Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([CH3:35])[C:26]3[C:31]([C:32]=2O)=[CH:30][C:29]([CH3:34])=[CH:28][CH:27]=3)=O)CCCCC1>C1(C)C=CC=CC=1>[CH2:35]([N:25]1[C:26]2[C:31](=[CH:30][C:29]([CH3:34])=[CH:28][CH:27]=2)[C:32]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[O:8])[CH2:2][CH2:3]2)=[C:23]([C:21]#[N:20])[C:24]1=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2C
Reactant: O=C(c1cccs1)N1CCNCC1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2Cc1ccccc1
Temperature: 110 °C
Yield: 154.5 %

Procedure:
Piperazine-1-yl-thiophen-2-yl-methanone (490 mg, 2.5 mmol) was added to a solution of Compound 20 (309 mg, 1 mmol) in toluene (20 mL) and heated overnight at 110° C. The solvent was removed under vacuum. The residue was suspended in water, sonicated, and filtered. The crude product was purified by flash chromatography eluting with 0–2% methanol in dichloromethane gradient to yield 362 mg (77%) of white solids. M.P. 183° C. 1H NMR DMSO-d6): δ 2.36 (s, 3H), 3.69 (m, 4H), 3.94 (m, 4H), 5.47 (s, 2H), 7.16–7.20 (m, 4H), 7.23–7.33 (m, 3H), 7.44 (d, J=8.8 Hz, 1H), 7.50 (d, J=3.8 Hz, 1H), 7.70 (s, 1H), 7.81 (d, J=4.8 Hz, 1H). EIMS m/z 491 (M+23). Anal. (C27H24N4O2S) C, H, N.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[F:11][CH:12]([F:22])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[CH:21])[CH:15]=1.N>>[F:11][CH:12]([F:22])[O:13][C:14]1[CH:15]=[C:16]([C:20]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C#Cc1cccc(OC(F)F)c1
Reactant: ON=C(Cl)c1cncnc1
Agent: N
Product: FC(F)Oc1cccc(-c2cc(-c3cncnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1-(difluoromethoxy)-3-ethynylbenzene (Fluorochemicals, 84 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.33-7.46 (m, 2H), 7.56-7.74 (m, 2H), 7.81 (dt, J=7.9, 1.1 Hz, 1H), 7.87 (s, 1H), 9.33 (s, 2H), 9.35 (s, 1H) ppm; MS (DCI/NH3) m/z 290 (M+H)+.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>CN(C)C=O>[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncc(CBr)c(N)n1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncc(CN2CC=C(c3ccccc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 65 h
Yield: 56.4 %

