Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])=[N:14][NH:13][C:12](=[O:23])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])=[N:14][N:13]([C:31]4[N:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[C:12](=[O:23])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: Brc1ncccn1
Reactant: Cn1c2cc(F)ccc2c2c(C(=O)N3CCCC3)n[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c2cc(F)ccc2c2c(C(=O)N3CCCC3)nn(-c3ncccn3)c(=O)c21

Procedure:
A solution of 0.24 g (0.73 mmol) of 1-[[7-fluoro-5-methyl-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]carbonyl]pyrrolidine (obtained in stage 5.1.), of 0.120 g (0.63 mmol) of cuprous iodide, of 0.15 g (1.09 mmol) of potassium carbonate and of 0.30 g (1.89 mmol) of 2-bromopyrimidine in 40 ml of N,N-dimethylformamide is heated at 150° C. for 16 h. The reaction mixture is cooled and concentrated under reduced pressure. Dichloromethane, water and a concentrated sodium hydroxide solution are added. The organic phase is separated by settling, filtered through Celite®, washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: dichloromethane/ethyl acetate: 80/20 to 0/100; ethyl acetate/methanol: 100/0 to 90/10). The solid obtained is recrystallized from a dichloromethane/ethyl acetate mixture and washed with diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C@@H:16]([CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([NH:15][C@@H:16]([CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:18])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](N)C1CCOCC1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C1CCOCC1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
In a 100 mL round-bottomed flask, (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (128 mg, 630 μmol, Eq: 1.5), (S)-ethyl 1-((S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (140 mg, 420 μmol, Eq: 1.00) and HATU (240 mg, 630 μmol, Eq: 1.5) were combined with DMF (2 mL) to give a light yellow solution. Diisopropylethylamine (110 μL, 630 μmol, Eq: 1.5) was added and the reaction was stirred at rt over the weekend. The reaction mixture was partitioned between EtOAc and water and the separated organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 40% EtOAc in hexanes) to give (S)-ethyl 1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (188 mg), m/z=519 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34]5[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=5)[N:33]=[C:29]4[N:28]=[C:27]([CH3:42])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:45][O:46][C:47]([CH3:63])([CH3:62])[C:48]([NH:50][NH:51][C:52](=[O:61])[C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[C:55]([OH:60])[CH:54]=1)=[O:49]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:45]/[O:46][C:47]([C:48](=[O:49])[NH:50][NH:51][C:52](=[O:61])[C:53]2[CH:58]=[CH:57][C:56]([OH:59])=[C:55]([OH:60])[CH:54]=2)([CH3:62])[CH3:63])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34]5[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=5)[N:33]=[C:29]4[N:28]=[C:27]([CH3:42])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(-c3ccc(O)c(O)c3)nc2n1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)NNC(=O)c4ccc(O)c(O)c4)c4csc(N)n4)[C@H]3SC2)n2nc(-c3ccc(O)c(O)c3)nc2n1
Reaction time: 8 h
Yield: 93.9 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(3,4-dihydroxyphenyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (1.3 g) and 0.79 g of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 10 ml of dimethylacetamide. After standing overnight the mixture is evaporated in a vacuum. The residue is digested with 25 ml of water and the precipitate formed is filtered off under suction and dried. There are obtained 1.7 g of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[2-(3,4-dihydroxyphenyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a colourless powder.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.C[O:12][C:13]([CH2:15][CH2:16][C:17]1[C:21]([CH3:22])=[CH:20][NH:19][CH:18]=1)=[O:14]>ClC(Cl)C>[C:13]([CH2:15][CH2:16][C:17]1[C:21]([CH3:22])=[C:20]([CH:3]=[O:4])[NH:19][CH:18]=1)([OH:12])=[O:14]
Reactant: CN(C)C=O
Reactant: COC(=O)CCc1c[nH]cc1C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1c(CCC(=O)O)c[nH]c1C=O
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 90.2 %

