Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][C@@H:48]([CH2:62][C:63]1[CH:68]=[C:67]([F:69])[CH:66]=[C:65]([F:70])[CH:64]=1)[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1>C(Cl)Cl>[F:69][C:67]1[CH:68]=[C:63]([CH:64]=[C:65]([F:70])[CH:66]=1)[CH2:62][C@H:48]([NH:47][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]=[CH:1]2)=[CH:6][CH:7]=1)=[O:13])[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1
Reactant: O=C(O)c1ccc2ccncc2c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc3ccncc3c2)c1
Reaction time: 18 h
Yield: 17.8 %

Procedure:
To a stirred solution of isoquinoline-7-carboxylic acid (200 mg, 1.15 mmol) and N,N-diisopropyl ethylamine (1.20 mL, 6.88 mmol) in methylene chloride (14.0 mL) was added HBTU (438 mg, 1.15 mmol) and the reaction stirred for 0.5 h. (2R,3S)-3-Amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (470 mg, 1.15 mmol) was added in one portion and the reaction mixture was stirred under nitrogen for 18 h. The reaction mixture was then diluted with additional methylene chloride and washed with saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 0–5% methanol/methylene chloride) gave N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isoquinoline-7-carboxamide (100 mg) which was characterized as its bis-HCl salt: mp 142–143° C.; ESI MS m/z 490 [M+H]+
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:7](=[S:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24]>COCCO>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:7]([S:10][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[N:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)CCl
Reactant: CCCCc1n[nH]c(=S)n1Cc1ccc([N+](=O)[O-])cc1
Solvent: COCCO
Product: CCCCc1nnc(SCC(=O)OC)n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A stirred solution of 2.00 g (6.84 mmole) of 5-n-butyl-2,4-dihydro-4-(4-nitrobenzyl)-3H-1,2,4-triazole-3-thione in 10 ml of 2-methoxyethanol was treated with 2.38 ml (1.77 g, 13.7 mmole) of N,N-disopropylethylamine followed by 1.20 ml (1.48 g, 13.7 mmole) of methyl chloroacetate. The solution was stirred at room temperature under N2 for 2 hours and then concentrated in vacuo at 45° C. The residual oil was partioned between 70 ml of ethyl acetate and 70 ml of H2O. The organic phase was washed with 70 ml of H2O and then with 50 ml of saturated NaCl solution. The ethyl acetate solution was dried (MgSO4), filtered, concentrated and dried in vacuo to yield 2.50 g (100%) of the titled compound as an oil, homogenous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 365 (M+1 )+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19](Br)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:41][CH2:40][CH2:39][C@@H:38]([NH2:42])[CH2:37]1>C(C(C)=O)C(C)C>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:36]2[CH2:37][C@H:38]([NH2:42])[CH2:39][CH2:40][CH2:41]2)=[N:18][C:17]2[N:16]([CH3:29])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]
Reactant: N[C@@H]1CCCNC1
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 95 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine (11.5 gm) were added to the reaction mixture at 30° C. The reaction mixture was heated to 95° C. and maintained at that temperature for 8 hours. The reaction mixture was cooled to 30° C. and filtered and washed with MIBK (40 mL). The filtrate was charged into another flask and added 10% aqueous acetic acid solution and stirred for one hour at 30° C. The aqueous layer was separated and washed with 60 mL of dichloromethane. The aqueous layer was charged into another flask and 200 mL of dichloromethane and 100 mL of aqueous sodium hydroxide solution (16 gm of sodium hydroxide in 100 mL of water) was added drop-wise at room temperature (pH is 10). The mixture was stirred for one hour 30° C. and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45° C. Ethyl acetate (100 mL) was added to the residue and stirred for 3 hours at 30° C. Filtered the compound and washed with ethyl acetate (40 mL) and dried the compound at below 60° C. under vacuum to give 17.6 gm of Linagliptin. PXRD pattern: FIG. 2, Purity: 98.72%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[OH-].[Na+].CO.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O>[N:29]1([CH2:28][CH2:27][S:20][C:11]2[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: ClCCN1CCCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCC(SCCN1CCCCCC1)=N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7.5 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 30 ml of a 10% aqueous sodium hydroxide solution and 30 ml of methanol is added dropwise under ice cooling with stirring an aqueous solution of 7.0 g of 1-chloro-2-(perhydroazepin-1-yl)ethane hydrochloride over a period of about 10 minutes, and the resulting mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is rinsed with a 5% aqueous sodium hydroxide solution, washed with water and dried. Thereafter the solvent is distilled off to obtain an oily residue of 2-(2-perhydroazepin-1-ylethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with 2.74 g of fumaric acid and recrystallized from isopropyl alcohol to obtain 9.9 g of 2-(2-perhydroazepin-1-ylethylthio)-5-(2-chlorophenyl)-7 -chloro-3H-1,4-benzodiazepine fumarate, m.p. 170°-171° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:32][C:33]1([CH3:41])[O:37][CH:36]([CH2:38][O:39][NH2:40])[CH2:35][O:34]1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([NH:40][O:39][CH2:38][C@H:36]1[CH2:35][O:34][C:33]([CH3:41])([CH3:32])[O:37]1)=[O:7]
Reactant: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Reactant: CC1(C)OCC(CON)O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](CONC(=O)c2cc(Br)ncc2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.7 %