Procedure:
A solution of 1.0 g (0.0051 mol) of 4-phenyl-1,2,3,6-tetrahydro-pyridine hydrochloride in 40 ml of dimethylformamide was treated with 2.13 ml (0.0153 mol) of triethylamine and 0.62 g (0.00170 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 65 hours. The mixture was completely freed from the solvents. The residue was chromatographed over silica with methanol as the eluent, digested in dichloromethane/water 1:1 and subsequently filtered off under suction. The organic phase was then completely freed from the solvents and the residue was digested in diethyl ether and subsequently filtered off under suction. A total of 0.27 g (56%) of 5-(4-phenyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-pyrimidine-2,4-diamine was obtained as white crystals; m.p. 239°-241°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[BH4-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH:10]=[CH:11][OH:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(C=CC=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cccc(CC=CO)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To 3-cyano-1-(2-formylethenyl)benzene (1 g) in 30 mL of MeOH were added CeCl3 (1.88 g) and the resulting solution was stirred for 30 minutes and cooled to 0° C. To the solution was then added NaBH4 (0.29 g). The resulting solution was stirred for 1 hour at 0° C. and concentrated. The residue was taken up in 100 mL of saturated aqueous NaHCO3 and extracted with ethyl acetate (3×). The organic layer was dried, concentrated and purified on silica gel column (ethyl acetate/hexane, 1:4) to give 0.73 g of 3-cyano-1-(3-hydroxyprop-2-en-1 yl)benzene.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:8]2=[O:19])[CH2:4]1.Br[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=1.C([O-])(=O)C.[Cs+]>CS(C)=O.[Cu]>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:2][C@H:3]2[CH2:6][C@H:5]([N:7]3[C:11]4=[N:12][CH:13]=[CH:14][N:15]=[C:10]4[N:9]([CH:16]4[CH2:17][CH2:18]4)[C:8]3=[O:19])[CH2:4]2)=[N:22][CH:23]=1
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Reactant: Clc1ccc(Br)nc1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CS(C)=O
Product: O=c1n(C2CC2)c2nccnc2n1[C@H]1C[C@H](Nc2ccc(Cl)cn2)C1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a round bottomed flask was added 1-(trans-3-aminocyclobutyl)-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride (Intermediate 79, 0.1128 g, 0.400 mmol), 2-bromo-5-chloropyridine (0.092 g, 0.480 mmol, Matrix Scientific), copper (2.035 mg, 0.032 mmol, Fisher Scientific), and cesium acetate (0.476 g, 2.482 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO (0.500 ml) to stir at 100° C. for 2 days. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 900 over 12 min. Fractions containing product peak were concentrated in vacuo. The product was taken up in DCM and loaded onto a Silicyle Si-carbonate cartridge to remove any salts to give the title compound (5.4 mg, 0.015 mmol, 3.8% yield). LCMS showed product peak at 1.448 min (m+1=356.9). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.03 (m, 2 H) 1.02-1.09 (m, 2 H) 2.26-2.36 (m, 2 H) 2.96 (tt, J=7.09, 3.77 Hz, 1 H) 3.15-3.28 (m, 2 H) 4.42 (d, J=5.67 Hz, 1 H) 5.13 (quin, J=8.26 Hz, 1 H) 6.50 (d, J=9.00 Hz, 1 H) 7.30 (d, J=6.06 Hz, 1 H) 7.47 (dd, J=9.00, 2.54 Hz, 1 H) 7.92-8.03 (m, 3 H)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH:32][CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.[CH3:46][O:47][C:48]1[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=1O>C1COCC1>[CH3:46][O:47][C:48]1[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=1[O:32][CH:33]1[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]1
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 81.6 %

Procedure:
To a mixture of triphenylphosphine (3.10 g, 11.8 mmol) and diethylazodicarboxylate (2.06 g, 11.8 mmol) under N2 in THF (40 mL) was added t-butyl 4-hydroxypiperidine-1-carboxylate (2.00 g, 9.94 mmol). After stirring 10 min, 2-methoxy-4-nitrophenol (1.00 g, 5.91 mmol) was added. The reaction was stirred for 16 h and the solvent was evaporated under reduced pressure to give orange oil. The crude product was purified by column chromatography on silica gel using 25% EtOAc/hexane yielding t-butyl 4-(2-methoxy-4-nitrophenoxy)piperidine-1-carboxylate as a beige solid (1.70 g, 82%). LC/MS (m/z): 353.2 (MH+), Rt 3.23 minutes
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:19][CH:18]=1>>[CH:13]1([CH2:12][CH2:11][NH:10][C:8]([C:5]2[N:6]=[N:7][C:2]([N:25]3[CH2:24][CH2:23][CH:22]([O:21][C:20]4[CH:28]=[CH:29][C:17]([F:16])=[CH:18][CH:19]=4)[CH2:27][CH2:26]3)=[CH:3][CH:4]=2)=[O:9])[CH2:15][CH2:14]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: Fc1ccc(OC2CCNCC2)cc1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(Oc3ccc(F)cc3)CC2)nn1

Procedure:
The title compound was prepared in the same manner as described for Example 1, step 3 from 6-chloro-N-(2-cyclopropylethyl)pyridazine-3-carboxamide and 4-(4-fluorophenoxy)piperidine. 1H NMR (500 MHz, acetone-d6): δ 0.11-0.13 (m, 2H), 0.45-0.49 (m, 2H), 0.76-0.84 (m, 1H), 1.56 (q, 2H), 1.78-1.85 (m, 2H), 2.08-2.16 (m, 2H), 3.54 (q, 2H), 3.70-3.76 (m, 2H), 4.16-4.22 (m, 2H), 4.69-4.75 (m, 1H), 7.05-7.11 (m, 4H), 7.34 (d, 1H), 7.91 (d, 1H), 8.24 (s, 1H); MS (+ESI) m/z 385 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[C:16]([Si:13]([CH3:15])([CH3:14])[O:12][CH2:11][CH2:10][N:6]1[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]1=[O:8])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=c1ccc(I)c[nH]1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Product: CC(C)(C)[Si](C)(C)OCCn1cc(I)ccc1=O

