Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[CH:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1.O>[Cl:21][C:22]1[C:27]([CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)[OH:37])=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: COc1cccc(C=O)c1
Reactant: Clc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2cccnc2Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51 %

Procedure:
Combine 2.5 M n-butyl lithium in hexane (40 mL), diisopropyl amine (14 mL, 0.10 mol) and cold (−68° C.) tetrahydrofuran (250 mL) and stir for 20 minutes, to generate lithium diisopropylamide. Add 2-chloro-pyridine (9.5 mL, 0.10 mol) dissolved in tetrahydrofuran (10 mL) and stir for 45 minutes. Add m-anisaldehyde (13.6 g, 0.10 mol) in 10 mL tetrahydrofuran, stir for 45 minutes and let warm to room temperature over the weekend. Pour reaction mixture into water, add saturated ammonium chloride (50 mL), separate and dry. Extract with ether (twice), wash combined aqueous layers with saturated sodium chloride, dry, evaporate and purify by flash (silica) chromatography using a graded solvent mixture of dichloromethane to 10% ethyl acetate in dichloromethane to give the title compound as an oil (12.74 g, 51% Yield). NMR agrees with the final, desired compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([F:16])([F:15])[F:14])=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].Cl.Cl[CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23]>>[CH2:20]([N:21]([CH2:24][CH3:25])[CH2:22][CH2:23][N:9]1[C:10]2[C:6](=[C:5]([C:13]([F:16])([F:14])[F:15])[CH:4]=[CH:3][C:2]=2[I:1])[C:7](=[O:12])[C:8]1=[O:11])[CH3:19]
Reactant: CCN(CC)CCCl
Reactant: O=C1Nc2c(I)ccc(C(F)(F)F)c2C1=O
Agent: Cl
Product: CCN(CC)CCN1C(=O)C(=O)c2c(C(F)(F)F)ccc(I)c21
Yield: 76 %

Procedure:
The title compound (245 mg, 76%) was prepared from 7-iodo-4-trifluoromethylisatin (250 mg, 0.733 mmol) and 2-chloroethyl-N,N-diethylamine hydrochloride by the procedure similar to that described in Reference Example 8.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[F:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][C:52]([N:54]=[C:55]=[S:56])=[O:53])=[CH:47][CH:46]=1.C(OCC)C>C(O)C.C1(C)C=CC=CC=1.CCCCCC>[F:44][C:45]1[CH:46]=[CH:47][C:48]([CH2:51][C:52]([NH:54][C:55](=[S:56])[NH:1][C:2]2[CH:28]=[CH:27][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:17][CH2:18][CH:19]([CH2:22][N:23]5[CH2:26][CH2:25][CH2:24]5)[CH2:20][CH2:21]4)=[O:15])[CH:8]=3)=[CH:4][CH:3]=2)=[O:53])=[CH:49][CH:50]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)cc1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOCC
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)cc1
Reaction time: 0.08 h
Yield: 34.2 %

Procedure:
4-(Azetidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (143 mg) was dissolved in ethanol (4 ml) under a nitrogen atmosphere, and then (S)-(+)-10-camphorsulfonic acid (131 mg) was added thereto, followed by stirring for 5 min. A 0.25 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (2.25 ml) was added thereto, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:8, then ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure to give a residue, to which diethyl ether (4 ml) and hexane (4 ml) were then added to suspend. The solid was filtered off, and dried under aeration to provide the titled compound (74.0 mg, 34.2%) as white powder.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2[C:14]3[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:15]=3[N:16]=[C:17]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:18]=2)[CH2:9]1)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:9][C@H:10]([NH:12][C:13]2[C:14]3[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:15]=3[N:16]=[C:17]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:18]=2)[CH2:11]1
Reactant: Cn1cc(Nc2nc(N[C@H]3C[C@H](NC(=O)OC(C)(C)C)C3)c3ccn(COCC[Si](C)(C)C)c3n2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(Nc2nc(N[C@H]3C[C@H](N)C3)c3ccn(COCC[Si](C)(C)C)c3n2)cn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93.1 %