Procedure:
Dimethylformamide was charged to a 500 mL, 3 neck round bottom flask equipped with mechanical stirring, a thermometer, and a dropping funnel, and maintained under a nitrogen atmosphere. The flask was cooled to 0° C., and 58.4 mL of phosphorus oxychloride was added dropwise over 80 min. Dichloroethane (280 mL) was added, and the mixture was allowed to warm to room temperature, and then was cooled to −10° C. 3-(2-Methoxycarbonylethyl)-4-methylpyrrole (55.7 g) dissolved in 80 mL of dichloroethane was added dropwise over 1 hr, and the mixture stirred for another 35 min. The mixture was rotary evaporated at <30° C. The fluid residue was poured into 2700 mL of ice-cold 2 N sodium hydroxide solution. The resulting solution was heated to 88° C. over 20 minutes and then was maintained at this temperature for an additional 30 minutes. The solution was cooled to ambient temperature and was extracted with 200 mL of ethyl ether. The aqueous solution was cooled to 0° C. and was acidified to pH 3.5 by slowly adding about 1350 mL of 5 N hydrochloric acid. The yellow precipitate was collected by vacuum filtration, was washed four times with 100 mL of water each time, and was dried in a vacuum oven at ambient temperature to give 54.4 g (90.2% yield) of crude 4-(2-carboxyethyl)-2-formyl-3-methylpyrrole.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.Cl.[NH2:13][OH:14].CC([O-])=O.[Na+]>CCO.O>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:13][OH:14])[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCOc2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCOc2ccccc21
Temperature: 25 °C

Procedure:
To a mixture of 4-chromanone (10.00 g, 67.50 mmol) and hydroxylamine hydrochloride (7.04 g, 101 mmol) in EtOH (100 ml) was added a solution of NaOAc (16.61 g, 202.5 mmol) in H2O (30 mL). The reaction was heated to reflux for 2 h. The mixture was cooled to RT and concentrated in vacuo. The residue was diluted with H2O and acidified with 1N HCl. The aqueous was extracted with EtOAc until tlc analysis showed no evidence of title compound in the aqueous layer. The combined organics were dried with MgSO4 and concentrated in vacuo to furnish the crude title compound which was used without further purification. MS (APCI pos) 164 (M+H).
Reaction SMILES: C(NCC1SC(C2C=C3C(=C(C(N)=O)C=2)NC=C3[CH:22]2[CH2:27][CH2:26][N:25](S(CC)(=O)=O)CC2)=CC=1)C.[CH:33]([C:35]1[S:39][C:38]([B:40]([OH:42])[OH:41])=[CH:37][CH:36]=1)=O.C1(N)CC1.[BH3-]C#N.[Na+]>>[CH:26]1([NH:25][CH2:33][C:35]2[S:39][C:38]([B:40]([OH:42])[OH:41])=[CH:37][CH:36]=2)[CH2:22][CH2:27]1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: OB(O)c1ccc(CNC2CC2)s1