Procedure:
The title compounds were prepared as white solids from the alkylation of 5-iodo-1H-pyridin-2-one with BrCH2CH2OTBS (Aldrich) using the procedure described in Step A of Example 38.
Reaction SMILES: C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)CO)(C)(C)C.C([O:34][CH2:35][C@@H:36]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:37]1[C:38]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[CH:42][CH:41]=[CH:40]2)(=O)C(C)(C)C>>[C:56]([O:55][C@@H:36]([C:37]1[C:38]([C:48]2[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[CH:42][CH:41]=[CH:40]2)[CH2:35][OH:34])([CH3:59])([CH3:57])[CH3:58]
Reactant: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(Cl)cc2n1
Product: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C

Procedure:
Compound 3K was prepared following the procedure used to prepare compound 1K of example 1, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)ethyl pivalate (3J) was used instead of compound 1J. LCMS-ESI+ (m/z): 370.2, 372.2 (M+H)+.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].OP([O-])(O)=O.[K+].CC1[N+:31](CC2C=NC(C)=NC=2N)=CSC=1CCO.Cl.[Cl-].[OH:46][C:47]([CH2:49][CH2:50][CH2:51][CH2:52][C@H:53]1[C@@H:61]2[C@@H:56]([NH:57][C:58]([NH:60]2)=[O:59])[CH2:55][S:54]1)=[O:48].[OH-].[K+].[C:64](=[O:67])([O-:66])[O-].[Ca+2]>[O-]S([O-])(=O)=O.[Mn+2]>[NH2:31][C@H:49]([C:47]([OH:46])=[O:48])[CH2:50][CH2:51][C:64]([OH:66])=[O:67].[OH:48][C:47]([CH2:49][CH2:50][CH2:51][CH2:52][C@H:53]1[C@@H:61]2[C@@H:56]([NH:57][C:58]([NH:60]2)=[O:59])[CH2:55][S:54]1)=[O:46]
Reactant: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Reactant: O=C([O-])[O-]
Agent: [Mn+2]
Agent: Cl
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Product: N[C@@H](CCC(=O)O)C(=O)O
Temperature: 31.5 °C

Procedure:
The single cross-over recombinant thus obtained was named 2A-1 strain. The wild-type 13869 strain and 2A-1 strain were inoculated in 20 ml of a flask medium (30 g/l glucose, 15 g/l ammonium sulfate, 1 g/l KH2PO4, 0.4 g/l MgSO4.7H2O, 0.01 g/l FeSO4.7H2O, 0.01 g/l MnSO4.4-5H2O, 200 μg/l VB1 (vitamin B1), 300 μg/l Biotin, and 0.48 g/l soybean hydrolysates (T-N: total nitrogen), adjusted to pH 8.0 with KOH: autoclaved at 115° C. for 10 minutes), followed by addition of 1 g of heat-sterilized calcium carbonate, and each of the strains was cultured with shaking at 31.5° C. After the sugar was completely consumed, the concentration of L-glutamic acid which had accumulated in the medium was determined. The results are shown in Table 1 (OD620 is turbidity at 620 nm of culture solution diluted to 101 times, and indicates the cell amount, and Glu (g/L) indicates the amount of accumulated L-glutamic acid). It was found that the 2A-1 strain produced L-glutamic acid in the presence of an excess amount of biotin, whereas the parent strain ATTCC 13869 did not produce L-glutamic acid at all.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:11][CH2:10][CH2:9]2
Reactant: O=Cc1ccccc1
Reactant: COc1cccc(CCN)c1
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCNC2c1ccccc1
Temperature: 60 °C

