Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].CO[C:12](OC)(OC)[CH2:13][CH2:14][CH2:15][CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1>COCCO>[CH2:13]([C:12]1[NH:9][C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[Cl:1])[N:8]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(OC)(OC)OC
Reactant: Nc1ncnc(Cl)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: CCCCc1nc2ncnc(Cl)c2[nH]1
Yield: 26.8 %

Procedure:
A mixture of 6-Chloro-4,5-diaminopyrimidine (0.289 g, 2 mmol) (from Step 1 of Example 12), trimethylorthovalerate (0.52 ml, 3 mmol) and p-TsOH (0.04 g) in 2-methoxyethanol (10 ml) was refluxed for 24 hours. The product was isolated and purified as described in Step 2 of Example 12 to give the crystalline titled compound (0.113 g, 23%). NMR (CDCl3): δ 0.997 (t, J=9 Hz, 3H), 1.484 (m, 2H), 1.925 (m, 2H), 3.075 (m, 2H), 7.27 (s, 1H) and 8.723 (s, 1H). FAB-MS: m/e 211 and 213 (M+H). Analysis calculated for C9H11N4Cl: C, 51.31; H, 5.26; N, 26.60. Found: C, 51.34; H, 5.30, N, 26.46.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11](OS(C)(=O)=O)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O1CCCC1>[C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: C1CNCCN1
Reactant: CC(=O)O[C@H](C)c1nccc(OS(C)(=O)=O)n1
Solvent: C1CCOC1
Product: CC(=O)O[C@H](C)c1nccc(N2CCNCC2)n1
Yield: 88 %

Procedure:
A mixture of (R)-1-(4-methanesulfonyloxy-pyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Six, 24.1 g, 92 mmol) and piperazine (16.0 g, 184 mmol) in tetrahydrofuran (200 mL) was heated at reflux for 1 h. This mixture was cooled, filtered, concentrated, and purified by flash column chromatography (9:1 dichloromethane/methanol) to give 24.4 g (88%) of the title compound as an oil. 1H NMR (CDCl3, 300 MHz) δ 1.56 (d, 3H), 2.25 (s, 3H), 2.83 (m, 4H), 3.63 (m, 4H), 5.54 (q, 1H), 6.38 (d, 1H), 8.24 (d, 1H); MS (Cl) 251 (MH+).
Reaction SMILES: [Mn:1].[C:2]([OH:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([OH:12])=[O:11])([C:6]([OH:8])=[O:7])[OH:5].[O-2].[Mn+2]>O>[C:2]([O-:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([O-:12])=[O:11])([C:6]([O-:8])=[O:7])[OH:5].[Mn+3:1]
Reactant: [Mn]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Mn+2]
Agent: [O-2]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [Mn+3]

Procedure:
A fertilizer additive containing 5% manganese was prepared by adding 360 grams of citric acid to 1181 grams of water. After the citric acid was dissolved, 128 grams of manganese (II) oxide was added to the mix and allowed to react and form manganese citrate, an insoluble white to very light pink precipitate. After the precipitate formed, 320 grams of 2-hydroxyethylamine and 10 grams of dimethylaminopropylamine were added. The precipitate was dissolved to produce a clear 5% manganese chelated solution having a pH of 10.8. This additive was added to conventional, N--P--K liquid fertilizers to produce clear fertilizer compositions.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH:9]1[CH2:28][OH:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:32](I)[CH3:33]>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)[CH2:10][CH:9]1[CH2:28][O:29][CH2:32][CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: COc1cc(C(=O)N2CCN(Cc3ccccc3)C(CO)C2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1Cc1ccccc1
Reaction time: 0.08 h

Procedure:
In N,N-dimethylformamide (2 ml) is dissolved 1-benzyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-methanol (1.0 g). The solution is added dropwise to a mixture of sodium hydride (0.15 g) and N,N-dimethylformamide (4 ml) taking 5 minutes at 0 ° C while stirring. To the mixture is further added ethyl iodide (0.5 g) at 0° C., followed by stirring for 30 minutes at room temperature. The reaction mixture is poured into icewater and extracted with ethyl acetate. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure to afford 1-benzyl-2-ethoxymethyl-4-(3,4,5trimethoxybenzoyl)piperazine as a colorless oily product (1.0 g). This product is led to its hydrochloride, followed by recrystallization from acetone to give colorless needles, m.p. 130-132° C.
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].[Mg].C(Br)C.C#CC.[C:13]1([C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CCOCC.C1COCC1>[C:13]1([C:19]([C:1]#[C:2][CH3:3])([OH:24])[C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C(=O)c1ccccc1
Reactant: CC#C[Mg]Br
Agent: C#CC
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: CCBr
Solvent: C1CCOC1
Product: CC#CC(O)(C(=O)OC)c1ccccc1
Reaction time: 24 h

