Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(C)(C)C(Cl)=O.[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([Li])CCC>C1COCC1>[C:1]([N:27]1[C@@H:26]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:30][O:29][C:28]1=[O:31])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)/C=C/c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of 222 g (1.5 mol) of trans-cinnamic acid and 250 mL (1.77 mol) of TEA in 3 L of THF at −78° C. was treated with 200 mL of trimethylacetyl chloride maintaining the internal temperature at less than −65° C. The resulting mixture was warmed to 0° C., then cooled to −78° C. In a separate flask, a solution of 4-(S)-benzyl-oxazolidin-2-one in 2.05 L of THF at −20° C. was treated with 660 mL of 2.5 M n-butyllithium in hexanes over 45 min. The resulting turbid mixture was cooled to −78° C. and then transferred via cannula to the flask containing the mixed anhydride. The resulting mixture was allowed to warm to rt and was stirred for 20 h. The reaction was quenched with 300 mL of sat'd NH4Cl; the resulting mixture was partitioned between EtOAc and H2O and the layers were separated. The organic layer was dried over MgSO4. The aqueous layer was extracted with 2×EtOAc; the extracts were dried and all of the organic extracts were combined. Partial concentration in vacuo caused precipitation of a solid; the mixture was diluted with hexanes and allowed to stand at rt for 1.5 h. The precipitate was filtered and dried to afford the title compound: 1H NMR (500 MHz, CDCl3) δ2.86 (dd, J=13.5, 9.5, 1H), (3.38, J=13.5, 3.5, 1H), 4.20-4.27 (m, 2H), 4.78-4.83 (m, 1H), 7.24-7.42 (5H), 7.63-7.65 (m, 1H), 7.92 (app d, J=2.5, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[N:34]=[CH:33][N:32](COCC[Si](C)(C)C)[N:31]=5)=[C:26]([F:43])[CH:25]=4)=[C:17]3[N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C([C@H]2COC(=O)N2C2C=CN3N=CC(C4C=CC(C5N(COCC[Si](C)(C)C)N=CN=5)=C(F)C=4)=C3N=2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[N:34]=[CH:33][NH:32][N:31]=5)=[C:26]([F:43])[CH:25]=4)=[C:17]3[N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccc(F)c(Cl)c5)nc34)cc2F)n1
Agent: C[Si](C)(C)CCOCn1ncnc1-c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)c(Cl)c4)nc23)cc1F
Product: O=C1OC[C@H](c2ccc(F)c(Cl)c2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Yield: 77 %

Procedure:
(S)-4-(3-chloro-4-fluorophenyl)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (19 mg, 77%) was prepared by the procedure described in Example 1, Step 9, using a mixture of (S)-4-(3-chloro-4-fluorophenyl)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one and (S)-4-(3-chloro-4-fluorophenyl)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one. LCMS (APCI+) m/z 495, 497 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(N(CC)CC)C.Cl[Si](C)(C)C.[Cl-].[Mg+2].[Cl-].[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1C(Cl)=O>C1(C)C=CC=CC=1>[CH2:7]([O:6][P:4]([CH2:9][C:10]([C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[F:28])=[O:12])(=[O:5])[O:3][CH2:1][CH3:2])[CH3:8]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(CC(=O)c1ccccc1F)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 2.34 g (11.9 mmol) of diethylphosphonoacetic acid in toluene at 0° C. was added 4.82 g (47.7 mmol) of triethylamine followed by 1.94 g (17.9 mmol) of chlorotrimethylsilane. The mixture was stirred at ambient temperature for 1 hour, then 1.13 g (11.9 mmol) of magnesium chloride was added and the mixture was stirred for a further 1 hour. To the mixture was added 2.0 g (14.3 mmol) of 2-fluorobenzoyl chloride and the mixture was stirred for 72 hours. The mixture was partitioned between 200 ml of water and 250 ml, 100 ml of dichloromethane. The combined organic portions were dried (magnesium sulphate), filtered and evaporated. The residue was purified by column chromatography eluting with 3-5% methanol/dichloromethane to give 2.1 g (64%) of [2-(2-fluorophenyl)-2-oxoethyl]phosphonic acid diethyl ester as a colorless oil; MS: m/e 274.9 [M+H]+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[O:12][C:11]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:10][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[O:12][C:11]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(CN2CCNCC2)o1