Procedure:
3-Methoxyphenylethylamine (1.5 g) and benzaldehyde (1.0 mL) were reacted together in benzene (10 mL) in a modified Dean-Stark apparatus, where the side arm contained activated 3 Å molecular sieve beads. The reaction was vigorously refluxed for 1 h until a uniform solution resulted. The reaction was cooled and evaporated. The resulting residue was taken up in trifluoroacetic acid (6 mL) and heated to 60° C. for 18 h. The reaction was cooled, concentrated then partitioned between 1N sodium hydroxide (70 mL) and diethyl ether (50 mL). The organic layer was washed with 0.5 N sodium hydroxide (70 mL), dried, concentrated to 20 mL and cooled in an ice-water bath. The crystals that formed were collected and dried to give the title compound (1.90 g). MS: 240.0 (MH+); HPLC tR: 1.62 min (method D); 1H NMR (DMSO-d6+TFA-d): 7.47-7.49 (m, 3H), 7.37-7.39 (m, 2H), 6.90 (broad s, 1H), 6.79 (dd, 1H, J=2.4, 8.7 Hz), 6.66 (d, 1H, J=8.7 Hz), 5.75 (s, 1H), 3.77 (s, 3H), 3.39-3.44 (m, 2H), 3.17-3.28 (m, 1H), 3.04-3.12 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[CH3:22][S:23]([C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:28][CH:27]=1)(=[O:25])=[O:24]>>[CH3:22][S:23]([C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][N:34]([C:10]([C:9]3[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:33][CH2:32]2)=[N:28][CH:27]=1)(=[O:24])=[O:25]
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: CS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(C)(=O)=O)s2)CC1)C(F)(F)F
Yield: 29 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 29%). MS (m/e): 542.2 (M+H+, 100%), 559.2 (M+NH4+, 65%).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:14]=[N:13][C:12]([C:15]([NH2:17])=[O:16])=[N:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(O[C:22](=[O:24])[CH3:23])(=O)C>N1C=CC=CC=1>[C:2]([O:3][C@@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:8][O:9][C:22](=[O:24])[CH3:23])[O:7][C@H:1]1[N:10]1[CH:14]=[N:13][C:12]([C:15]([NH2:17])=[O:16])=[N:11]1)(=[O:3])[CH3:1]
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(N)=O)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
A solution of 1-(β -D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (488 mg., 2.00 mmol) in pyridine (10.0 ml.) containing acetic anhydride (1.0 ml.) was added and the solution was stirred at room temperature for 2 hrs. The solvent was removed and water was added to the residue. The mixture was extracted with methylene chloride (three 20-ml. portions) and the organic layer was extracted with aqueous sodium hydrogen carbonate and water. The organic phase was dried over magnesium sulfate, filtered, and evaporated to a syrup which was applied to a silica gel column. Elution with chloroform-methanol (19:1) provided the pure product as an amorphous solid (560 mg., 75.6%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:25])[N:3]=1.[CH3:26][C:27]1[C:31]([CH3:32])=[C:30]([NH2:33])[O:29][N:28]=1>>[CH3:26][C:27]1[C:31]([CH3:32])=[C:30]([NH:33][C:2]2[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=3)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:25])[N:3]=2)[O:29][N:28]=1
Reactant: Cc1noc(N)c1C
Reactant: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)nc(Cl)n1
Product: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)nc(Nc2onc(C)c2C)n1

Procedure:
The title compound is prepared from 2-chloro-6-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.05 mmol, Step-1, single enantiomer) and 3,4-dimethylisoxazol-5-amine (12 mg, 0.1 mmol) according to the procedure similar to that described in Step-4 of Example 445.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:40])([CH3:39])[CH:37]=[CH2:38])[NH:13]2)=[O:11])[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][NH:9][C:10]([CH:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:40])[CH:37]=[CH2:38])[NH:13]1)=[O:11]
Reactant: C=CC(C)(C)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 95.7 %

