Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH3:3].Cl[C:28]1[C:33]([C:34]#[N:35])=[C:32]([CH2:36][CH3:37])[N:31]=[C:30]([S:38][CH3:39])[N:29]=1.CCN(CC)CC>C1COCC1.CCOC(C)=O>[C:34]([C:33]1[C:28]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH3:3])=[N:29][C:30]([S:38][CH3:39])=[N:31][C:32]=1[CH2:36][CH3:37])#[N:35]
Reactant: CCc1nc(SC)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1nc(SC)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a 20 mL vial were added (S)-tert-butyl 4-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)piperazine-1-carboxylate (63 mg, 0.175 mmol) in THF (5 mL), 4-chloro-6-ethyl-2-(methylthio)pyrimidine-5-carbonitrile (37.5 mg, 0.175 mmol) and Et3N (0.027 mL, 0.193 mmol). The resulting yellow solution was heated to 60° C. and stirred overnight. The next day LCMS indicated the reaction was mostly complete. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (ISCO 12 g, 30-100% EtOAc/hexane gradient) to give the title compound as a yellow solid. ESI-MS m/z [M+H]+ calc'd for C27H36N8O2S, 537. found 537.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)#[N:2].[F:12][C:13]([F:18])([F:17])[C:14]([O-:16])=[O:15].[H][H]>CO.[Ni]>[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].[NH2:2][CH2:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: O=C([O-])C(F)(F)F
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: [Ni]
Solvent: CO
Product: NCc1ccc(C(=O)O)cn1
Product: O=C(O)C(F)(F)F

Procedure:
6-Cyanonicotinic acid as the trifluoroacetate (1 g) was dissolved in methanol (300 ml), treated with Raney nickel (0.224 g) and hydrogenated in a shaker autoclave at 80° C. for 20 h under 10 bar hydrogen pressure. Subsequently, the mixture was filtered, the residue was washed with a water/methanol mixture and the filtrate was concentrated. The residue was taken up with ACN/water and freeze-dried. 500 mg of product were obtained, which were sufficiently clean for use in the next stage.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[OH:42]>>[OH:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1O
Product: CON=C1C[C@@H](C(=O)Nc2ccccc2O)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2-aminophenol, the title compound was obtained in 88% purity by HPLC. MS(ESI+): m/z=444.
Reaction SMILES: [CH2:1]([CH:4]1[O:8][CH2:7][CH2:6][O:5]1)[CH2:2][CH3:3].[C:9]1([CH:16]=[CH:15][C:13]([OH:14])=CC=1)O.P(=O)(O)(O)O.C(O)CCC>[Pd].C(O)CO>[CH2:4]([O:5][CH2:6][CH2:7][OH:8])[CH2:1][CH2:2][CH3:3].[CH2:4]([O:5][CH2:6][CH2:7][O:14][CH2:13][CH2:15][CH2:16][CH3:9])[CH2:1][CH2:2][CH3:3]
Reactant: Oc1ccc(O)cc1
Reactant: CCCC1OCCO1
Agent: [Pd]
Agent: O=P(O)(O)O
Solvent: CCCCO
Solvent: OCCO
Product: CCCCOCCO
Product: CCCCOCCOCCCC
Reaction time: 3 h

Procedure:
The mixture consisting of 50 g (0.431 moles) of 2-propyl-1,3-dioxolane and 250 g of ethylene glycol is hydrogenolyzed in a mechanically agitated autoclave of 1-liter capacity, in the presence of 9 mg of hydroquinone, 5 g of palladium catalyst deposited on carbon at a rate of 5% of palladium by weight and of 210 mg of concentrated phosphoric acid. After 3 hours at a temperature of 170° C. under a hydrogen pressure kept constant at 30 bars, the degree of conversion of the 2-propyl dioxolane reaches 98.2%; 46.1 g (0.390 moles) of 2-butoxy-1-ethanol are produced besides 2.35 g (0.0135 moles) of 1,2-dibutoxy ethane and 0.31 g (0.004 moles) of normal butanol.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:3]([OH:20])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1cccc([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.2 %