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Tert-butyl 4-((5-(tert-butylcarbamoyl)furan-2-yl)methyl)piperazine-1-carboxylate (6.57 mmol, 2.4 g) was dissolved in dichloromethane (20 mL). 2,2,2-Trifluoro-acetic acid (20 mL) was added and the reaction mixture was stirred for 2 hours. The reaction was concentrated under reduced pressure and purified by SCX chromatography to give the title compound (1.51 g). MS (ESI) m/z 266.4 [M+H]+
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C@H:12]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C@H:12]([CH:15]([OH:19])[CH2:16][CH2:17][CH3:18])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
Add sodium borohydride (5.19 g, 145 mmol) portion wise to a solution of (S)-3-butanoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (7.0 g, 29.0 mmol) in methanol (200 mL) and stir at room temperature over night. Add more sodium borohydride (1.4 g, 39 mmol) and stir an hour at room temperature. Evaporate the methanol to half volume, add brine and extract with ethyl acetate. Dry the combine organic phases (MgSO4), filter and concentrate under reduced pressure. Separate the diastereoisomers by silica gel chromatography eluting with 5% isopropylamine in hexanes to provide (3S)-3-(1-hydroxy-butyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, isomer 1 (S-1) as the first eluting isomer (2.6 g, 37%) and (3S)-3-(1-hydroxy-butyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, isomer 2 (S-2) as the second eluting isomer (1.8 g, 26%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:31]2[CH2:36][CH2:35][C:34]([CH3:38])([CH3:37])[CH2:33][CH2:32]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23](OS(C)(=O)=O)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C=O)C.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:31]2[CH2:36][CH2:35][C:34]([CH3:38])([CH3:37])[CH2:33][CH2:32]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([N:39]=[N+:40]=[N-:41])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](N=[N+]=[N-])CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(4,4-dimethyl-cyclohexyl)-3-[(cis-4-methanesulfonyloxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (2.56 g, 4.50 mmol) in 30 ml of DMF was added sodium azide (1.5 g, 23 mmol). The reaction mixture was stirred for 48 h at 50° C. The mixture was diluted with diethyl ether and washed 3 time with water and 1 time with brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane to 100% ethyl acetate followed by 10% MeOH/CH2Cl2) to give 3-[(trans-4-Azido-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4,4-dimethyl-cyclohexyl)-thiophene-2-carboxylic acid methyl ester (1.6 g, 69%).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH:1]([C:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:3])[CH3:2]
Reactant: O=C1CCCCC1
Reactant: CC(C)[Mg]Cl
Product: CC(C)C1(O)CCCCC1
Reaction time: 0.08 h

Procedure:
According to Example 2, i-PrMgCl (3.30 mL; 3.30 mmol; 1.10 equiv) was reacted with cyclohexanone (294 mg; 3.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 9.09 mL, 3.00 mmol, 1.00 equiv), the conversion was complete after 5 min (GC monitoring). After workup and careful evaporation of the solvents under reduced pressure, the desired product was obtained as colorless oil (418 mg, 98%). The analytical data were found to be in accordance with the literature data.