Procedure:
Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), cyclopropylamine (0.022 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 63 mg of crude {5-[(cyclopropylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(cyclopropylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give impure title compound. The impure title compound was purified again with the Agilent MDAP and isolated as the free base according to the procedure shown in Example 5 to give 6.8 mg of the title compound (7.2%).
Reaction SMILES: CN([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)CCCCCCCCCCCO.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1)([O-:25])=[O:24].C(O)(=O)C>O>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([NH:32][N:33]=[CH:19][C:18]2[CH:17]=[CH:16][CH:15]=[CH:22][CH:21]=2)=[CH:30][CH:31]=1)([O-:25])=[O:24]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CN(CCCCCCCCCCCO)c1ccc(C=O)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(NN=Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A mixture of 8.62 g of 4-[N-methyl-N-(11-hydroxyundecyl)-amino]-benzaldehyde, 4.33 g of 4-nitrophenylhydrazine and 25 ml of glacial acetic acid were [sic] refluxed for 30 minutes and left to stand overnight at room temperature. 70 ml of ice water were added to the resulting reaction mixture and the mixture was stirred thoroughly After the water had been removed from the reaction mixture, the reaction product, which had now precipitated, was separated off and then subjected to preliminary purification by boiling with active carbon in acetone. The prepurified product was then purified by flash chromatography on silica gel, a mixture of hexane and ethyl acetate in a volume ratio of 6:4 being used as the mobile phase. A total of 3.4 g of 4'-N-methyl-N-(11-hydroxyundecyl)-amino]-benzaldehyde-4-nitrophenylhydrazone were obtained, corresponding to a yield of 28% of theory. In its IR spectrum, this product, in the form of a KBr pellet, had bands at 3,400, 3,250, 1,585, 1,510, 1,490, 1,460, 1,320, 1,290, 1,270, 1,170, 1,100, 830 and 810 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]N(C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CN(C)C=O
Reactant: Cc1cccc(C)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1c(C)cccc1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of 2,6-dimethylbenzoic acid (20.2 g, 134 mmol) in dichloromethane (200 mL) is added DMF (1 mL) followed by oxalyl chloride (14 mL, 162 mmol). On complete addition, the cold bath is removed and stirring continued for 3 h. The resulting solution is concentrated under vacuum and the residue added slowly to a cooled (0° C.) solution comprising methanol (200 mL) and triethylamine (40 mL). On complete addition the reaction mixture is stirred for 30 min. then poured into hydrochloric acid solution (400 mL, 2N) which is then extracted with ether. The ether extract is washed with hydrochloric acid solution (1N), sokium bicarbonate solution and brine; then dried over MgSO4 and concentrated to give the title compound which is used without further purification. MS (EI) 164 (M)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[C:7]([Cl:13])[N:6]=[CH:5]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:7]1[N:6]=[CH:5][C:4]2[C:9](=[C:10]([F:12])[CH:11]=[C:2]([C:18]3[CH:17]=[C:16]([O:15][CH3:14])[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=3)[CH:3]=2)[N:8]=1
Reactant: Fc1cc(Br)cc2cnc(Cl)nc12
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2cc(F)c3nc(Cl)ncc3c2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
A mixture of 6-bromo-2-chloro-8-fluoroquinazoline (4.0 g, 15.4 mmol), 3,5-dimethoxyphenylboronic acid (4.47 g, 16.9 mmol), cesium carbonate (10.0 g, 30.8 mmol) and Pd(PPh3)2Cl2 (236 mg, 0.77 mmol) in THF (200 mL) and water (10 mL) was degassed with nitrogen three times, and stirred at 80° C. for 3 h. Both TLC and LCMS showed the reaction was completed. The reaction mixture was cooled to RT and directly concentrated. The residue was purified by silica gel chromatography (petroleum ether:dichloromethane=2:1 to 1:1) to afford the title compound (2.5 g, 51%) as a yellow solid. MS (ES+) C16H12ClFN2O2 requires: 318/320. found: 319/321 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][C@@H:7]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3].[Li+].[CH3:23][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[N:1]([CH2:4][C@@H:5]([N:14]([CH3:23])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:6][C@@H:7]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@@H]1CCCCOC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])C[C@@H]1CCCCOC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (S)-1-azido-3-((S)-oxepan-3-yl)propan-2-ylcarbamate (83 mg, 0.28 mmol) in anhydrous THF (5 mL) at −78° C. was added 1.0 M LHMDS solution in THF (1.1 mL, 1.12 mmol), then stirred at this temperature for 30 min. To this mixture was added MeI (237 mg, 104 μL, 1.67 mmol), then the temperature was allowed to warm to 0° C., and stand for 12 h and −20° C. The reaction mixture was quenched with saturated aq. NH4Cl, extracted with EtOAc (30 mL), the separated organic phase was washed with H2O (2×10 mL), brine, and dried over Na2SO4, and filtered. The filtrate was concentrated, the resulting slurry was purified through flash chromatography on silica gel (eluted with gradient system, 0-30% EtOAc in hexane) to afford tert-butyl (S)-1-azido-3-((S)-oxepan-3-yl)propan-2-yl(methyl)carbamate. MS ESI +ve m/z 321 (M+Na).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:37])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C@@H:17]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@H:16]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:38][C:39]1[CH:44]=[C:43]([CH2:45][O:46][CH3:47])[CH:42]=[C:41]([F:48])[C:40]=1[C:49]1[N:54]=[C:53]([C:55](O)=[O:56])[CH:52]=[CH:51][C:50]=1[F:58].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>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:37][C:55]([C:53]3[CH:52]=[CH:51][C:50]([F:58])=[C:49]([C:40]4[C:39]([F:38])=[CH:44][C:43]([CH2:45][O:46][CH3:47])=[CH:42][C:41]=4[F:48])[N:54]=3)=[O:56])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C@@H:17]([O:21][Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:24])[CH3:23])[C@H:16]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COCc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (324 mg, 0.606 mmol), 6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxylic acid (180 mg, 0.606 mmol) and HATU (0.460 g, 1.21 mmol) in DMF (3.0 mL) and DIPEA (0.316 mL, 1.82 mmol) was stirred at room temperature for 2 h. After quenching the reaction with water, the mixture was extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to give an amide intermediate, 4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)-3-[({6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:3]=1[C:21]#[N:22].Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[O:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6]([O:8][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[O:28][C:29]=2[CH3:30])[N:7]=1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCl
Reactant: N#Cc1c(N)[nH]c(=O)c(C#N)c1-c1ccc(OCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(F)cc2)nc1COc1nc(N)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 70 °C
Reaction time: 2 h

