Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=O)=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.Cl.NO.C([N:24](CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:24])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2c(c1)COC2c1ccc(F)cc1
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
1-(4′-Fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde (17.00 g) was dissolved in toluene (200 ml) and hydroxylamine hydrochloride (5.5 g) and triethylamine (8.0 g) were added. The mixture was stirred at 80-100° C. for 2 hr. The obtained triethylamine hydrochloride was filtered and the solvent was evaporated. Thereto was added acetic anhydride (36.5 g) and the mixture was stirred at 125-130° C. for 5 hr. The reaction mixture was poured into 10% aqueous sodium hydroxide solution (300 ml) and extracted twice with toluene (200 ml). The toluene layer was washed successively with 5% aqueous sodium hydroxide solution, water and saturated brine and dried over magnesium sulfate. Silica gel (5 g) was added and the mixture was thoroughly stirred and filtered. The solvent was evaporated to give crude 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (14.2 g). This was recrystallized from a mixed solvent of ethanol/hexane to give 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (9.52 g, 59.8%).
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:29][C:30]([NH2:34])([CH3:33])[CH2:31][OH:32]>C(Cl)Cl>[OH:32][CH2:31][C:30]([NH:34][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13])([CH3:33])[CH3:29]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC(C)(N)CO
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(CO)NC(=O)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To an oven dried 250 mL round bottomed flask was weighed quinaldic acid (866 mg, 5.0 mmol). A magnetic stir bar was added and the flask was put under N2 atmosphere. The flask was charged with DCM (50 mL) and cooled to 0° C. in an ice bath. The flask was charged with N-methyl morpholine (720 μL, 7.5 mmol) and isobutlychloroformate (752 μL, 5.75 mmol) via syringe addition. The reaction was allowed to stir at 0° C. for 10 min until the solution became cloudy. At which point 2-methyl-2-aminopropanol (550 uL, 5.75 mmol) was added slowly to the flask via syringe. The reaction mixture was allowed to slowly warm to room temperature. The reaction was quenched after 2 h with 1M HCl solution (30 mL) and transferred to a separatory funnel with DCM (50 mL). The layers were partitioned and the organic phase was washed with H2O (2×30 mL) and brine (1×40 mL). After drying over Na2SO4 and filtration, the mixture was concentrated under reduced pressure. The crude mixture was purified by flash chromatography eluting with a 1:1 mixture of EtOAc and hexanes to afford N-(1-hydroxy-2-methylpropan-2-yl)quinoline-2-carboxamide as a colorless oil in 91% yield (1.112 g, 4.55 mmol) according to the following reaction
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([N:18]1[N:22]=[N:21][C:20]([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([OH:26])=[O:25])=[N:19]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].IC>C1COCC1>[CH2:6]([N:18]1[N:22]=[N:21][C:20]([C:23]([CH3:2])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:24]([OH:26])=[O:25])=[N:19]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCn1nnc(C(C(=O)O)c2ccccc2)n1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCCCCCCCCCCCn1nnc(C(C)(C(=O)O)c2ccccc2)n1
Reaction time: 3 h
Yield: 1073.2 %

