Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[S:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:18]COCC.C([Li])CCC.CI>O>[CH3:18][C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[S:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: Brc1ccc(C=Cc2csc3ccccc23)s1
Agent: [Li]CCCC
Solvent: O
Solvent: CI
Product: Cc1ccc(C=Cc2csc3ccccc23)s1
Temperature: -70 °C
Reaction time: 0.03 h
Yield: 88 %

Procedure:
To a chilled (-70° C.), stirred solution of 3-[2-(5-bromo-2-thienyl)ethenyl]-benzo[b]thiophene (5.00 g) and ether (250 ml) was added n-butyllithium (6.8 ml of a 2.5M solution in hexanes), under nitrogen, over 2 mins. The mixture was stirred and chilled for 1.5 hrs. Methyl iodide (8.83 g) was added, and the mixture was allowed to warm to ambient temperature, with stirring, overnight. Water (200 ml) was added. The mixture was agitated, and the organic phase was separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by high performance liquid chromatography (silica gel, eluted with 10% dichloromethane in hexane). The appropriate fractions were combined and evaporated to yield 3.53 g (88%) of product, mp 62°-64° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:16])[C:5]([Cl:17])=[CH:4][N:3]=1.[O:18]1[CH2:23][CH2:22][CH:21](O)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]([O:16][CH:21]3[CH2:22][CH2:23][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: OC1CCOCC1
Reactant: Oc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: Fc1cccc(OC2CCOCC2)c1Nc1nc(Cl)ncc1Cl

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(tetrahydro-pyran-4-yloxy)-phenyl]-amine was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenol and Tetrahydro-pyran-4-ol in an analogous manner to Example 1273c. Title compound was obtained as a white solid (274 mg, 84%). HPLC purity 97%, LCMS 360.09 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 7.25-7.21 (m, 1H), 6.87-6.77 (m 3H), 4.58-4.55 (m, 1H), 3.89-3.84 (m, 2H), 3.61-3.56 (m, 2H), 2.06-2.01 (m, 2H), 1.80-1.72 (m, 2H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[S:12][N:11]=1>O.C(O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[S:12][N:11]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2F)ns1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2F)ns1
Temperature: 50 °C
Reaction time: 6 h
Yield: 85.8 %

Procedure:
A solution of sodium hydroxide (0.17 g, 4.2 mmol) in water (4 mL) is added to a stirred solution of ethyl 3-(2-fluorophenyl)isothiazole-5-carboxylate (0.88 g, 3.5 mmol) in ethanol. The mixture is stirred for 6 h at 50° C. The ethanol is then removed by distillation and the resulting aqueous phase is washed with diethyl ether, acidified with 2N hydrochloric acid and filtered. The filtercake is dried in vacuo to give 3-(2-fluorophenyl)isothiazole-5-carboxylic acid (0.67 g, 86%) as beige crystals, mp 191°-192° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH:23]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:28]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:29])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: O=C(O)C1CCCC1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)C3CCCC3)c21
Yield: 25 %

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and cyclopentyl carboxylic acid in 25% yield. H NMR (DMSO-d6, 400 MHz, 80° C.): 1.40 (m, 1H), 1.53 (m, 2H), 1.63 (m, 8H), 1.77 (m, 4H), 3.00 (m, 1H), 3.97 (br m, 1H), 4.20 (m, 1H), 4.50 (t, J=8.0 Hz, 1H), 5.06 (br s, 1H), 6.67 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.80 (br s, 2H), 10.6 (br s, 1H). MS=407 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:18]=[C:19]([N:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[C@H:10]([CH3:36])[CH2:9]2)=[C:4]([C:37]([F:40])([F:39])[F:38])[CH:3]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:36])[CH2:9]2)=[C:4]([C:37]([F:39])([F:38])[F:40])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(N2CCNCC2)c1
Yield: 98.7 %