Reaction SMILES: ClC1N=C(N)C=NC=1.CN1CCNCC1.Cl[C:17]1[N:35]=[C:20]2[C:21]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)=[CH:22][CH:23]=[CH:24][N:19]2[N:18]=1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[N:47][CH:46]=[C:45]([NH2:49])[N:44]=2)[CH2:39][CH2:38]1>CN(C)C=O.O>[CH3:36][N:37]1[CH2:38][CH2:39][N:40]([C:43]2[CH:48]=[N:47][CH:46]=[C:45]([NH2:49])[N:44]=2)[CH2:41][CH2:42]1.[CH3:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([C:21]2[C:20]3[N:19]([N:18]=[C:17]([NH:49][C:45]4[N:44]=[C:43]([N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)[CH:48]=[N:47][CH:46]=4)[N:35]=3)[CH:24]=[CH:23][CH:22]=2)=[CH:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Agent: CN1CCN(c2cncc(N)n2)CC1
Agent: CN1CCNCC1
Agent: Nc1cncc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2cncc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)n2)CC1
Temperature: 100 °C

Procedure:
4-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-ylamine was prepared from 6-chloro-pyrazin-2-ylamine (1.00 g, 7.72 mmol) and 1-methylpiperazine (942 L, 8.49 mmol) combined in N,N-dimethylformamide (35 mL) and heated at 100° C. overnight. The reaction was poured into water and extracted with 3 portions of dichloromethane. The combined organic was dried over magnesium sulfate, filtered and evaporated to yield an off-white solid. This solid was purified via chromatography (silica gel 40 g methanol in dichloromethane). Product isolated as a tan oil that solidified upon standing. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 7.33 (s, 1H), 7.16 (s, 1H), 5.93 (s, 2H), 3.40 (s, 4H), 2.36 (s, 4H), 2.20 (s, 3H). 386b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-yl)-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (133 mg, 0.434 mmol) and 4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-ylamine (92.159 mg, 0.47689 mmol) in a manner analogous to Example 2d. Product isolated as an off-white foam (28.64 mg, 14.2%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.07 (s, 1H), 8.91 (d, J=6.6 Hz, 1H), 8.59 (s, 1H), 8.41 (d, J=8.5 Hz, 2H), 8.08 (d, J=8.3 Hz, 2H), 8.00 (d, J=7.6 Hz, 1H), 7.83 (s, 1H), 7.23 (t, J=14.5, 7.4 Hz, 1H), 3.32 (s, 3H), 3.56 (s, 4H), 2.40 (s, 4H), 2.23 (s, 3H). MS=465 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1.[C:10](OCC)(OCC)(OCC)[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.ClCCl>[Br:9][C:4]1[N:3]=[C:2]2[N:1]=[C:10]([CH3:11])[NH:8][C:7]2=[CH:6][CH:5]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1ccc(Br)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nc2nc(Br)ccc2[nH]1
Temperature: 25 °C

Procedure:
2,3-Diamino-6-bromopyridine (8.16 g) and triethyl orthoacetate (12.0 ml) were mixed in acetic acid (41 ml), and the mixture was refluxed under heating for 29 hr. The mixture was allowed to cool and the solvent was evaporated to give a crude product (10 g). This was dissolved in a sufficient amount of dichloromethane. Anhydrous potassium carbonate and active carbon were added and the mixture was stirred at room temperature. The insoluble matter was filtered off and the solvent was evaporated to give the objective compound (7.59 g) as a pale-yellow powder.
Reaction SMILES: BrBr.[OH-:3].[Na+].[Cl:5][C:6]1[C:11]([CH3:12])=[C:10]([F:13])[CH:9]=[CH:8][C:7]=1[C:14](=[O:16])C>O.O1CCOCC1>[Cl:5][C:6]1[C:11]([CH3:12])=[C:10]([F:13])[CH:9]=[CH:8][C:7]=1[C:14]([OH:16])=[O:3]
Reactant: CC(=O)c1ccc(F)c(C)c1Cl
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(F)ccc(C(=O)O)c1Cl
