 82 to give diethyl (2-bromo-5-iodophenyl)oxomethylphosphonate. The diethyl (2-bromo-5-iodophenyl)oxomethylphosphonate was converted to diethyl(2-bromo-5-iodophenyl)difluoromethylphosphonate following procedures similar to those in Example 80C. Compound 94 was synthesized according to procedures similar to those of Example 40 from this corresponding diethyl phosphonate. MS (ES-): m/z 411.0, 413.0 (M−H). 1H NMR: (DMSO-d6, 400 MHz) δ 7.93 (s, 1H), 7.67-7.69 (m, 1H), 7.45 (d, J=8.2, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([NH:23][S:24]([CH2:27][CH2:28][NH2:29])(=[O:26])=[O:25])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:17]1[CH2:18][CH2:19][N:20]([NH:23][S:24]([CH2:27][CH2:28][NH:29][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])(=[O:26])=[O:25])[CH2:21][CH2:22]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCS(=O)(=O)NN1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc(Cl)s1
Product: O=C(NCCS(=O)(=O)NN1CCN(Cc2ccccc2)CC1)c1ccc(Cl)s1

Procedure:
5-Chloro-thiophene-2-carboxylic acid [2-(4-benzyl-piperazin-1-ylsulfamoyl)-ethyl]-amide was prepared by an analogous procedure as described in example 5 iii) starting from 100 mg (1 equiv.) 5-chloro-thiophene-2-carboxylic acid and 183 mg (0.61 mmol) 2-amino-ethanesulfonic acid (4-benzyl-piperazin-1-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid [2-(4-benzyl-piperazin-1-ylsulfamoyl)-ethyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material. Yield: 41 mg
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.ClCC(Cl)=O.[C:34]([O:38][C:39]([N:41]1[CH2:46][C@H:45]([CH2:47][N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[N:44]([CH2:54][C:55](O)=[O:56])[CH2:43][C@H:42]1[CH3:58])=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[C:34]([O:38][C:39]([N:41]1[CH2:46][C@H:45]([CH2:47][N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[N:44]([CH2:54][C:55]([N:15]2[C:9]3[CH:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=4)[N:12]=[CH:11][C:10]=3[C:13]([CH3:17])([CH3:16])[CH2:14]2)=[O:56])[CH2:43][C@H:42]1[CH3:58])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC1(C)CNc2cc(Cc3ccc(F)cc3)ncc21
Reactant: C[C@@H]1CN(CC(=O)O)[C@@H](CN2CCOCC2)CN1C(=O)OC(C)(C)C
Agent: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccc(F)cc4)cc32)[C@@H](CN2CCOCC2)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
To a stirred solution of 6-(4-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (0.11 g, 0.43 mmol) and diisopropylethylamine (0.082 mL, 0.061 g, 0.47 mmol) in DCM (3 mL) at 0° C. under nitrogen was added chloroacetyl chloride (0.036 mL, 0.051 g, 0.45 mmol) and the mixture was stirred at 20° C. for 1 h. Further diisopropylethylamine (0.22 mL, 0.166 g, 1.29 mmol) was added, followed by a solution of (2R,5S)-4-carboxymethyl-2-methyl-5-morpholin-4-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (0.141 g, 0.47 mmol) in DCM (2 mL). The mixture was stirred at 35° C. for 64 h, then the mixture was partitioned between saturated aqueous NaHCO3 and DCM (×3) and combined organic extracts were dried and evaporated. Chromatography (SiO2, gradient elution with 0-100% EtOAc in 40-60 PE) gave the title compound (0.184 g) as an oil. MS: [M+H]+=596.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[NH:14]([CH2:16]C(O)=O)[CH3:15].O>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:9])[CH2:15][N:14]([CH3:16])[C:7](=[O:8])[C:6]=2[CH:13]=1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: CNCC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2ccc(F)cc2C1=O
Temperature: 100 °C

Procedure:
24 g (132.5 mmol) of 5-fluoroisatoic acid anhydride are dissolved in 140 ml of dimethyl sulphoxide and treated with 11.8 g (132.5 mmol) of sarcosine. The solution is stirred at 100° C. until the gas evolution ceases (duration: ca 1.5 hours) and subsequently poured into ca 1.2 liters of water. After stirring for 10 minutes, a solid crystallises out. The crystals are filtered off under suction, washed with 1 liter of water and dried. There is obtained 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 262°-263° C.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6](F)=[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4]=1[CH3:30])#[N:2].C(N(CC)CC)C.[CH3:38][N:39]([CH3:45])[C@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([N:42]2[CH2:43][CH2:44][C@H:40]([N:39]([CH3:45])[CH3:38])[CH2:41]2)=[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4]=1[CH3:30])#[N:2]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCOC(=O)C1CCN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)C1CCN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)CC1
Temperature: 150 °C
Reaction time: 4 h