Procedure:
To tert-butyl((trans)-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)carbamate (115 mg, 0.218 mmol) in DCM (5 mL) was added 4 N HCl in 1,4-dioxane (0.3 mL, 1.2 mmol). The reaction was allowed to stir at rt for 3.5 hrs and then quenched with saturated aqueous NaHCO3 (2 mL). DCM (10 mL) was added and the DCM extract was dried over MgSO4, filtered and concentrated to afford the title compound (87 mg, 93% yield) as a tan foam.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[N:11]([C:14]3[N:15]([CH3:20])[N:16]=[C:17]([CH3:19])[CH:18]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34](B(O)O)=[CH:33][N:32]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34]([C:2]2[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]3[CH:10]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[N:11]([C:14]4[N:15]([CH3:20])[N:16]=[C:17]([CH3:19])[CH:18]=4)[C:12](=[O:13])[C:4]=3[CH:3]=2)=[CH:33][N:32]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Cc1cc(N2C(=O)c3cc(Br)n(C(C)C)c3C2c2ccc(C#N)cc2)n(C)n1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)cc2)N(c2cc(C)nn2C)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 4-[2-bromo-5-(2,5-dimethyl-2H-pyrazol-3-yl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl]-benzonitrile (Intermediate AX) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The title compound was obtained as a white solid. ESI-MS: tR=0.94 min, [M+H]+ 498 (LC-MS 1).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 72 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and ethyl chloroformate. Yield: 72% of theory, C29H31N7O5 (557.6) Rf value: 0.58 (silica gel; dichloromethane/methanol=9:1) ##EQU70##
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:10][CH:9]=2)[C:5]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:4][N:3]=1.Br[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:28]=O>C(O)C>[CH2:22]([C:5]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:12][CH:13]=2)[C:2]2[N:3]([C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][N:1]=2)[N:4]=1)[CH2:23][CH2:24][CH3:25]
Reactant: O=CC(Br)c1ccccc1
Reactant: CCCCc1nnc(N)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CCO
Product: CCCCc1nn2c(-c3ccccc3)cnc2n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 23.6 %

Procedure:
A mixture of 212 mg (0.640 mmole) of 3-amino-5-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-4H-1,2,4-triazole (from Example 1, Step D), 151 mg (0.757 mmol) of α-bromophenylacetaldehyde [T. L. Jacobs and W. R. Scott, Jr., J. Am. Chem. Soc., 75, 5500 (1953)], and 2.0 ml of absolute ethanol was stirred at reflux under N2 for 6 hours. The mixture was cooled and concentrated in vacuo. The residue was chromatographed on a column of silica gel (27×2.5 cm) packed in CH2Cl2 (elution with 1% and then 4% MeOH in CH2Cl2). Concentration of the appropriate pooled product fractions afforded 65.3 mg (24%) of the title compound as a yellow oil; homogeneous by TLC in 19:1 CH2Cl2 -MeOH.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1.[C:33](Cl)(=[O:35])[CH3:34].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:33]([NH:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1)(=[O:35])[CH3:34]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(N)sc2n1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (161 mg, 363 μmol) produced in Example D25(iii) in pyridine (4 mL) was added acetyl chloride (65 μL, 908 μmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (20 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (129 mg, 73%) as colorless crystals.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]C(C)(C)C)=[CH:16][CH:15]=2)[CH:7]=[CH:8][N:9]=1.[OH-].[Na+]>Cl>[CH3:1][S:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:7]=[CH:8][N:9]=1
Reactant: CSCCc1nccn1CCCCc1ccc(OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CSCCc1nccn1CCCCc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
tert-Butyl 4-[4-[2-[2-(methylsulfanyl)ethyl]-1H-imidazol-1-yl]butyl]phenyl ether (2.11 g) was dissolved in 4N hydrochloric acid (6 ml), and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was neutralized with 30% aqueous sodium hydroxide solution to give crystals, which were collected by filtration and washed with diethyl ether to give the titled compound (1.12 g) as a colorless crystal powder.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([C:17]([O:19]CC)=[O:18])[CH2:8][C:7]2=1.[OH-].[Li+]>O1CCCC1.CO>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([C:17]([OH:19])=[O:18])[CH2:8][C:7]2=1
Reactant: CCOC(=O)C1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A stirred solution of ethyl 6-(trifluoromethoxy)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylate of Step 1 (1.8 g, 5.5 mmol) in tetrahydrofuran (20 mL) and methanol (3 mL) was treated with 1N lithium hydroxide (11 mL) and heated under nitrogen in an oil bath kept at 40° C. for 2 hours. The organic solvents were evaporated, the residue was diluted with water, cooled in an ice bath and acidified with 2N hydrochloric acid (10 mL). The suspension was extracted with ethyl acetate, and the extracts were washed with brine and dried over anhydrous magnesium sulfate. Removal of the solvent provided a colorless foam that was dried in vacuo to yield the title compound (1.6 g). MS [(+)ES, m/z]: 300.1 [M+H]+. MS [(−)ES, m/z]: 298.0 [M−H]−. HPLC: Chromolith Monolith column, 0.46×10 cm, gradient of acetonitrile in water (0.01% TFA), 4 mL/min, detection at 254 nm; Rt 2.0 min.
Reaction SMILES: C[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1F)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[C:22](=O)([O-])[O-].[Na+].[Na+]>CO>[C:10]1([C:3]2([C:7]([O:9][CH3:22])=[O:8])[CH2:4][CH2:5][CH2:6][CH2:2]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC1CCCC1(C(=O)O)c1ccccc1F
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCCC1