Procedure:
To a THF solution (30 mL) of n-BuLi (0.0055 mol, 1.6M in hexanes) at -78° C. under N2 with stirring was added 1.0 g (0.00027 mol) of (±)-2-dodecyl-α-phenyl-2H-tetrazole-5-acetic acid (Compound d, Example 13). The resulting yellow solution was stirred at -78° C. for 30 minutes before iodomethane (0.34 mL, 0.0055 mol) was added. This solution was stirred for 3 hours before quenching with 1N HCl (20 mL). The mixture was then partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo to yield 1.12 g of pure product.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16]([O:18]CC)=[O:17])C.[OH-].[K+]>C(O)C.O>[CH3:27][C:15]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH2:14][CH2:13][CH2:12][CH2:11][C:10](=[O:28])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:35])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:4]([OH:36])=[O:3])[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)C(C)(CCCCC(=O)CCCCC(C)(C(=O)OCC)c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CCCCC(=O)CCCCC(C)(C(=O)O)c1ccccc1)(C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
According to the procedure given for 210f, 209d (3.93 g, 7.9 mmol) was hydrolyzed with KOH (85%, 4.0 g, 60.6 mmol) in ethanol (60 mL) and water (10 mL) at reflux for 3 h and at room temperature overnight. After the usual workup and drying, 210d (3.0 g, 87%) was obtained as an oil. 1H NMR (CDCl3): δ 7.40-7.10 (m, 10H), 2.32 (t, 4H, J=7.2), 2.10-1.80 (m, 4H), 1.60-1.45 (m, 4H), 1.54 (s, 6H), 1.25-1.10 (m, 4H). 13C NMR (CDCl3): δ 211.1, 182.5, 142.8, 128.4, 126.9, 126.0, 49.9, 42.3, 38.7, 24.2, 24.0, 22.3. HRMS (LSIMS, nba): Calcd for C27H35O5 (MH4): 439.2484, found: 439.2497. HPLC: 93.7% pure.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[C:14]([NH:19][CH2:20][CH2:21][CH2:22][OH:23])=[N:15][CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11]>N1C=CC=CC=1.C1C=CC=CC=1>[C:1]([O:23][CH2:22][CH2:21][CH2:20][NH:19][C:14]1[C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=[CH:16][N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1cccnc1NCCCO
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(OCCCNc1ncccc1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
70 ml of benzoyl chloride are introduced dropwise into a solution of 77.8 g (0.04 mol) of 3-[(3-nitro-2-pyridyl)amino]propanol (M. ISRAEL, N. TIROSH, J. Med. Chem. 1973, 16, 520) in 48.5 ml of pyridine and 800 ml of benzene. The mixture is stirred for 2 h at ambient temperature and the precipitate is filtered. The filtrate is washed with 1N hydrochloric acid and then with water. Drying, filtering and evaporation are carried out. A crystallized product is obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[N:30]([C:33]1[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=1[C:35]([O:37][CH3:38])=[O:36])=[C:31]=[O:32]>C(Cl)Cl>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[CH:40][CH:41]=[CH:42][C:33]=1[NH:30][C:31]([N:16]([C:12]1[N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[CH:15]=[CH:14][N:13]=1)[CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)=[O:32]
Reactant: CC(C)c1ccc(-c2ccnc(NCc3cccs3)n2)cc1
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)N(Cc1cccs1)c1nccc(-c2ccc(C(C)C)cc2)n1
Temperature: 100 °C
Yield: 2.6 %

Procedure:
To a solution of [4-(4-isopropyl-phenyl)-pyrimidin-2-yl]-thiophen-2-ylmethyl-amine (50 mg, 0.16 mmol) in DCM (2 mL) was added triethylamine (33 μL, 0.24 mmol) and methyl 2-isocyanatobenzoate (32 mg, 0.18 mmol). The resulting reaction mixture was heated in a CEM Exployer PLS™ microwave at 100° C. for 30 min. After cooling to room temperature the solvent was evaporated. Purification was carried out by silica gel chromatography eluting with hexanes/ethyl acetate 9:1 to give 2 mg of 2-{3-[4-(4-isopropyl-phenyl)-pyrimidin-2-yl}-3-thiophen-2-ylmethyl-ureido}-benzoic acid methyl ester. LCMS m/z: 488 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[C:32]([O:34][CH2:35][CH3:36])=[CH2:33])CCC>O1CCOCC1.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>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:32]([O:34][CH2:35][CH3:36])=[CH2:33])[CH:3]=1)=[O:15]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.1 g, 0.24 mmol) and tributyl(1-ethoxyvinyl)stannane (0.09 mL, 0.26 mmol) in 1,4-dioxane (2 mL) was purged with argon for 10 min. Then, Pd(PPh3)4 (0.014 g, 0.012 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was refluxed for 4 h. After completion of the reaction, solvent was removed under reduced pressure to afford crude material which was as such used for next step (0.12 g).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:26][N:27]=2)=[CH:19][CH:18]=1.[C:33](O)(=[O:39])/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH3:38]>CN(C)C1C=CN=CC=1.ClCCl>[C:33]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[S:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:26][N:27]=2)=[CH:21][CH:22]=1)(=[O:39])/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH3:38]
Reactant: CCCCCc1nnc(-c2ccc(O)cc2)s1
Reactant: CCC/C=C/C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/C(=O)Oc1ccc(-c2nnc(CCCCC)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dicyclohexylcarbodiimide (0.2 g) is added to a solution of 2-(4-hydroxyphenyl)-5-pentyl-1,3,4-thiadiazole [Mol. Cryst. Liq. Cryst., (1990) Vol., 191, pp 223] (0.25 g), (E)-hex-2-enoic acid, (0.1 g) 4-(dimethylamino)pyridine (0.05 g) and dichloromethane (20 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture is stirred overnight at room temperature, filtered to remove inorganic material and the filtrate evaporated down. The residue is purified by column chromatography on silica gel using hexanelethyl acetate (9/1 v/v) as eluent and recrystallisation from hexane to yield 0.17 g of 2-(4-[(E)-hex-2-enoyloxy]phenyl)-5-pentyl-1,3,4-thiadiazole.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.I[CH3:16]>CN(C=O)C>[Cl:3][C:4]1[N:5]([CH3:16])[C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CI
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(Cl)c(C=O)c2ccccc21
Temperature: 0 °C
Yield: 75.5 %