Procedure:
Ethyl 1-(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)piperidine-4-carboxylate (I-161) (0.27 g, 0.66 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (0.19 ml, 1.37 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.17 ml, 1.34 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11](/[CH:10]=[CH:9]/[C:8]([NH:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([CH:20]=[CH:19][CH:18]=2)[O:1][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:17])[CH:12]=1
Reactant: O=C(/C=C/c1cccnc1)NCCc1cccc(O)c1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(CCNC(=O)/C=C/c2cccnc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
(E)-N-(3-hydroxyphenethyl)-3-(3-pyridyl)-2-propenoic acid amide (1.07 g, 4.0 mmol) obtained in Example 81 and methyl chloroacetate (0.52 g, 4.8 mmol) were dissolved in dimethylformamide (12 ml) and potassium carbonate (1.66 g, 12 mmol) was added and stirred at 60° C. for 8 hours. After allowing to cool, ethyl acetate was added to the reaction mixture and insoluble materials were filtered out. The filtrate was washed with water and dried over magnesium sulfate. After the solvent was distilled out under reduced pressure, the residue was recrystallized to yield the titled compound (0.83 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:27]3[C:13](=[CH:14][C:15]4[O:16][CH2:17][CH2:18][CH2:19]S[CH2:21][CH2:22][CH2:23][O:24][C:25]=4[CH:26]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O[O:29][S:30]([O-:32])=O.[K+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:27]3[C:13](=[CH:14][C:15]4[O:16][CH2:17][CH2:18][CH2:19][S:30](=[O:32])(=[O:29])[CH2:21][CH2:22][CH2:23][O:24][C:25]=4[CH:26]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(Nc2ncnc3cc4c(cc23)OCCCSCCCO4)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=S1(=O)CCCOc2cc3ncnc(Nc4cccc(Cl)c4)c3cc2OCCC1
Reaction time: 4 h

Procedure:
(3-Chloro-phenyl)-(2,10-dioxa-6-thia-14,16-diaza-tricyclo[9.8.0.013,18]nonadeca-1(11),12,14,16,18-pentaen-17-yl)-amine (19, 100 mg, 0.23 mmol) was suspended in MeOH, to which was added a cloudy aqueous solution of oxone (monopersulfate compound) (551 mg, 0.897 mmol) at room temperature. The suspension was stirred and monitored by TLC which indicated that the reaction was completed in 4 h. The reaction mixture was poured into H2O (40 mL), and extracted with EtOAc (3×50 mL). The organic layers were collected, dried and concentrated to give a pale yellow residue which was recrystalized from EtOAc to give the product as an off-white solid: 31.5 mg (30%). 1H NMR (CDCl3) δ 8.75 (s, 1H), 7.95 (s, 1H), 7.65 (d, 1H), 7.50 (s, 1H), 7.35 (t, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 7.15 (d, 1H), 4.25 (m, 4H), 3.05 (t, 2H), 2.80 (t, 2H), 2.30 (m, 2H), 2.00 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH2:23][CH3:24])[C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH2:23][CH3:24])[C:15]4[C:20]([C:21]=3[CH:22]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c2ccccc2c2cc(Nc3ccnc(Cl)n3)ccc21

Procedure:
Briefly, 2,4-dichloropyrimidine (1) was reacted with 3-amino-9-ethylcarbazole (2) by heating in iso-propanol in the presence of N,N-diisopropylethylamine. Separation of the regioisomers provided the pure 4-substituted pyrimidine derivative (3), which was reacted with 4-(3-Aminopropyl)morpholine (4) in sec-butanol under microwave heating in the presence of N,N-diisopropylethylamine to provide EHop-016 (5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:21](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][O:15][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.9 %

Procedure:
To a stirred solution of trans-1-tert-butoxycarbonyl-(2S)-hydroxymethyl-4-hydroxypyrrolidine (2.17 g, 10.0 mmol) and imidazole (2.04 g, 30.0 mmol) in DMF (50 ml) was added TBDPS-Cl (3.03 g, 11.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. Water was added thereto, and extracted with EtOAc. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc(3:2, v/v) as eluent to give trans-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methyl-4-hydroxypyrrolidine (1.5 g, 33%) as a white crystalline solid. 1H-NMR (CDCl3) δ 1.03 (s9H), 1.25 and 1.32 (each s, 9H), 1.90–2.10 (m, 1H), 2.30–2.40 (m, 1H), 3.40–3.80 (m, 3H), 3.95–4.15 (m, 2H), 4.45–4.55 (m, 1H), 7.37–7.39 (m, 6H), 7.63–7.64 (m, 4H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:34]=[C:12]3[CH:13]=[C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:33])[N:22]=[CH:23][C:24]=4[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:26])=[O:19])[CH:15]=[CH:16][N:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl.O>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[N:34]=[C:12]3[CH:13]=[C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:33])[N:22]=[CH:23][C:24]=4[C:25]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[O:26])=[O:19])[CH:15]=[CH:16][N:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc3cc(NC(=O)c4c(C(=O)N5CCOCC5)cnn4C)ccn3n2)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(O)c3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
To a solution of 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (Example 75) (2.7 g, 5.86 mmol) in DCM (50 ml) was added a solution of boron tribromide in DCM (1 M solution; 15 ml, 14.6 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 4 h under nitrogen atmosphere. The mixture was diluted with water (100 ml) and stirred for 15 min. The resultant precipitated solid was filtered, washed thoroughly with water and dried azeotropically with toluene (3×100 ml) to give 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(3-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide as off-white solid (2.5 g, 96%). LC-MS: m/z=448.4 [M+H]+.
Reaction SMILES: C(OC1C=CN([C:15]2[CH:20]=[CH:19][C:18]([O:21]CCN(C)C)=[CH:17][CH:16]=2)C(=O)C=1)C1C=CC=CC=1.C(OC1C=CNC(=O)C=1)C1C=CC=CC=1.[F:43][C:44]1[CH:58]=[CH:57][C:47]([CH2:48][O:49][C:50]2[CH:55]=[CH:54][NH:53][C:52](=[O:56])[N:51]=2)=[CH:46][CH:45]=1>>[F:43][C:44]1[CH:58]=[CH:57][C:47]([CH2:48][O:49][C:50]2[CH:55]=[CH:54][N:53]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[C:52](=[O:56])[N:51]=2)=[CH:46][CH:45]=1
Reactant: CN(C)CCOc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Reactant: O=c1nc(OCc2ccc(F)cc2)cc[nH]1
Agent: O=c1cc(OCc2ccccc2)cc[nH]1
Product: O=c1nc(OCc2ccc(F)cc2)ccn1-c1ccc(O)cc1