Procedure:
2-bromo-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized as described in General Method 3: to a solution of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (145.0 mg, 0.33 mmol) in DMF (1.5 ml) was added 1,1′-carbonylbis(1H-imidazole) (60 mg, 0.36 mmol). The reaction mixture was stirred at room temperature under argon for 6 hrs. Then, O-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]hydroxylamine (125 mg, 0.83 mmol) was added, and stirred overnight. The reaction mixture was poured into water (10 ml). Extracted with EtOAc (3×15 ml), the combined organic layer was washed with brine (2×15 ml), and dried over MgSO4. The solvent was evaporated, and the residue was purified on silica gel column (Hex:EtOAc=3:1) to obtain 104 mg (55%) of 2-bromo-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-[(2-fluoro-4-iodophenyl)-amino]isonicotinamide. LC/MS: 10.43 min, 566, 568.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH2:10]Cl)=[CH:4][CH:3]=1.[CH3:18][NH:19][CH3:20]>>[CH3:18][N:19]([CH2:10][CH:9]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH3:20]
Reactant: CNC
Reactant: ClCC=C(c1ccc(Br)cc1)c1cccnc1
Product: CN(C)CC=C(c1ccc(Br)cc1)c1cccnc1
Reaction time: 2 h

Procedure:
The brown solution of the chloride from step 3 (from 0.1 moles ketone) in ca 160 ml of solvent was stirred at ca 0° C. and 26 g dimethylamine were added in one portion. This solution was stirred at 0°-5° C. for 2 hours. The solvent was then evaporated. A crude brown oil of the desired end product was obtained.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:37]=[CH:36][C:26]2[C:27]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:28][O:29][C:25]=2[CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:33]4[CH2:32][CH2:31][CH:30]([C:27]5[C:26]6[CH:36]=[CH:37][C:23]([F:22])=[CH:24][C:25]=6[O:29][N:28]=5)[CH2:35][CH2:34]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 6-fluoro-3-piperidine-4-yl-benzo[d]isoxazole (Table No.1, SM 8) in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=506.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[I:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1.Br[C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C>[I:16][C:17]1[CH:21]=[CH:20][N:19]([C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:18]=1
Reactant: Ic1cc[nH]n1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)n1ccc(I)n1
Temperature: 40 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
A stirred solution of NaHMDS in THF (1.0 M, 3.1 mL, 3.1 mmol) was cooled in an ice water bath under Ar. 3-iodo-1H-pyrazole (500 mg, 2.6 mmol) was added as a solution in DMF (1 mL), washing with additional DMF (2×1 mL). tert-butyl 2-bromo-2-methylpropanoate (0.58 mL, 3.1 mmol) was added and the reaction mixture was removed from the cold bath and heated to 40° C. After 16 h, the reaction mixture was cooled and diluted with water and EtOAc. The phases were separated, and the organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-20% EtOAc in hexanes) to afford tert-butyl 2-(3-iodo-1H-pyrazol-1-yl)-2-methylpropanoate 7.03 (649 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.36 (d, J=2.4 Hz, 1H), 6.42 (d, J=2.4 Hz, 1H), 1.79 (s, 6H), 1.38 (s, 9H).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28]([C:30]1[CH:34]=[CH:33][S:32][CH:31]=1)=N>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([C:30]4[CH:34]=[CH:33][S:32][CH:31]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N=C(NO)c1ccsc1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccsc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-thiophene-3-carboxamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.78 min; Mass spectrum (ESI+): m/z=462 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2([CH3:31])[CH2:29][CH2:28][O:27][C:26]2=[O:30])(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:26](=[O:30])[C:25]([S:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)(=[O:24])=[O:23])([CH3:31])[CH2:29][CH2:28][OH:27])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CC1(S(=O)(=O)c2ccc(Cl)cc2)CCOC1=O
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)C(C)(CCO)S(=O)(=O)c2ccc(Cl)cc2)no1
Reaction time: 0.25 h
Yield: 4.5 %