Procedure:
To a solution of (R)-tert-butyl 4-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)piperazine-1-carboxylate (970 mg, 1.655 mmol) in DCM (15 mL) was added TFA (5 mL) at room temperature. The resultant mixture was stirred for 4 h then basified with 5% aq. NH3. The precipitate was collected and washed with water to give the desired product as a light yellow solid (795 mg, 99%). HRMS: calcd for C22H26F4N4O2S+H+, 487.17853. found (ESI-FTMS, [M+H]1+), 487.17747.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10](N)[C:11]([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(O)CCC>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)CN
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)(C)Cc1cc(Cl)nc(N)n1

Procedure:
A solution of 2-amino-4,6-dichloropyrimidine (1 mmol), neopentylamine (1.05 mmol), and triethylamine (2 mmol) in n-butanol was stirred at 110° C. for 12 h. Extraction and chromatography gave 2-amino-4-chloro-6-neopentylpyrimidine as a yellow solid. TLC: Rf=0.2, 30% EtOAc-hexane.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[C:16]([C:17]([NH:19][CH2:20][C:21]4[CH:32]=[CH:31][C:24]([O:25][C@H:26]([CH3:30])[C:27]([OH:29])=O)=[CH:23][C:22]=4[F:33])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:7]=[CH:6][C:5]=12.O1C2C=CC(OC3C(C(NCC4C=CC(O[C@H](C)C(O)=O)=CC=4F)=O)=CC=C[N:45]=3)=CC=2OC1>>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([NH:19][CH2:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][C@@H:26]([C:27](=[O:29])[NH2:45])[CH3:30])=[CH:23][C:22]=3[F:33])=[O:18])[CH:7]=[CH:6][C:5]=12
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)c(F)c1)C(=O)O
Product: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)c(F)c1)C(N)=O

Procedure:
The compound of Formula (5.5.15) was prepared in a manner analogous to that described in Example 14, substituting (R)-2-[4-({[2-(benzo[2,1,3]oxadiazol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid for the corresponding (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid material.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][N:25]=[C:26]2[Cl:29])=[CH:21][CH:20]=1>C1COCC1.CN(C=O)C.C1COCC1>[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:18][C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[CH:24][N:25]=[C:26]3[Cl:29])=[CH:21][CH:20]=2)[C:11]1=[O:15])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: Clc1nccc2ccc(CBr)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Reaction time: 0.03 h
Yield: 81.3 %

Procedure:
Sodium hydride (0.24 g, 6.05 mmol, 60% mineral oil dispersion) is added to a solution of [2-oxopyrrolidin-3(S)-yl]-carbamic acid tert-butyl ester (1.18 g, 5.89 mmol) in THF/DMF (62 mL, 9/1, v/v) at 0° C. The mixture is stirred for 2 minutes, then a solution of 7-bromomethyl-1-chloro-isoquinoline (1.4 g, 5.46 mmol) in THF (10 mL) is added dropwise via a cannula. The resulting yellow solution is stirred for 1 hour at 0° C. then at room temperature for 3 hours. The reaction mixture is quenched with saturated ammonium chloride solution, then diluted with EtOAc. The organic layer is washed with water and brine, then dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 50% EtOAc/hexanes to 70% EtOAc/hexanes to give the product (1.67 g, 4.44 mmol) as a foamy white solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH2:25]([O:27][C:28](=[O:32])[CH2:29][CH2:30][NH2:31])[CH3:26].Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:25]([O:27][C:28](=[O:32])[CH2:29][CH2:30][NH:31][CH2:2][C:3](=[O:4])[N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)[CH3:26]
Reactant: O=C(CCl)N1CCc2cc(OC3CCC(C(F)(F)F)CC3)ccc21
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCNCC(=O)N1CCc2cc(OC3CCC(C(F)(F)F)CC3)ccc21
Yield: 10 %