Procedure:
To a solution of methyl 1-(2-fluorophenyl)cyclopentanecarboxylic acid (10 g, 52.56 mmol) in anhydrous methanol was added 1 mL of the concentration of sulfuric acid. The mixture was refluxed for overnight. The mixture was neutralized to pH 4-5 with sodium carbonate. The solvent was evaporated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (3×10 mL), dried over MgSO4. The crude product was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([CH:33]=1)[CH2:7][C@H:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:23][CH3:24])[C:20](O)=[O:21])=[O:17])[CH2:12][C:11](=[N:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][CH2:9]1.C(Cl)Cl.[CH3:39][NH:40]C.CO>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([CH:33]=1)[CH2:7][C@H:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@@H:19]([C:20](=[O:21])[NH:40][CH3:39])[CH2:23][CH3:24])=[O:17])[CH2:12][C:11](=[N:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][CH2:9]1
Reactant: CC[C@@H](NC(=O)N1CC(=NOc2ccccc2)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)C(=O)O
Reactant: CNC
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)N1CC(=NOc2ccccc2)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)C(=O)NC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the compound 54 (70 mg) in a methylene chloride (3 ml) solution, dimethylamine in a methanol solution (2M, 0.14 ml), triethylamine (0.291 ml), and propyl phosphonate anhydride (T3P) (50% ethyl acetate solution, 0.21 ml) were successively added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off, and the residue was diluted with ethyl acetate. Then the resultant mixture was successively washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogencarbonate solution, and brine. The organic layer was dried over anhydrous sodium sulfate, then was concentrated. The residue was purified by flash column chromatography (silica gel, chloroform/ethyl acetate=9/1 to 1/1) to obtain the title compound (42.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:6]([O:8][CH2:9][C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)=O)=O.C([O-])(=O)C.[NH4+:32]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:8][CH:9]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[N:32]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: [NH4+]
Reactant: COc1ccc(C(=O)OCC(=O)c2ccc3c(c2)CCC(=O)N3)cc1OC
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(-c3ccc4c(c3)CCC(=O)N4)co2)cc1OC
Temperature: 130 °C
Reaction time: 3 h
Yield: 6.3 %

Procedure:
In 25 ml of acetic acid was dissolved 2 g of 6-[2-(3,4-dimethoxybenzoyloxy)acetyl]-3,4-dihydrocarbostyril. Thereto was added 2 g of ammonium acetate. The mixture was stirred at 130° C. for 3 hours with heating. The solvent was removed by distillation. The residue was dissolved in ethanol. The solution was treated with active carbon, and then recrystallization was conducted to obtain 120 mg of 2-(3,4-dimethoxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)oxazole as light brown acicular crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH3:19])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].CC(O)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH3:19])[C@H:9]([OH:10])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(C(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: COc1cccc([C@@H](O)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A mixture of tert-butyl[(1S)-2-(3-methoxyphenyl)-1-methyl-2-oxoethyl]carbamate (13.6 g, 48.7 mmol), aluminium isopropoxide (1.99 g, 9.70 mmol), 2-propanol (41 mL, 535 mmol) in toluene (63 mL) was stirred under an atmosphere of argon at 50° C. overnight. LC/MS showed complete conversion into the alcohol. The mixture was partitioned between ethyl acetate (200 mL) and hydrochloric acid (1M, 200 mL). The organic phase was washed with water (200 mL), dried over magnesium sulfate and concentrated to give the subtitle compound as a syrup (13.5 g). The compound was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 30.0 g (155 mmol) of 2,3,4,5-tetrafluorobenzoic acid in 75 ml of dichloromethane was added 14.8 ml (1.1 equivalents) of oxalyl chloride. The mixture was then treated with three drops of dry N,N-dimethylformamide and the vigorous reaction was stirred at room temperature overnight. The mixture was then concentrated to an oil, taken up in toluene, and reconcentrated to afford 2,3,4,5-tetrafluorobenzoyl chloride which was used in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[CH:6][C:5]([C@H:28]2[CH2:32][C@@H:31]([CH2:33][OH:34])[NH:30][CH2:29]2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:41]#[C:42]Br>C(O)C.O>[NH2:1][C:2]1[C:7]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[CH:6][C:5]([C@@H:28]2[CH2:29][N:30]3[C:42](=[NH:41])[O:34][CH2:33][C@@H:31]3[CH2:32]2)=[CH:4][N:3]=1
Reactant: N#CBr
Reactant: Nc1ncc([C@@H]2CN[C@H](CO)C2)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Product: N=C1OC[C@@H]2C[C@H](c3cnc(N)c(-c4ccc(C(=O)N[C@H](CO)c5cccc(Cl)c5)c(F)c4)c3)CN12
Reaction time: 1 h