Procedure:
In a manner similar to the method described in Example 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 80d (0.36 g, 0.59 mmol) was reacted with aqueous HCl solution (1 N, 1 mL) in tetrahydrofuran (10 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.32 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[N:13][CH:12]=1)=[O:10].[C:35]1([Mg]Br)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:11]1[N:15]([C:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[N:13][CH:12]=1)[OH:10]
Reactant: Cc1cccc(C(=O)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Reactant: Br[Mg]c1ccccc1
Solvent: ClCCl
Product: Cc1cccc(C(O)(c2ccccc2)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2,3-dimethylphenyl)(1-trityl-1H-imidazol-5-yl)methanone, (Intermediate 3) (1.2 g, 2.7 mmol) in dichloromethane (30 mL) was treated with phenyl-magnesium bromide (1.35 mL, 4.05 mmol, 3 M in THF) 0° C. and then stirred for 16 h at rt. The mixture was quenched with water (10 mL) and a saturated solution of ammonium chloride (10 mL). The residue was isolated in a typical aqueous workup to give (2,3-dimethylphenyl)(phenyl)(1-trityl-1H-imidazol-5-yl)methanol, (Intermediate 4), (crude).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[CH2:14][C:15]([O:17]C)=O)([O-])=O>[Pd]>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:9]=[C:4]2[C:5]([CH2:14][C:15](=[O:17])[NH:1]2)=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: O=C1Cc2ccc(C(F)(F)F)cc2N1
Temperature: 100 °C

Procedure:
Methyl 2-nitro-4-trifluoromethylphenylacetate (26 mg) was hydrogenated over 10% palladium on carbon and then heated at 100° C. for 3 hours. The catalyst was removed by filtration and the solvent evaporated to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1.[C:16]([O-:19])(=[O:18])[CH3:17].[Na+]>C(N(CC)CC)C.C(O)(=O)C>[C:16]([O:19][CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: NS(=O)(=O)c1cc2cc(CBr)ccc2s1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)OCc1ccc2sc(S(N)(=O)=O)cc2c1
Yield: 87.6 %

Procedure:
To a mixture of 5-bromomethyl-2-sulfamoylbenzo[b]thiophene (3.06, 0.01 mol), anhydrous sodium acetate (0.98 g, 0.01 mol) and glacial acetic acid (15 ml) was added three drops of triethylamine. The mixture was heated and the resulting solution was stirred at reflux for 6 hours and was left at room temperature over night. The acetic acid was removed in vacuo and the residual gum was diluted with 25 ml of ice water. The product was extracted into 3×50 ml of ether. The combined extracts were washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 2.5 g of yellow solid (88% yield). Recrystallization from chloroform gave material with a m.p. 113°-115° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][NH2:11].C([O:14][C:15]([C:17]1[C:18](=[O:45])[C:19]2[CH:24]=[N:23][C:22]([NH:25][CH2:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)=[N:21][C:20]=2[N:34]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)CCC3)[CH:35]=1)=O)C>CO.O>[CH3:9][O:10][NH:11][C:15]([C:17]1[C:18](=[O:45])[C:19]2[CH:24]=[N:23][C:22]([NH:25][CH2:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)=[N:21][C:20]=2[N:34]([CH:36]2[CH2:44][CH2:43][CH2:42][CH2:38][CH2:37]2)[CH:35]=1)=[O:14]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCn3ccnc3)ncc2c1=O
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CONC(=O)c1cn(C2CCCCC2)c2nc(NCCCn3ccnc3)ncc2c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triethylamine (0.5 mL) was added to a mixture of O-methylhydroxylamine hydrochloride (220 mg) and 2-(3-Imidazol-1-yl-propylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 28 Step F, 6.0 mg, 0.013 mmol) in 0.5 mL of methanol. The reaction mixture was kept in a sealed tube at 110° C. for 2 days with stirring. After cooling to room temperature, the solution was diluted with water and extracted with dichloromethane. The crude product, after concentration, was loaded to HPLC for purification (32 mL/min 5-100% MeCN/H2O gradient over 10 min). 2-(3-Imidazol-1-yl-propylamino)-8-cyclohexyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methoxy-amide was obtained as a white solid (4.3 mg, 70%). 1H NMR (400 MHz, CDCl3) δ (ppm): 12.02 (br, 1H), 9.26 (s, 1H), 8.75 (s, 1H), 7.32 (br, 1H), 7.10 (s, 1H), 6.95 (br, 1H), 5.82 (br, 1H), 5.06 (m, 1H), 4.10 (t, J=6.7 Hz, 2H), 3.88 (s, 3H), 3.51 (m, 2H), 2.20-1.20 (m, 12H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C21H27N7O3: 426.22 (M+H). Found: 426.2.