Procedure:
1-Propynylmagnesium bromide (0.2 mole) was made from magnesium (4.8 g., 0.2 g. atom) ethyl bromide (21.8 g., 0.2 mole) and excess propyne gas in 400 ml. of THF. The Grignard reagent then was siphoned under nitrogen into an addition funnel and added dropwise over a 40 minute period to a cooled solution of methyl phenylglyoxylate (32.8 g., 0.2 mole) in 200 ml. of THF. A slight temperature rise took place. The reaction mixture was stirred for 24 hours, and then poured onto a slurry of ice and 25 ml. conc. HCl. Ether was added, and the layers were separated. Several more ether extracts were made and the organic extracts combined and dried. The volatile components were stripped subsequently in vacuo and the residue distilled to yield 13.1 g. (32%) of the product, b.p. 109°-12° (0.2 mm.). The oil solidified on standing and melted at 64°-65° after recrystallization from 20°-40° petroleum ether.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1.C=O.[CH2:12](N(CC)CC)C.[Cl:19][C:20]1[CH:21]=[C:22]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH2:23][N:24]([CH3:36])[C:25](=[O:35])[CH:26]=[C:27]1[C:31](=[O:32])OC(C)(C)[O:28]1>CO>[Cl:19][C:20]1[CH:21]=[C:22]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH2:23][N:24]([CH3:36])[C:25]([C:26]1[CH2:12][N:3]([CH:4]2[CH2:9][CH2:8][CH2:7][NH:6][CH2:5]2)[C:31](=[O:32])[C:27]=1[OH:28])=[O:35]
Reactant: CCN(CC)CC
Reactant: NC1CCCNC1
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Agent: C=O
Agent: Cl
Solvent: CO
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(C2CCCNC2)C1
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a stirred warm (60° C.) solution of 3-aminopiperidine dihydrochloride (150 mg, 0.867 mmol), paraformaldehyde (34 mg, 1.04 mmol) and triethylamine (0.3 mL, 2.14 mmol) in methanol (5 mL) was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (300 mg, 0.872 mmol). After 1 h, the reaction mixture was cooled and purified by preparative HPLC using a C18 column and water/methanol (0.001 mM HCl) as eluent. The fractions containing the desired product were combined, concentrated and lyophilized to give the corresponding hydrochloride salt of the title compound as a white powder (162 mg, 43% yield). 1HNMR (500 MHz, DMSO-d6) δ: 11.06 (1H, br s), 9.35 (1H, d, J=10.1 Hz), 9.10–8.99 (1H, m), 7.62 (1H, d, J=8.2 Hz), 7.52 (1H, s), 7.29–7.20 (1H, br s), 4.59 (2H, d, JAB=15.7 Hz), 4.34–3.88 (4H, m), 3.40–2.73 (6H, m), 1.90–1.74 (4H, m). HRMS calcd for C18H22Cl2N3O3 (M+H): 398.1038; found: 398.1042.
Reaction SMILES: [CH2:1]([C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)([CH2:7][CH2:8][OH:9])[CH2:4][CH2:5][OH:6])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1(C)C=CC=CC=1>[CH3:26][S:27]([O:6][CH2:5][CH2:4][C:3]([CH2:1][CH3:2])([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:7][CH2:8][O:9][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:29])=[O:28]
Reactant: CCC(CCO)(CCO)c1cccc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(CCOS(C)(=O)=O)(CCOS(C)(=O)=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-ethyl-3-(3-nitrophenyl)-1,5-pentanediol (Preparation 61, 661 mg, 2.27 mmol) in toluene (24 ml) was added triethylamine (0.76 ml, 5.43 mmol) followed by methanesulfonyl chloride (0.42 ml, 5.4 mmol). The reaction mixture was stirred at room temperature under nitrogen for 18 h. The reaction mixture was poured onto water (10 ml), the phases were separated and the aqueous layer was extracted with dichloromethane (10 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an oil which was used without further purification (850 mg, 81% crude yield).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O.[CH3:34][O:35][CH2:36]/[CH:37]=[CH:38]/B1OC(C)(C)C(C)(C)O1>O1CCOCC1.CCOC(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>[OH:26][C:6]1[C:5]2[C:10](=[CH:11][C:2](/[CH:38]=[CH:37]/[CH2:36][O:35][CH3:34])=[CH:3][CH:4]=2)[C:9]([CH3:13])([CH3:12])[C:8](=[O:14])[C:7]=1[C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[O:16]
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=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: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC/C=C/c1ccc2c(c1)C(C)(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Temperature: 80 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
1,1-Dimethylethyl N-((7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (500 mg, 1178 μmol, see Example 53) was dissolved in 1,4-dioxane (11785 μL). 2M K2CO3 in water (2357 μL, 4714 μmol), Pd(Ph3P)4 (136 mg, 118 μmol), and (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 μL, 1414 μmol) were added, and the reaction was stirred at 80° C. for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (385 mg) after flash chromatography. MS m/e=438 (M+Na)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH:3]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.C(N(CC)CC)C.C(#N)C>O>[CH:20]1([NH:23][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([CH2:11][C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH:3]=2)[CH2:22][CH2:21]1
Reactant: N#Cc1cccc(Cc2cc(Cl)n3nccc3n2)c1
Reactant: NC1CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cccc(Cc2cc(NC3CC3)n3nccc3n2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To the reaction flask, 3-((7-chloropyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile (400 mg, 1.5 mmol) was added along with cyclopropylamine (115 μL, 1.6 mmol), triethylamine (230 μL, 1.6 mmol), and acetonitrile (3 mL). The reaction was stirred at room temperature for 8 hours at 80° C. then cooled to room temperature, diluted with water, filtered and washed with water. The product, 3-((7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile, was collected as a solid in 83% yield after drying under vacuum overnight. LCMS (M+1=290)
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCOCC1)CC2