Procedure:
To a solution of 5-tert-butyl-isoxazol-3-ylamine (0.280 g; 2.00 mmol) in methylene chloride (5 mL) was added dropwise trimethylaluminum (1.0 mL of a 2.0 M solution in toluene; 2.00 mmol). The mixture was stirred 15 minutes and 3-(4-chloro-benzenesulfonyl)-3-methyl-dihydrofuran-2-one (0.440 g; 1.60 mmol) added. The mixture was stirred 18 hours and carefully quenched with 10% aqueous citric acid, aqueous sodium tartrate and chloroform. The organic layer was dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was purified by silica gel chromatography using ethyl acetate and hexanes as the eluent. Removal of the volatiles from the product-rich fractions provided 0.030 g of the desired product. 1H NMR (CDCl3) δ 9.4 (bs, 1H), 7.76 (d, 2H), 7.52 (d, 2H), 6.49 (s, 1H), 3.90 (m, 1H), 3.82 (m, 1H), 2.58 (m, 1H), 2.25 (m, 1H), 1.65 (s, 3H), 1.3 (s, 9H). MS (ESI): m/e 415, 417 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]#[CH:13])[CH:5]=1>C(N(CC)C1C=CC=CC=1)C.CCOCC>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:13]=[CH:12][CH2:11][O:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:14]
Reactant: C#CCOc1cccc(C(=O)OC)c1
Solvent: CCN(CC)c1ccccc1
Solvent: CCOCC
Product: COC(=O)c1cccc2c1C=CCO2
Temperature: 25 °C

Procedure:
A solution of 3-prop-2-ynyloxy-benzoic acid methyl ester (10.5 mmol) in N,N-diethylaniline (20 mL) is heated to reflux for 15 h. The mixture is cooled to RT, diluted with ether and washed with aq. HCl (5%) and brine. The solvents are removed in vacuo and the residue is purified by FC (heptane to heptane/EtOAc 95/5) to give the desired chromene derivative. 1H-NMR (CDCl3): δ=3.91 (s, 3H); 4.80 (bs, 2H); 5.93-5.98 (m, 1H); 6.99 (d, J=8.03 Hz, 1H); 7.16 (t, J=7.66 Hz, 1H); 7.34 (d, J=10.3 Hz, 1H); 7.50 (d, J=7.28 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH3:26][NH:27][CH2:28][C:29]1[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:14])[N:27]([CH3:26])[CH2:28][C:29]3[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=3)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Reactant: CNCc1cncn1C
Product: CN(Cc1cncn1C)C(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with methyl-(3-methyl-3H-imidazol-4-ylmethyl)-amine gives “A95”; method 1: HPLC/MS: 1.07 min, [M+H]=442;
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][O:12][CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][O:12][CH2:13][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1ccccc1C(C)=O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A 10 g quantity of 1-(2-hydroxyphenyl)ethanone was dissolved in 100 ml of dimethylformamide, and 11.2 ml of chloromethyl methyl ether and 25.4 g of potassium carbonate were added. The mixture was stirred at 50° C. for 6 hours and then at room temperature for 4 days. After insolubles were removed from the reaction mixture by filtration, ice water was added to the filtrate and extraction with ethyl acetate was performed. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to give 6.26 g of colorless oily 1-(2-methoxymethoxyphenyl)ethanone.
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[C:5]([Br:13])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1COCC1.C([Li])CCC>O>[Br:13][C:5]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:2][S:3][CH:4]=1
Reactant: CCCCCCc1c(Br)sc(Br)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCc1cscc1Br
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
Compound 51 (70 g, 0.173 mol) was mixed with dry THF (400 mL). To this mixture, n-butyllithium (138 mL, 2.5M in hexane, 0.345 mol) was added dropwise at −78° C. under argon. The resulting mixture was stirred for 10 minutes, then water (30 mL) was added to quench the reaction. The THF was evaporated and the organic was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×100 mL), water (70 mL) and dried over MgSO4. After evaporation of the solvent, the resulting crude product was purified by vacuum distillation (72-74° C. at 0.17 mbar) to yield 52 (35.3 g, 82.6% yield). GC/MS: 246 g/mol (M-1). 1H NMR (CD2Cl2): δ 7.22 (s, 1H), 6.96 (s, 1H), 2.57 (t, 2H), 1.61 (m, 2H), 1.32 (m, 6H), 0.88 (t, 3H). 13C NMR: 141.92, 122.87, 120.95, 112.89, 31.88, 30.07, 29.53, 29.20, 22.88, 14.14.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[S:11](=[O:22])(=[O:21])[NH:12][C:13]2[C:18]([C:19]=1[OH:20])=[N:17][CH:16]=[CH:15][N:14]=2.N1C=CC=CC=1.[CH3:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[S:11](=[O:21])(=[O:22])[NH:12][C:13]2[C:18]([C:19]=1[O:20][C:31](=[O:32])[C:30]([CH3:35])([CH3:34])[CH3:29])=[N:17][CH:16]=[CH:15][N:14]=2
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=S1(=O)Nc2nccnc2C(O)=C1c1c(F)ccc(F)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OC1=C(c2c(F)ccc(F)c2Cl)S(=O)(=O)Nc2nccnc21
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a suspension of Compound No. A2 (Example 3.1) in dichloromethane (10 ml) was added pyridine (0.205 ml) followed by 2,2-dimethylpropionyl chloride (0.15 ml). The reaction mixture was heated to 40° C. for 4 hours and then stored at ambient temperature of 16 hours. The reaction mixture was partition between dichloromethane (30 ml) and aqueous hydrochloric acid (2M) (30 ml). The phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were concentrated. The residue was triturated with iso-hexane and dried under vacuum to give Compound No. B3 of Table B (408 mg) as a yellow solid.
Reaction SMILES: [OH:1][C@@H:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][C@@H:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@@H](O)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@@H](O)c1ccc(C(=O)NCCC(=O)OCC)cc1
Reaction time: 1 h
Yield: 100.2 %