Procedure:
A solution of 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid methyl ester (0.55 g, 2.0 mmol) in tetrahydrofuran/water (12 mL, 3:1) was treated with lithium hydroxide (185 mg, 4.40 mmol). The reaction was stirred at 25° C. for 48 h. The tetrahydrofuran was then removed in vacuo. The residue was diluted with water (25 mL) and extracted with ether (1×20 mL). The aqueous layer was acidified to pH=2 with a 3N aqueous hydrochloric acid solution. The solution was extracted with methylene chloride (3×25 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (2×25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid (0.48 g, 91.9%) as a tan solid: mp 95-99° C.; EI-HRMS m/e calcd for C14H17NO4 (M+) 263.1157, found 263.1156.
Reaction SMILES: [C:1]([O:4][C:5]1[N:6]=[C:7]([CH3:22])[C:8]2[C:13]([C:14]=1[N+:15]([O-:17])=[O:16])=[CH:12][C:11]([O:18][CH3:19])=[C:10]([O:20][CH3:21])[CH:9]=2)(=[O:3])[CH3:2].[Br:23]N1C(=O)CCC1=O.C(Cl)Cl.CCCCCC>C(Cl)Cl>[OH2:3].[C:1]([O:4][C:5]1[N:6]=[C:7]([CH2:22][Br:23])[C:8]2[C:13]([C:14]=1[N+:15]([O-:17])=[O:16])=[CH:12][C:11]([O:18][CH3:19])=[C:10]([O:20][CH3:21])[CH:9]=2)(=[O:3])[CH3:2].[C:1]([O:4][C:5]1[N:6]=[C:7]([CH2:22][Br:23])[C:8]2[C:13]([C:14]=1[N+:15]([O-:17])=[O:16])=[CH:12][C:11]([O:18][CH3:19])=[C:10]([O:20][CH3:21])[CH:9]=2)(=[O:3])[CH3:2]
Reactant: COc1cc2c(C)nc(OC(C)=O)c([N+](=O)[O-])c2cc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cc2c(CBr)nc(OC(C)=O)c([N+](=O)[O-])c2cc1OC
Product: O
Yield: 62.1 %

Procedure:
A mixture of 3-acetoxy-6,7-dimethoxy-1-methyl-4-nitroisoquinoline (4.0 g, 13.06 mmol) in methylene chloride (100 mL) and N-bromosuccinimide (2.8 g, 15.66 mmol) was heated to reflux under nitrogen for 17 hours. The mixture was evaporated to dryness. The residue was redissolved in methylene chloride (60 mL) and the major product was isolated by chromatography on a silica gel column (low pressure) using 7:3 methylene chloride/hexane as the eluent to yield the title compound (2.13 g, 39%). One recrystallization from methylene chloride/ether gave the purified title compound as a lemon yellow crystalline solid (2.08 g, 38.7%), mp 194°-195° C. (d). IR (KBr) 1777, 1174 cm-1 ; NMR (CDCl3): δ 2.40 (s, 3H, OCOCH3), 4.05 (s, 3H, OCH3), 4.10 (s, 3H, OCH3), 4.90 (s, 2H, 1-CH2Br), 7.30 (s, 1 H, B 5- or 8-H), 7.43 (s, 1H, 5- or 8-H); MS (DCI): 385 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[F:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([F:46])=[C:24]([NH:23][C:8]([C:6]5[N:5]([CH3:11])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=5)=[O:10])[CH:25]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Reactant: CCc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2F)n(C)n1
Yield: 81.2 %