Procedure:
NaH (60% dispersion in mineral oil) (0.9 g, 22.5 mmole) was added portionwise over 5 min to a solution of 2-chloro-1H-indole-3-carboxaldehyde (3.8 g, 21.2 mmole) and iodomethane (1.5 mL, 24 mmole) in DMF (50 mL) with stirring at 0° C. The reaction was allowed to warm to RT and stir for 4 h, then was concentrated under vacuum. The remaining residue was taken up in EtOAc, and the solution was washed with water then brine, dried (MgSO4), and concentrated to dryness. Trituration with 1:1 Et2O/petroleum ether, filtration, and drying under vacuum gave the title compound (3.10 g, 76%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 8.29 (m, 1H), 7.33 (m, 3H), 3.81 (s, 3H); MS (ES) m/e 194.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2=[C:15]3[N:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[CH:16]=[CH:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.[C:25]([C:27]1[C:28](=[C:43]([C:46]#[N:47])[C:44]#[N:45])[O:29][C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:33]([F:36])([F:35])[F:34])[C:31]=1[CH3:32])#[N:26]>C(O)C.O1CCCC1>[C:25]([C:27]1[C:28](=[C:43]([C:46]#[N:47])[C:44]#[N:45])[O:29][C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:33]([F:36])([F:34])[F:35])[C:31]=1[CH:32]=[CH:23][C:21]1[S:22][C:18]([CH:17]=[CH:16][C:4]2[CH:5]=[C:6]3[C:15]4[N:10]([CH2:9][CH2:8][CH2:7]3)[CH2:11][CH2:12][CH2:13][C:14]=4[C:3]=2[O:2][CH3:1])=[CH:19][CH:20]=1)#[N:26]
Reactant: COc1c(C=Cc2ccc(C=O)s2)cc2c3c1CCCN3CCC2
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: COc1c(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)cc2c3c1CCCN3CCC2
Temperature: 60 °C
Yield: 44.9 %

Procedure:
In 5 ml of ethanol and 1.5 ml of tetrahydrofuran were dissolved 120 mg (0.35 mmol) of 5-[2-(8-methoxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-yl)vinyl]thiophene-2-carboaldehyde and 123 mg (0.39 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred with heating at 60° C. for 3 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 100 mg of a dark brown crystal (yield: 44.4%; mp: 156-160° C.)
Reaction SMILES: [NH2:1][C:2]1([NH:7][C:8](=[O:17])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][NH:4][C:3]1=[O:6].N1C=CC=CC=1.[C:24](OC=O)(=[O:26])C>ClCCl>[CH:24]([NH:1][C:2]1([NH:7][C:8](=[O:17])[CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5][NH:4][C:3]1=[O:6])=[O:26]
Reactant: CC(=O)OC=O
Reactant: NC1(NC(=O)COc2ccccc2)CNC1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=CNC1(NC(=O)COc2ccccc2)CNC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
The amine (27) (66 mg) in dry dichloromethane (5 ml) was cooled to 0° and treated with pyridine (49 mg) followed by formic-acetic anhydride (27 mg). The mixture was stirred at 0° for 15 minutes then allowed to warm to room temperature over 15 minutes, and evaporated to dryness. The residue was chromatographed on silica gel to give the product (28) (53 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[F:9][C:10]([F:19])([F:20])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:13][CH:12]=1
Reactant: CN1CCC(=O)CC1
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: CN1CCC(NCc2ccc(C(F)(F)F)cc2)CC1