Procedure:
A mixture of crude 2-chloro-1-[5-(4-trifluoromethyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-ethanone (80 mg, 0.22 mmol), 3-amino-propionic acid ethyl ester as HCl salt (68 mg, 0.44 mmol) and potassium carbonate (98 mg, 0.71 mmol) in acetonitrile (2 mL) was heated to reflux for 4 hrs. The mixture was treated with water and extracted with ether. The organic phase was dried over MgSO4, concentrated, and purified via a silica gel column to give desired product (11 mg, yield 10%). ESI-MS: 443.20 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Li])CCC.[C:27]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br)([OH:29])=[O:28]>O1CCCC1.CCCCCC>[C:12]([C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([S:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH2:33][C:32]1[CH:31]=[C:30]([CH:37]=[CH:36][CH:35]=1)[C:27]([OH:29])=[O:28])#[N:13]
Reactant: O=C(O)c1cccc(CBr)c1
Reactant: COc1ccc(C(C#N)Sc2ccc(C)cc2)cc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)(Cc2cccc(C(=O)O)c2)Sc2ccc(C)cc2)cc1OC
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 85.1 %

Procedure:
To a cold (-78° C.) solution of 1.86 g of 3,4-dimethoxy-α-[(4-methylphenyl)thio]benzene acetonitrile in 15 mL of tetrahydrofuran is added drop-wise a solution of 2.9 mL of n-butyl lithium (2.2M) in hexane. This solution is stirred at -78° C. for 35 minutes. A solution of 0.67 g of m-carboxybenzyl bromide in 5 mL of anhydrous tetrahydrofuran is added drop-wise, stirred at -78° C. for 40 minutes and then at room temperature for 15 minutes. The mixture is quenched with water and extracted with ethyl acetate. The ethyl acetate extract is washed with brine, dried and filtered. The filtrate is evaporated in vacuo to yield a yellow oil. This oil is purified by flash chromatography using methylene chloride/methyl alcohol (95:5) to yield 1.15 g of the desired product as a yellow foam.
Reaction SMILES: C1C=CC([I+][C:8]2[C:13]([C:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=CC=1.O.[NH2:18][C:19]1[C:20]([Cl:28])=[C:21]([CH:25]([CH3:27])[OH:26])[CH:22]=[CH:23][CH:24]=1>C(O)(C)C>[Cl:28][C:20]1[C:21]([CH:25]([OH:26])[CH3:27])=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: O=C([O-])c1ccccc1[I+]c1ccccc1
Reactant: CC(O)c1cccc(N)c1Cl
Solvent: O
Solvent: CC(C)O
Product: CC(O)c1cccc(Nc2ccccc2C(=O)O)c1Cl
Yield: 65.6 %

Procedure:
A mixture of diphenyliodonium-2-carboxylate monohydrate (11.4 g, 33.3 mmol), 3-amino-2-chloro-α-methylbenzenemethanol (5.2 g, 30.3 mmol), and cupric acetate (0.5 g) in isopropanol (100 mL) is heated at reflux for 12 hours under an argon atmosphere. The solvent is evaporated under vacuum and the remaining dark oil is taken up in 10% aqueous KOH. The insoluble material is removed by filtration through Celite-545, and the filtrate is extracted with ether to remove nonacidic impurities. The aqueous solution is acidified to pH=3 with concentrated HCl. The resulting precipitate is collected by filtration and purified by column chromatography (silica, ethyl acetate) to give pure 2-[[2-chloro-3-(1-hydroxyethyl)phenylamino]benzoic acid (5.8 g, 60%), mp=169-171° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][NH2:11].O1CCOCC1>ClCCl>[NH:10]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[CH:8]=[N:11]1
Reactant: NN
Reactant: O=Cc1cccnc1Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1cnc2[nH]ncc2c1
Temperature: 150 °C

Procedure:
2-Chloro-3-formylpyridine (15.02 g, 106 mmol, 1 equiv), hydrazine (10 mL, excess), and dioxane (90 mL) were combined in a sealed tube and heated at 150° C. for 16 hr. After cooling to room temperature, the solvent was evaporated in vacuo to provide a crude residue which was diluted with dichloromethane (600 mL). The organic solution was washed with water (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to provide 1H-pyrazolo[3,4-b]pyridine as a yellow powder which was used without further purification: LCMS (ES) M+H 120.3, Rf 0.20 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 ml/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile).
Reaction SMILES: C([O-])(=[O:3])C.[K+].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1([C:17]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)([CH3:19])[CH3:18])[CH2:16][O:15]1.C1OCCOCCOCCOCCOCCOC1>O.CC(N(C)C)=O>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]([OH:3])([C:17]([S:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)([CH3:19])[CH3:18])[CH2:16][OH:15]
Reactant: COc1ccc(CSC(C)(C)C2(c3ccc(F)cc3F)CO2)cc1
Reactant: CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(CSC(C)(C)C(O)(CO)c2ccc(F)cc2F)cc1
Temperature: 110 °C
Reaction time: 30 h
Yield: 75.2 %