Procedure:
250 mg (0.81 mmol) of the compound from Example 102A, 228 mg (1.013 mmol) of 4-(chloromethyl)-2-(4-fluorophenyl)-5-methyl-1,3-oxazole and 224 mg (1.62 mmol) of potassium carbonate are initially charged in 8.6 ml of dry DMF and stirred at 70° C. for 2 h. The solvent is then removed on a rotary evaporator and the residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). The product is then purified once more by HPLC (column: Waters Sunfire C 18 5 nm, 250 mm×20 mm; mobile phase gradient: water/ethanol 55:45→5:95; flow rate: 25 ml/min; temperature: 30° C.; detection: 210 nm).
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]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].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>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([CH2:38][NH:39][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]2)=[O:29])=[CH:40][CH:41]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1ccc(CN)cc1
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)NCc2ccc(C(C)(C)C)cc2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 36.2 %

Procedure:
In a manner similar to the method described in Example 1e, 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, 0.2 mmol) prepared in Example 1d was reacted with 4-tert-butylbenzylamine (48.98 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight 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 4-tert-butyl-benzylamide (41.8 mg, 36.25%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.[CH2:23]=[O:24]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:23][OH:24])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: C=O
Reactant: Cc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2
Solvent: Cc1ccccc1C
Product: OCCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, 8-fluoro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in xylene is heated in an oil bath with repeated additions of portions of paraformaldehyde to give 8-fluoro-1-(2-hydroxyethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)=[O:36]>O1CCCC1>[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:4](=[O:5])[C:3]([OH:7])([C:8]([F:11])([F:10])[F:9])[C:2]([F:13])([F:12])[F:1])=[CH:39][CH:38]=1)=[O:36]
Reactant: Nc1ccc(C(=O)c2ccccn2)cc1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Product: O=C(c1ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)cc1)c1ccccn1
Temperature: 43 °C
Reaction time: 0.25 h
Yield: 18.5 %

Procedure:
Tetrahydrofuran (15ml, dry) was added to a mixture of 2,2-bis-trifluoromethyl-2-hydroxyacetic acid (1.08g, 5.1 mmol) and 1,1'-carbonyldiimidazole (0.83 g, 5.1 mmol) while under a nitrogen atmosphere. There was an immediate evolution of carbon dioxide. The reaction was placed in an ultrasound bath at 23° C. for 15 min. The reaction was treated with 4-(2-pyridylcarbonyl)benzeneamine (1.01 g, 5.1 mmol), and heated to 43° C. in an ultrasound bath for 48 hr. The incomplete reaction was treated with a solid mixture of 2,2-bis-tri-fluoromethyl-2-hydroxyacetic acid (0.22g, 1.04 mmol) and 1,1'-carbonyldiimidazole (0.20 g, 1.2 mmol) and heated to 53° C. in an ultrasound bath for 72 hr. The reaction was evaporated to a gold oil, which was treated with water (100 ml) and extracted with ethyl acetate (2×100 ml). the combined organic portions were dried (MgSO4) and evaporated to a gold oil. Chromatography of this oil on silica gel eluting with methylenechloride/ethyl acetate (first 100:0 and then 85:15) provided a tan solid (0.37 g, 19%); mp 197°-200° C. 1H--NMR (250 MHz, d6 --DMSO): 7.68 (m, 1H, ArH), 8.00 (m, 6H, ArH), 8.74 (d, J=4.33, 1H, ArH), 9.93 (br s, 1H, OH), 10.83 (br s, 1H, NH). MS(CI,CH4): 393 (M+1).