Procedure:
Steps (3) and (4) of Example 1 were repeated except that 4-benzyloxy-1H-pyridin-2-one which was used in Step (3) of Example 1 was replaced with 4-(4-fluorobenzyloxy)-1H-pyrimidin-2-one, to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[NH2:30][CH2:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][NH:30][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]1)=[O:28]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCC(CO)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCC(CO)CO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 2-aminomethyl-propane-1,3-diol (31.5 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-2-hydroxymethyl-propyl)-amide (31.2 mg, 30.9%) as an off-white powder. HRMS (ES+) m/z Calcd for C26H31Cl2N3O3S+H [(M+H)+]: 504.455. found: 504.1815.
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][NH:15][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: NN=C(c1ccccc1)c1ccccc1
Product: Fc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1

Procedure:
General procedure A was used to convert benzophenone hydrazone (1.962 g, 10.0 mmol; Aldrich) and 1-bromo-4-fluorobenzene (1.75 g, 10.0 mmol; source) to the title compound. MS (DCI/NH3) m/z 291 (M+H)+.
Reaction SMILES: CN(C)/N=[C:4](\[C:24]([F:27])([F:26])[F:25])/[CH2:5][C:6]([NH:17][S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[F:16])[CH2:7][F:8].Cl.C([O:32]CC)C>O.O1CCOCC1>[CH3:21][C:20]([S@:18]([NH:17][C@:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[F:16])([CH2:5][C:4](=[O:32])[C:24]([F:27])([F:26])[F:25])[CH2:7][F:8])=[O:19])([CH3:23])[CH3:22]
Reactant: Cc1cccc(C(CF)(C/C(=N/N(C)C)C(F)(F)F)N[S@](=O)C(C)(C)C)c1F
Reactant: CCOCC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc([C@](CF)(CC(=O)C(F)(F)F)N[S@](=O)C(C)(C)C)c1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of (R)-N-((Z)-4-(2,2-dimethylhydrazono)-1,5,5,5-tetrafluoro-2-(2-fluoro-3-methylphenyl)pentan-2-yl)-2-methylpropane-2-sulfinamide (5.66 g, 13.24 mmol) in 10% water (5 mL) in dioxane (50 mL) was added hydrogen chloride, 1m in diethyl ether (26.5 ml, 26.5 mmol) and the resulting mixture was stirred at 40° C. for 1 h. The reaction was quenched with water, diluted with EtOAc and washed with water. The organic phase was dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-40% EtOAc/hexanes to afford a yellow oil as (R)-2-methyl-N-((S)-1,5,5,5-tetrafluoro-2-(2-fluoro-3-methylphenyl)-4-oxopentan-2-yl)propane-2-sulfinamide (3.80 g, 75% yield). MS m/z=385.9 [M+H]+. Calculated for C16H20F5NO2S: 385.11.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:10][C:9]1[C:4]([CH2:3][NH:2][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCc1nccnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1nccnc1Cl)c1ccc(F)cc1
Reaction time: 24 h

Procedure:
To a suspension of 2-aminomethyl-3-chloropyrazine hydrochloride (900 mg, 5 mmol) in dichloromethane (25 mL) is added 4-fluorobenzoyl chloride (730 μL, 6.1 mmol) followed by DIPEA (2.0 mL, 11 mmol). After 1 day, the mixture is concentrated and diluted with saturated aqueous ammonium chloride and extracted with EtOAc (3×40 mL). The combined organic layers are washed with brine (3×25 mL), dried over magnesium sulfate, filtered and concentrated. The residue is passed through a pad of silica gel using dichloromethane-heptane (1:1) to load the sample and then eluting with dichloromethane to afford N-(3-chloro-pyrazin-2-ylmethyl)-4-fluoro-benzamide as an oil which partially solidified.