Procedure:
A solution of 1.12 g (11.4 mmol) of potassium acetate in 2 ml of water was added to a solution of 2.0 g (5.7 mmol) of (±)-2-(2,4-difluorophenyl)-2-(1-((4-methoxyphenyl)methylthio)-1-methylethyl)oxirane and 0.15 g (0.57 mmol) of 18-crown-6 in 12 ml of DMA, and the mixture was stirred at 110° C. for 30 hours. After being allowed to cool, 50 ml of water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried, and distilled under reduced pressure to remove the solvent. The residue was purified by column chromatography using a mixed solvent of hexane and ethyl acetate (5:1) as an eluent. The solvent was removed by distillation under reduced pressure, and the residue was recrystallized from a mixed solvent of isopropyl ether and diethyl ether to obtain 1.58 g (75%) of (±)-2-(2,4-difluorophenyl)-3-((4-methoxyphenyl)methylthio)- 3-methylbutane-1,2-diol as a colorless crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[C:8]([NH2:16])[CH:7]=1)=[O:5])[CH3:2].[CH:17](=O)[CH3:18]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:15])[F:14])=[C:8]([NH:16][CH2:17][CH3:18])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC=O
Reactant: CCOC(=O)c1ccc(C(F)(F)F)c(N)c1
Agent: [Pd]
Solvent: CCO
Product: CCNc1cc(C(=O)OCC)ccc1C(F)(F)F