Procedure:
In the same manner as in Example 18-4 and using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (188 mg, 1.22 mmol), tetrahydrofuran (7 mL), oxalyl chloride (160 μL, 1.83 mmol), N-[6-(3-amino-4-fluorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.611 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (230 mg, 81%) was obtained as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][N:6]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]([CH2:9][C@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:7]1.[CH3:21]O>>[ClH:3].[CH3:21][O:13][C:12](=[O:14])[C@@H:10]([CH2:9][C:8]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]([CH3:5])[CH:7]=1)[NH2:11]
Reactant: CO
Reactant: Cn1cc(C[C@@H](N)C(=O)O)c2ccccc21
Reactant: O=S(Cl)Cl
Product: COC(=O)[C@H](N)Cc1cn(C)c2ccccc12
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Thionyl chloride (1.3 mL, 18.4 mmol) was added dropwise to a suspension of 1-methyl-D-tryptophan (2.0 g, 9.2 mmol) in MeOH (30 mL) at 0° C. under a nitrogen blanket. The resulting mixture was warmed slowly to room temperature and stirred for a total of 20 hours. The solvent was removed under reduced pressure and triturated with Et2O (20 mL). The solids were collected by vacuum filtration, then dried in a vacuum oven at 60° C. for 3 days to provide Intermediate 1 as an off-white powder, which was used without further purification (2.4 g, 96%): TLC Rf (1:2 EtOAc/CHCl3)=0.22.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cncc(-c2ccccc2OC)c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of ethyl 5-bromonicotinate (2.29 g, 10 mmol), prepared as reported in the Journal of Medicinal Chemistry 1995, 38, 1608-28, 2-methoxy phenyl boronic acid (1.22 g, 10 mmol), Pd(PPh3)4 (5% mol), K2CO3 (5 g) in DMF/water (3/1) is stirred at 50° C. for 12 hours. The reaction mixture is then pored on water (150 mL). The aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water (3×200 mL). The organic phase is dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]3[NH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:14]=23)=[CH:8][CH:7]=1>[Ni].CO.C(O)C>[C:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]3[NH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:14]=23)=[CH:10][CH:11]=1)#[N:2].[NH3:2].[ClH:1]
Reactant: NCCCc1ccc(Nc2ncnc3[nH]nc(Nc4ccccc4)c23)cc1
Agent: [Ni]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: N
Product: N#CCCc1ccc(Nc2ncnc3[nH]nc(Nc4ccccc4)c23)cc1

Procedure:
There is obtained from 4-(4-[2-cyano-ethyl]-phenylamino)-3-phenylamino-1H-pyrazolo[3,4-d]pyrimidine (see Example 7), by reduction with Raney nickel in a solution of ammonia in methanol and subsequent treatment with hydrogen chloride in ethanol, 4-(4-[3-amino-propyl]-phenylamino)-3-phenylamino-1H-pyrazolo[3,4-d]pyrimidine hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:29])=O>>[N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]([Cl:29])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Cl