Procedure:
1-Methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.), 4-trifluoromethylbenzylamine (1.75 g, 1.0 eq.).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][CH3:32]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][CH3:32]
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Reactant: C=C(c1cc(Cl)c(OC)c(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1c(Cl)cc(C2(C(F)(F)F)CC(c3ccc4c(c3)C(C)(C)OB4O)=NO2)cc1Cl
Temperature: 0 °C
Reaction time: 12 h
Yield: 18.9 %

Procedure:
To a solution of crude compound N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxa-borole-5-carbimidoyl chloride (0.29 g, 1.23 mmol) and 1,3-dichloro-2-methoxy-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (0.4 g, 1.48 mmol) in DMF (10 mL) at rt was added TEA (0.51 mL, 3.67 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by preparative TLC to give the title compound (110 mg, yield 15.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.27 (s, 1 H), 7.82-7.75 (m, 5 H), 4.46 (d, J=18.4 Hz, 1 H), 4.36 (d, J=18.4 Hz, 1 H), 3.93 (s, 3 H), 1.53 (s, 6 H) ppm; MS: m/z=472 (M−1, ESI−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[CH:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:7][C:6]=12.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][NH2:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][NH:33][C:10]2[N:5]3[N:4]=[CH:3][C:2]([Br:1])=[C:6]3[N:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Clc1ccccc1-c1cc(Cl)n2ncc(Br)c2n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(-c3ccccc3Cl)nc3c(Br)cnn23)CC1
Temperature: 75 °C
Yield: 101.2 %

Procedure:
3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (300 mg, 0.875 mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1,4-dioxane (6.8 mL). 4-(aminomethyl)piperidine-1-carboxylic acid tert-butyl ester (225 mg, 1.05 mmoles) and diisopropyl ethylamine (0.3055 mL, 1.75 mmoles) were added and the mixture was heated at 75° C. for 24 h. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column (15×5 cm) using dichloromethane as the eluant to give 4-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester (461.2 mg, 100%): FABMS: m/z 520.1 (MH+); HRFABMS: m/z 520.1111 (MH+). Calcd. for C23H28N5O2BrCl: m/z 520.1115; δH (CDCl3) 1.30 (2H, m, CH2), 1.51 (9H, s, —COOC(CH3)3), 1.85 (2H, d, CH2), 1.95 (1H, m, CH), 2.76 (2H, m, CH2), 3.40 (2H, m, CH2), 6.37 (1H, s, H6), 6.55 (1H, m, NH), 7.42 (2H, m, Ar—H), 7.52 (1H, m, Ar—H), 7.76 (1H, m, Ar—H) and 8.07 ppm (1H, s, H2); δC (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 29.1, 29.1, 43.5, 43.5, 47.9; CH: 36.3, 87.5, 127.2, 130.2, 130.3, 131.6, 143.9; C: 79.7, 83.3, 132.1, 138.6, 145.4, 146.3, 154.7, 158.1.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[N:4]=1)#[N:2].Cl>[Pd].CO>[NH2:2][CH2:1][C:3]1[N:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[N:4]=1
Reactant: COc1cc(C)nc(C#N)n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc(C)nc(CN)n1
Yield: 39.8 %