Procedure:
To 0.466 g. of 2-amino-α,α,α-trifluoro-p-toluic acid ethyl ester (prepared according to the procedure described in Example 2) predissolved in 20 ml. of anhydrous ethanol is added 5 ml. of 31% aqueous acetaldehyde and 46 mg. of 10% palladium on carbon. The resultant mixture is then hydrogenated at 60° for 18 hours. The reaction mixture is then cooled, filtered, the solvent removed, and the resultant oil is chromatographed on preparative thin layer plates to yield 2-ethylamino-α,α,α-trifluoro-p-toluic acid ethyl ester (N-ethyl-4-trifluoromethylanthranilic acid ethyl ester).
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.CO.[ClH:31].C[CH2:33][O:34]CC>C(Cl)(Cl)Cl>[ClH:31].[C:4]1(=[O:23])[N:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][C:18]([C:19](=[NH:20])[O:34][CH3:33])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[C:1](=[O:28])[C:2]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:3]12
Reactant: CCOCC
Reactant: N#Cc1ccc(CCc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=N)c1ccc(CCc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 6 g of 4-[2-(4-phthalimidomethylphenyl)ethyl]benzonitrile in 300 ml of chloroform, was added at room temperature slowly dropwise 50 ml of anhydrous methanol saturated with anhydrous hydrogen chloride. The mixture was stirred at room temperature for 15 hours. The reaction mixture was stripped of the solvent under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to yield 6 g of methyl 4-[2-(4-phthalimidomethylphenyl)ethyl]benzimidate hydrochloride; m.p. 238°-240° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[NH2:14][CH2:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][C@@H:22]([N:25]([CH2:29][CH3:30])[CH:26]([CH3:28])[CH3:27])[CH2:21][C@H:20]1[CH2:31][O:32][CH3:33])=[O:17].C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH:14][CH2:15][C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][C@@H:22]([N:25]([CH2:29][CH3:30])[CH:26]([CH3:28])[CH3:27])[CH2:21][C@H:20]2[CH2:31][O:32][CH3:33])=[O:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CCN(C(C)C)[C@@H]1CC[C@H](NC(=O)CN)[C@H](COC)C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(C)C)[C@@H]1CC[C@H](NC(=O)CNc2nc(Cl)nc3ccc(Cl)cc23)[C@H](COC)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,4,6-trichloroquinazoline (103 mg) and the bis-trifluoroacetic acid salt of 2-amino-N-((1S,2R,4R)-4-(ethyl(isopropyl)amino)-2-(methoxymethyl)cyclohexyl)acetamide (152 mg) in tetrahydrofuran (3 mL) was treated with diisopropylethylamine (0.31 mL) and the mixture was stirred overnight at rt. The mixture was concentrated and purified by reverse phase HPLC and lyophilization to provide the bis-trifluoroacetic acid salt of the title compound, 2-(2,6-dichloroquinazolin-4-ylamino)-N-((1S,2R,4R)-4-(ethyl(isopropyl)amino)-2-(methoxymethyl)cyclohexyl)acetamide, as a white powder (79 mg). MS found: (M+H)+=482.2.
Reaction SMILES: CO.[C:3]([NH:11][C:12]1[CH:20]=[C:19](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[C:3]([NH:11][C:12]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Nc1cc(/C=C/c2cccc(Cl)c2)ccc1C(=O)O)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(CCc2cccc(Cl)c2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9 mg of 5% palladium-carbon was added to a mixed solution of 2.7 mL of methanol and 2.7 mL of ethyl acetate containing 30 mg of 2-benzamido-4-((E)-2-(3-chlorophenyl)vinyl)benzoic acid and stirred under hydrogen atmosphere at room temperature for 3 hours. Insoluble were removed by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 60-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 2.0 mg of 2-(benzamido)-4-(2-(3-chlorophenyl)ethyl)benzoic acid as white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]4[C:25]5[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=5[N:27]=[CH:28][N:29]=4)=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:13][NH2:14])=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]4[C:25]5[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=5[N:27]=[CH:28][N:29]=4)=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:13][NH:14][CH:2]([CH3:4])[CH3:1])=[CH:8][CH:7]=1
Reactant: CC(C)=O
Reactant: C[C@@H]1CCc2ncnc(-c3ccc4c(C(CN)c5ccc(Cl)cc5)c[nH]c4c3)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NC[C@H](c1ccc(Cl)cc1)c1c[nH]c2cc(-c3ncnc4c3[C@H](C)CC4)ccc12
Reaction time: 0.17 h
Yield: 16.7 %

Procedure:
Acetone (0.0195 mL, 0.266 mmol) was added to a solution of 2-(4-chlorophenyl)-2-(6-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indol-3-yl)ethanamine (107 mg, 0.266 mmol) and N,N-diisopropylethylamine (0.139 mL, 0.797 mmol) in methylene chloride (2.0 mL). The reaction mixture was stirred for 10 minutes, and then sodium triacetoxyborohydride (0.0188 g, 0.0885 mmol) was added. After stirring for 2.5 hours, saturated NaHCO3 was added, and the mixture was stirred vigorously 10 minutes. The mixture was extracted with DCM (3×10 mL). The combined organic were dried (Na2SO4), filtered and concentrated. The crude product was purified by SFC chiral chromatography (Chiral OJH (21.2×250 mm) 25% methanol+0.1% TEA) to give N-((R)-2-(4-chlorophenyl)-2-(6-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indol-3-yl)ethyl)propan-2-amine (19.8 mg, 16.8%) as the first peak. LCMS: M+1 445.3. 1H NMR (CDCl3, 400 MHz) δ 11.16 (s, 1H), 8.93 (s, 1H), 7.93 (s, 1H), 7.49-7.46 (m, 3H), 7.38 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 4.36 (t, 1H), 3.89 (m, 1H), 3.23 (m, 1H), 3.14-2.99 (m, 2H), 2.94-2.86 (m, 1H), 2.77 (m, 1H), 2.34 (m, 1H), 1.68 (m, 1H), 0.96 (d, 6H), 0.92 (d, 3H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:30]2[CH:31]=[N:32][CH:33]=[C:28]([Cl:27])[CH:29]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cncc(Cl)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2cncc(Cl)c2)nc1

Procedure:
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 5-chloro-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=40%).