Procedure:
An amount of 550 g of 2-(p-nitrophenoxy)-myristic acid is heated together with 550 ml of thionyl chloride for 1 h to 60° C. so that a solution is obtained. The excess thionyl chloride is filtered off. Yield: 585 g (100%) of 2-(p-nitrophenoxyl]-myristoyl chloride (oil).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)[C:15](=[O:32])[CH2:14]1.O.NN>CCO>[NH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:14][C:15]1=[O:32]
Reactant: COc1ccc2nccc(N3CCN(CCN4C(=O)c5ccccc5C4=O)C(=O)C3)c2n1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc2nccc(N3CCN(CCN)C(=O)C3)c2n1
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 2-(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-oxo-1-piperazinyl}ethyl)-1H-isoindole-1,3(2H)-dione (100 mg, 0.232 mmol) in EtOH (2 mL) was added hydrazine hydrate (120 μL, 3.85 mmol). After 2 h at 85° C., the solution was concentrated and the residue purified by column chromatography (silica, 5-10% MeOH in DCM (1% NH4OH)) yielding the title compound (46 mg, 66%) as a yellow oil: LCMS (ES) m/e 302 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:7][CH2:6][NH:5][CH:4]([CH2:8][N:9]2[C:17](=O)C3C(=CC=CC=3)C2=O)[CH2:3]1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([C:31]2[N:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[C:26]([CH:30]=1)[C:27]([OH:29])=O.ClC1[N:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=1>>[F:20][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:27]([C:26]2[CH:30]=[C:22]([CH3:21])[CH:23]=[CH:24][C:25]=2[C:31]2[N:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[O:29])[C@H:4]([CH2:8][NH:9][C:17]2[N:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=2)[CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CC(F)(F)CCN1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)O)c1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC(F)(F)C[C@H]2CNc2ncc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A210 using 2-((4,4-difluoropiperidin-2-yl)methyl)isoindoline-1,3-dione and 5-methyl-2-(pyrimidin-2-yl)benzoic acid and Example A45 using 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 493 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]=[CH:7][C:8]=1[N:9]([CH3:28])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1
Reactant: CI
Reactant: CCOC(=O)CCc1ccc(Nc2ccc([N+](=O)[O-])cn2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(N(C)c2ccc([N+](=O)[O-])cn2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-[3-methoxy-4-(5-nitropyridin-2-ylamino)phenyl]propionate (3.70 g, 11 mmol) in DMF (60 mL) were added under ice-cooling sodium hydride (60%, 490 mg, 12 mmol) and methyl iodide (0.77 mL, 12 mmol), and the resulting reaction solution was stirred for 2 hours gradually warming up to room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, washed with water and brine, and then dried with anhydrous magnesium sulfate. The solvent was evaporated, to thereby yield 4.27 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[C:4]([OH:17])[C:3]=1[CH:18]1[CH:23]2[CH2:24][CH:21]([C:22]2([CH3:26])[CH3:25])[C:20]([C:27]([OH:29])=[O:28])=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][C:38](=[O:40])[CH3:39].[I-].[CH3:42][C:43]([CH3:45])=[O:44]>>[C:38]([CH2:39][O:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:15])([CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[C:4]([O:17][CH2:42][C:43](=[O:44])[CH3:45])[C:3]=1[CH:18]1[CH:23]2[CH2:24][CH:21]([C:22]2([CH3:26])[CH3:25])[C:20]([C:27]([OH:29])=[O:28])=[CH:19]1)(=[O:40])[CH3:37]
Reactant: CCCCCCC(C)(C)c1cc(O)c(C2C=C(C(=O)O)C3CC2C3(C)C)c(O)c1
Reactant: CC(=O)CCl
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCCCCC(C)(C)c1cc(OCC(C)=O)c(C2C=C(C(=O)O)C3CC2C3(C)C)c(OCC(C)=O)c1
Reaction time: 3 h
Yield: 67 %

Procedure:
To a suspension of compound XII (0.109 g, 0.25 mmol) and potassium carbonate (0.138 g, 1 mmol) in anhydrous acetone (4 mL) was added chloroacetone (60 microliters, 0.75 mmol). The reaction mixture was stirred at reflux and a catalytic amount of potasssium iodide was added. After 3 hours, the solids were removed by filtration and washed with dichloromethane. The dichloromethane solvent was combined with the acetone filtrate and the combined solvents removed by evaporation. The resulting residue was purified on a reverse phase C-18 column using 70% acetonitrile (30% water, 0.1% acetic acid) to afford 86 mg of pure (XIII) (67% yield).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][C:8]([OH:10])=[O:9].[CH3:17]O>>[NH2:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][C:8]([O:10][CH3:17])=[O:9]
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1ccccc1