Procedure:
N,N-dimethylformamide (16.9 mL) was added to a vial containing (R)-4-(1-hydroxybutyl)benzoic acid (2.6 g, 13.5 mmol), ethyl 3-aminopropanoate hydrochloride (4.16 g, 27.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (10.3 g, 27.1 mmol). Diisopropylethylamine (11.8 mL, 67.7 mmol) was then added. The reaction was stirred for 1 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded (R)-ethyl 3-(4-(1-hydroxybutyl)benzamido)propanoate (3.97 g, 100% yield) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.75 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 6.83 (br. s., 1H), 4.74 (t, J=8.2 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.73 (q, J=5.9 Hz, 2H), 2.64 (t, J=6.4 Hz, 2H), 1.87 (br. s., 1H), 1.84-1.62 (m, 2H), 1.49-1.30 (m, 2H), 1.28 (t, J=7.1 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (M+1): 294.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[I:14]Cl.C([O-])(O)=O.[Na+]>Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:10])([F:11])[F:12])=[CH:4][C:3]=1[I:14]
Reactant: ClI
Reactant: Nc1ccc(C(=O)C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc(C(=O)C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-2,2,2-trifluoroethanone (1.0 g, 5.28 mmol) in 1M aqueous HCl solution (70 mL) was added iodine monochloride (0.77 g, 4.76 mmol). The reaction mixture was stirred at r.t. for 2 h, then basified with the addition of aqueous sat. NaHCO3 solution and extracted with EtOAc (2×100 mL). The combined organic fractions were dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 15-20% EtOAc/hexanes) gave the title compound (0.983 g, 59%) as a cream solid. δH (CDCl3) 8.40 (1H, d, J 1.0 Hz), 7.92-7.85 (1H, m), 6.76 (1H, d, J 8.6 Hz), 4.91 (2H, br. s). LCMS (ES+) RT 2.86 minutes (Method 2).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13](=[O:25])[O:12][N:11]=2)=[N:7][O:8][N:9]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:26][S:27]([O:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=3)[C:13](=[O:25])[O:12][N:11]=2)=[N:7][O:8][N:9]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1onc(-c2nonc2NCCO)n1-c1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.08 h
Yield: 95.1 %

Procedure:
To a solution of 3-{4-[(2-hydroxyethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5(4H)-one (1.0 g, 2.9 mmol) in ethyl acetate (8.5 mL) was added methanesulfonyl chloride (0.29 mL, 3.7 mmol) in one portion. The reaction was stirred for 5 minutes and triethylamine (0.52 mL, 3.7 mmol) was added, also in one portion. After stirring for an additional 10 minutes, the reaction was quenched with the addition of water (5 mL). The product was extracted with ethyl acetate (2×5 mL), dried over sodium sulfate and concentrated in vacuo to give the desired product (1.2 g, 99%). LCMS calculated for C14H13F3N5O6S (M+H)+: m/z=436.0. 1H NMR (400 MHz, DMSO-d6): δ 8.10 (s, 1H), 7.92 (m, 2H), 7.80 (t, J=8.2 Hz, 1H), 6.77 (t, J=5.9 Hz, 1H), 4.36 (t, J=5.5 Hz, 2H), 3.58 (m, 2H), 3.17 (s, 3H).