Procedure:
A room temperature mixture of 4-(2-amino-5-((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (12.5 mg, 0.026 mmol) (Example 7) and cesium carbonate (33.6 mg, 0.103 mmol) in ethanol (0.75 mL) was treated with cyanogen bromide (6.2 μL, 0.031 mmol). After 1 h, the reaction was diluted with water (1.0 mL) and extracted into ethyl acetate (10 mL). The organics were washed with brine (2 mL), then dried over Na2SO4 and concentrate and purified by reverse phase prep HPLC yielding 4-(2-amino-5-((6R,7aS)-3-iminohexahydropyrrolo[1,2-c]oxazol-6-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide. LCMS (m/z): 510.1, 512.1 (MH+), 0.52 min. 1H NMR (400 MHz, CD3OD) δ ppm 8.63-8.54 (m, 1H), 7.92-7.85 (m, 2H), 7.80 (t, J=7.83 Hz, 1H), 7.40-7.31 (m, 3H), 7.29-7.24 (m, 2H), 7.24-7.16 (m, 1H), 5.14-5.06 (m, 1H), 4.97-4.88 (m, 1H), 4.61-4.49 (m, 2H), 3.88-3.70 (m, 4H), 3.32 (s, 1H), 2.41-2.31 (m, 1H), 2.02-1.89 (m, 1H).
Reaction SMILES: OCCN[N:5]1[NH:9][CH:8]=[C:7]([C:10]2[N:11]([CH3:18])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=2)[S:6]1.[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH2:24])[CH3:20].O1CCOCC1>O>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH:24][N:5]1[NH:9][CH:8]=[C:7]([C:10]2[N:11]([CH3:18])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=2)[S:6]1)[CH3:20]
Reactant: CCOC(CN)OCC
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(NCCO)S1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(CNN1NC=C(c2ncc([N+](=O)[O-])n2C)S1)OCC

Procedure:
A mixture composed 9.8 g. of 2-(2-chloro-5-thiadiazolyl)-1-methyl-5-nitroimidazole, (Example 16), 11.0 g. of 2,2-diethoxyethylamine, and 250 ml. of dioxane is stirred and heated on the steam bath for 12 hours. It is then diluted with 500 ml. of cold water, cooled, and the precipitated yellow solid collected and dried. Recrystallization from 505 aqueous ethanol gives the pure compound melting at 154°-155° C.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:7]=[N:8][C:9]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]5[CH:26]=[N:27][N:28]([CH2:30][C@H:31]6[O:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]6)[CH:29]=5)[N:19]=4)[CH2:14][CH2:13]3)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]#[C:5][C:6]2[CH:11]=[N:10][C:9]([N:12]3[CH2:13][CH2:14][N:15]([C:18]4[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]5[CH:26]=[N:27][N:28]([CH2:30][C@H:31]6[O:36][CH2:35][CH2:34][NH:33][CH2:32]6)[CH:29]=5)[N:19]=4)[CH2:16][CH2:17]3)=[N:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(C#CC6CC6)cn5)CC4)n3)cn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C(#CC1CC1)c1cnc(N2CCN(c3ncnc(Nc4cnn(C[C@@H]5CNCCO5)c4)n3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a solution of (S)-tert-butyl 2-((4-(4-(4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (30 mg, 0.05 mmol) in dichloromethane (2 mL) was dropwise added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 0.5 hour and concentrated. The residue was purified by Prep-HPLC to afford (S)-4-(4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazin-1-yl)-N-(1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-1,3,5-triazin-2-amine (14 mg, 57%) as a white solid.