Procedure:
A mixture of 4.4 g of the product from Example 8, 0.35 g 10% palladium-on-carbon catalyst, and 1.5 ml of concentrated hydrochloric acid in 70 ml methanol was shaken under an atmosphere of hydrogen at 46 p.s.i. on a Parr Hydrogenation Apparatus. After 31/2 hours, the solution was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The resulting solid was taken up in water and the aqueous layer was washed with several small portions of ether. Adjustment to pH 13 followed by extraction with methylene chloride, drying, and evaporation of the organic layer gave 1.8 g of the title compound as a light yellowish-orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:14]2[C:9]3([CH:18]=[CH:17][CH:16]=[CH:15][C:10]3=[N:11][CH2:12][CH2:13]2)[S:8][CH2:7]1)=[O:5])[CH3:2].[Cl:19]C1C=CC2SC=CC=2C=1>>[CH2:1]([O:3][C:4]([CH:6]1[CH:14]2[C:9]3([CH:18]=[CH:17][CH:16]=[CH:15][CH:10]3[N:11]([Cl:19])[CH2:12][CH2:13]2)[S:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CSC23C=CC=CC2=NCCC13
Reactant: Clc1ccc2sccc2c1
Product: CCOC(=O)C1CSC23C=CC=CC2N(Cl)CCC13

Procedure:
6-Chloro-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester was synthesized by following the same procedure as the synthesis of 1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester in Example 1 except that 42.3 g of 5-chlorobenzothiophene was used in place of 33.6 g of benzothiophene in Example 1.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@@H:2]([C:11]([OH:13])=O)[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[NH2:24][C@H:25]([C:29]([NH:31][C@H:32]([C:45]([O:47][CH3:48])=[O:46])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:36][CH:35]=1)=[O:30])[CH:26]([CH3:28])[CH3:27].Cl.CO>CN(C)C=O>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@@H:2]([C:11]([NH:24][C@H:25]([C:29]([NH:31][C@H:32]([C:45]([O:47][CH3:48])=[O:46])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[CH:38][CH:39]=1)=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:13])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(C)C

Procedure:
6.46 g (20 mmoles) of Z-D-Asp(OBut)-OH are subjected to a condensation reaction with 7.73 g (20 mmoles) of H-Val-Tyr(But)-OMe.HCl in 50 ml of dimethylformamide analogously to Examples 38 A. Yield 11.2 g (85%), melting point 90°-92°, [α]D27 =-3.5° (c=1, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[CH:15]=[CH:16][C:17]=2[C:18]#[N:19])=[O:10])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C@@H:29]([CH3:34])[C:30]([F:31])([F:32])[F:33])[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:15]=[CH:16][C:17]=2[C:18]#[N:19])=[O:10])=[CH:6][CH:7]=1
Reactant: C[C@H]([C@H](C(=O)Nc1cc(CCC(=O)OC(C)(C)C)ccc1C#N)c1ccc(Cl)cc1)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]([C@H](C(=O)Nc1cc(CCC(=O)O)ccc1C#N)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
16.5 mg (33 μmol) of tert-butyl 3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-4-cyanophenyl)propanoate were dissolved in 1.1 ml of dichloromethane, and 275 μl of trifluoroacetic acid were added. The reaction mixture was stirred at RT for 1.5 h, then diluted with 20 ml of dichloromethane and concentrated under reduced pressure. The residue was dried under high vacuum overnight. This gave 14.8 mg (97% of theory) of the title compound.
Reaction SMILES: C([O:8][C:9](=[O:24])[CH2:10][O:11][P:12]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:20]([O:19][P:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([O:11][CH2:10][C:9]([OH:24])=[O:8])=[O:13])([CH3:22])([CH3:23])[CH3:21]
Reactant: CC(C)(C)OP(=O)(OCC(=O)OCc1ccccc1)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OP(=O)(OCC(=O)O)OC(C)(C)C
Yield: 97.6 %

Procedure:
(Di-tert-butoxy-phosphoryloxy)-acetic acid benzyl ester (700 mg, 1.96 mmol) was dissolved in MeOH (40 mL) and passed through a “H-cube” hydrogenator with a 10% Pd on carbon cartridge under 40 psi of hydrogen at a flow rate of 1 mL/min. The reaction mixture was concentrated in vacuo to give 513 mg (98%) of (di-tert-butoxy-phosphoryloxy)-acetic acid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 4.53 (d, 2H), and 1.51 (s, 18H).