Procedure:
Thionyl chloride (19.1 g, 162 mmol) was added dropwise to a solution, cooled to 0° C., of 3-amino-3-phenylpropionic acid (8.9 g, 54 mmol) in methanol (150 ml). The reaction mixture was then heated under reflux for 12 h (TLC control). The solvent was removed completely and the residue was dried in vacuo. The crude product was employed in the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH2:10][C:11](O)([CH2:13][O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=3)[CH:10]=[C:11]([CH2:13][O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(COCc3ccc4ccccc4n3)N=C2c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(COCc3ccc4ccccc4n3)nc2-c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-[(2-quinolylmethoxy)methyl]-4,5-dihydro-1H-imidazole (1 mmol) and p-toluenesulfonic acid monohydrate (100 mg) in toluene (70 mL) is heated to reflux for 48 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is chromatographed on silica gel using hexane/ethyl acetate to give 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[(2-quinolylmethoxy)methyl]-1H-imidazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](O)=[O:15])=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[C:3]=1[F:19].C(Cl)(=O)C(Cl)=O.[CH3:26][N:27](C=O)C.Cl.CN.C(N(CC)CC)C>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:27][CH3:26])=[O:15])=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[C:3]=1[F:19]
Reactant: Cc1nccc(-c2ccc(Br)c(F)c2F)c1C(=O)O
Reactant: CN(C)C=O
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(Br)c(F)c2F)ccnc1C
Temperature: 45 °C
Reaction time: 2 h
Yield: 409.3 %

Procedure:
To a solution of 4-(4-bromo-2,3-difluorophenyl)-2-methylnicotinic acid (700 mg, 2.13 mmol) in dichloromethane (20 mL) at 0° C. was added oxalyl chloride (0.56 mL, 6.40 mmol) drop wise followed by DMF (0.03 mL, 0.43 mmol). The reaction mixture was heated to 45° C. for 4 h. The reaction mixture was evaporated to dryness. The residue was taken in dichloromethane (50 mL) at 0° C. and methylamine hydrochloride (1.56 g, 23.08 mmol) was added to it followed by triethylamine (4.83 mL, 34.6 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to afford 4-(4-bromo-2,3-difluorophenyl)-N,2-dimethylnicotinamide (600 mg, 1.76 mmol, 76% crude yield) as yellow semi-solid which was carried on without further purification. LC/MS (ESI) m/e 343.0 [(M+2H)+, calcd for C14H13BrF2N2O 343.0]; LC/MS retention time (method C): tR=1.61 min.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH:36]([C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)[OH:37]>>[OH:37][CH:36]([C:38]1[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=1)[CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=2)=[CH:33][CH:32]=1)=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccc([N+](=O)[O-])cc2)N(C(=O)c2ccc(-c3ccncc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(4-pyridinyl)benzoic acid, and (1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was obtained in 89% purity by HPLC. MS(ESI+): m/z=504.
Reaction SMILES: N1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[C:11](CC)[CH:10]=1.[CH3:19][N:20](C=O)[CH3:21]>CCOCC>[Br:8][C:9]1[CH:14]=[CH:13][C:5]([CH2:4][N:3]2[CH:21]=[N:20][CH:19]=[N:2]2)=[C:11]([CH2:12][CH3:15])[CH:10]=1
Reactant: c1c[nH]nn1
Reactant: CN(C)C=O
Reactant: CCc1cc(Br)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCc1cc(Br)ccc1Cn1cncn1
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
Triazole (275 mg, 3.99 mmol) dissolved in anhydrous DMF (15 mL) was treated with NaH (60%, 153 mg). After 5 min, 4-bromo-1-bromomethyl-2-ethyl-benzene was added. The reaction mixture was heated to 75° C. for 5 hours before it was cooled to room temperature. The mixture was diluted with Et2O and washed with H2O, brine, dried over MgSO4. The solvent was removed in vacuo to afford the desired product (580 mg, 55% yield). 1H NMR (300 MHz, CDCl3): δ 1.10 (t, J7.5 Hz, 3 H), 2.68–2.73 (m, 2 H), 5.46 (s, 2 H), 7.01–7.04 (m, 1 H), 7.38–7.46 (m, 2 H), 7.97–8.01 (m, 2 H).