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Bromine (7.61 mL, 148 mmol) was added dropwise to sodium hydroxide (19.70 g, 492 mmol) dissolved in Water (80 mL) maintaining temperature<10° C. 1-(2-chloro-4-fluoro-3-methylphenyl)ethanone (I73) (9.19 g, 49.2 mmol) dissolved in 1,4-dioxane (80 mL) was added dropwise at 0° C. and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with chloroform (2×20 mL) and the aqueous phase acidified to pH1 with concentrated hydrochloric acid. The resulting precipitate was filtered, washed with water, a little diethyl ether (Note: product has some ether solubility) and dried to afford product in 8.89 g. This was recrystalised from toluene to afford product in 6.25 g as fine white needles.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[C:16]1([CH3:19])[CH:17]=[CH:18][C:13]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:3](=[O:4])[CH3:2])=[CH:14][CH:15]=1
Reactant: O=C(CBr)Nc1ccccc1
Reactant: Cc1ccc(N)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(=O)Nc1ccccc1Nc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
An oven-dried resealable schlenk tube containing a stir bar was charged with Pd2(dba)3 (4.6 mg, 0.005 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (19.0 mg, 0.04 mmol), 2-bromoacetanilide (107 mg, 0.5 mmol), p-toluidine (80 mg, 0.75 mmol) and K3PO4 (265 mg, 1.25 mmol). The tube was capped with a rubber septum, evacuated and backfilled with argon. tbutanol (1 mL) was added through the septum via syringe. The septum was replaced with a Teflon screw cap. The schlenk tube was sealed and put into a pre-heated oil bath at 110° C. The reaction mixture was stirred for 18 h, allowed to cool down to room temperature and filtered through celite with ethyl acetate. The filtrate was concentrated under reduced pressure. Chromatography on silica gel column with 1:1 hexane:ethyl acetate gave 107 mg (89%) of the title compound as a brown solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:10][C:11]([C:13]1([Br:16])[CH2:15][CH2:14]1)=[O:12])[C:4]1C=CC=C[CH:5]=1.BrC1(C(Cl)=O)CC1.NC(CC)CO>>[OH:1][CH2:2][C@H:3]([NH:10][C:11]([C:13]1([Br:16])[CH2:15][CH2:14]1)=[O:12])[CH2:4][CH3:5]
Reactant: O=C(N[C@@H](CO)c1ccccc1)C1(Br)CC1
Agent: CCC(N)CO
Agent: O=C(Cl)C1(Br)CC1
Product: CC[C@H](CO)NC(=O)C1(Br)CC1

Procedure:
Analogously to the production of amide 110, 2.18 g of acid chloride 107 is reacted with 962 mg of (−)-2-amino-1-butanol, whereby 2.3 g of (1R)-1-bromocyclopropanecarboxylic acid-2-hydroxy-1-ethylethylamide 114 is obtained as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[NH4+:20]>C(O)C>[OH:1][CH2:2][C:3]1[NH:20][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1
Reactant: COc1ccc(COc2coc(CO)cc2=O)cc1
Reactant: [NH4+]
Solvent: CCO
Product: COc1ccc(COc2c[nH]c(CO)cc2=O)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
2-(Hydroxymethyl)-5-[(4-methoxybenzyl)oxy]-4H-pyran-4-one (1.2 g, 4.56 mmol) was dissolved in ethanol (3.0 mL), added an aqueous solution of ammonium (9.0 mL), sealed, and stirred at 100° C. for 6 hours. This operation was conducted for 4 lots, and the following treatments were conducted as a whole. The reaction solution was concentrated in vacuo. After adding diethylether, the reaction solution was cooled with ice. The deposited solid was filtered, washed with diethylether, and concentrated in vacuo. The title compound (4.0 g (yield 84%)) was obtained as a brown powder crystal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15](=[O:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][C:15](=[O:24])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)CCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-2-one and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:23])[O:13][C:14](=O)[C:15]=2[C:16]2[N:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)=[CH:3]1.C[N:25](C=O)C>N>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:23])[NH:25][C:14](=[O:13])[C:15]=2[C:16]2[N:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)=[CH:3]1
Reactant: Cn1cccc1C1=C(c2cn(C)c3ccccc23)C(=O)OC1=O
Reactant: CN(C)C=O
Agent: N
Product: Cn1cccc1C1=C(c2cn(C)c3ccccc23)C(=O)NC1=O

Procedure:
A solution of 800 mg of 3-(1-methyl-3-indolyl)-4-(1-methyl-2-pyrrolyl)furan-2,5-dione in 6 ml of DMF and 50 ml of 33% aqueous ammonia was heated to 130° C. for 3 hours. The precipitate was filtered off and dried to yield 400 mg of 3-(1-methyl-3-indolyl)-4-(1-methyl-2-pyrrolyl)-1H-pyrrole-2,5-dione, m.p. 248°-250° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([N:12]1[C:17](=[O:18])[C:16]2[S:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[O:29]C)=[CH:24][CH:23]=3)=[CH:21][C:15]=2[N:14]=[CH:13]1)[CH3:11].Cl>CO>[NH2:31][C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:20]2[S:19][C:16]3[C:17](=[O:18])[N:12]([C@H:10]([CH3:11])[C@:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])([OH:38])[CH2:32][N:33]4[CH:37]=[N:36][CH:35]=[N:34]4)[CH:13]=[N:14][C:15]=3[CH:21]=2)=[CH:27][CH:26]=1)=[O:29]
Reactant: COC(=N)c1ccc(-c2cc3ncn([C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)c(=O)c3s2)cc1
Agent: Cl
Solvent: CO
Product: C[C@@H](n1cnc2cc(-c3ccc(C(N)=O)cc3)sc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A solution of (1R,2R)-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-6-[4-imino(methoxy)methyl]phenyl]thieno[3,2-d]pyrimidin-4(3H)-one (0.35 g, 0.652 mmol) (obtained in example 63) and 1N HCl (2 mL) in MeOH (15 mL) was allowed to react at room temperature overnight. The solvent was removed by concentration and the residue was partitioned between CHCl3 and 10% NaHCO3 solution. The organic phase was separated, dried over Na2SO4, filtered, concentrated and purified by flash chromatography to give the title compound as a white solid: mp 280°-285° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.61 (s, 1H, N=CH--N), 7.92 (d, Jt =8.4, 2H, arom), 7.81 (d, Jt =8.4, 2H, arom), 7.78 (s, 1H, triazole), 7.74 (s, 1H, triazole, 7.63 (s, 1H, thiophene), 7.49 (dt, Jd =6.4, Jt =8.8, 1H, arom), 6.9-6.7 (m, 2H, arom), 6.2-5.5 (broad signal, 2H, NH2), 5.98 (dq, Jd =1.6, Jq =7.3, 1H, MeCH), 5.56 (d, J=1.6, 1H, OH), 5.20 (d, J=14.2, 1H, CH(H)), 4.03 (d, J=14.2, 1H, CH(H)), 1.32 (d, J=7.3, 3H, CHMe); MS 299 (N-ethylheterocycle, C15H13N3O2 S), 224 (Tr--CH2COHAr, C10H8F2N3O); [α]D =+63.6° (c 1, MeOH).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:30])[N:7]([CH3:29])[C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C=C(OC)C=CC=3COC2=O)CC1>>[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[C:6](=[O:30])[N:7]([CH3:29])[C:8]2=[O:28])[CH2:19][CH2:18]1
Reactant: Cn1c(=O)c2ccc(F)cc2n(CCN2CCC(NC(=O)OC(C)(C)C)CC2)c1=O
Agent: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c2ccc(F)cc2n(CCN2CCC(N)CC2)c1=O

Procedure:
tert-Butyl {1-[2-(7-fluoro-3-methyl-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 135) (200 mg, 0.476 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[C:17](=[O:19])[CH3:18].N1C=CC=CC=1.O>ClCCl>[CH2:6]([O:5][C:3](=[O:4])[C:2]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[C:17](=[O:19])[CH3:18])=[O:8])[CH3:7]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(=O)c1cc(Br)ccc1N
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)Nc1ccc(Br)cc1C(C)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 85 %

Procedure:
Ethyl chlorooxoacetate (352.7 μL, 3.15 mmol) was added to 1-(2-amino-5-bromophenyl)ethanone (519.8 mg, 2.43 mmol, Example 34c) and pyridine (589.1 μL, 7.28 mmol) in dichloromethane (8 mL) at 0° C. under argon and the reaction was allowed to warm to room temperature and stirred for 17 hours. Water was added, and the solution was extracted with diethyl ether. The organic layer was washed with 10% citric acid, then saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 1:4 ethyl acetate:hexanes to give 648.7 mg (85%) of ethyl[(2-acetyl-4-bromophenyl)amino](oxo)acetate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 12.61 (s, 1H), 8.47 (d, J=9 Hz, 1H), 8.26 (d, J=2 Hz, 1H), 7.88 (dd, J=9, 2 Hz, 1H), 4.31 (q, J=7 Hz, 2H), 2.69 (s, 3H), 1.32 (t, J=7 Hz, 3H). ESI-LCMS m/z 314 (M+H)+.