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), morpholine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 311 (M+, 2), 132 (3), 131 (5), 101 (6), 100 (bp), 56 (6).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.N1C=CC=CC=1.C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:21])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(Cl)Cc1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
Dissolve 4-bromophenylacetic acid (25.39; 118.07 mmol) in ether (200 mL). Add anhydrous pyridine (1 mL) and cool the reaction to 0° C., then add oxalyl chloride (18.44 g, 12.86 mL, 145.32 mmol). After 15 minutes, allow the reaction to come to ambient temperature. At 1.5 hours, add DMF (0.4 mL) and stir for an additional hour. Concentrate to a thick amber oil. Dilute with dichloromethane (118 mL) to provide a 1 N stock solution of (4-bromo-phenyl)-acetyl chloride (118 mmol).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:55][CH2:56][CH2:57][N:58]1[CH2:62][CH2:61][CH2:60][C@H:59]1[C:63](=[O:67])[N:64]([CH3:66])[CH3:65].OCCCN1CCC[C@H]1C(=O)N(CC)CC>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:55][CH2:56][CH2:57][N:58]4[CH2:62][CH2:61][CH2:60][C@H:59]4[C:63](=[O:67])[N:64]([CH3:65])[CH3:66])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: CN(C)C(=O)[C@@H]1CCCN1CCCO
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCN(CC)C(=O)[C@@H]1CCCN1CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCN1CCC[C@H]1C(=O)N(C)C
Product: Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
Diethyl azodicarboxylate (0.18 ml, 1.14 mmol) was added dropwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (111 mg, 0.35 mmol), (prepared as described for the staring material in Example 2), triphenylphosphine (312 mg, 1.19 mmol) and (S)-1-(3-hydroxypropyl)-2-(N,N-dimethylcarbamoyl)pyrrolidine (84 mg, 0.42 mmol) in methylene chloride (10 ml) cooled at 0° C. under nitrogen. The mixture was stirred for 15 minutes at 0° C., the mixture was allowed to warm to ambient temperature and was then stirred for 22 hours. Further (S)-1-(3-hydroxypropyl)-2-(N,N-diethylcarbamoyl)pyrrolidine (10 mg, 0.05 mmol), triphenylphosphine (35 mg, 0.13 mmol) and diethyl azodicarboxylate (20 μl, 0.13 mmol) were added and the mixture was stirred for a further 2 hours. The mixture was partitioned between water and methylene chloride and the aqueous phase was adjusted to pH2 with 2M hydrochloric acid. The aqueous layer was separated, adjusted to pH9 with sodium hydrogen carbonate and was extracted with methylene chloride. The combined organic extracts were washed with water and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica eluting with methylene chloride/methanol (85/15 followed by 75/25 and 60/40). The purified product was dissolved in methylene chloride (5 ml) and methanol (1 ml), 3.9M ethereal hydrogen chloride (0.5 ml) was added and the mixture was diluted with ether. The resulting precipitate was collected by filtration, washed with ether, and dried under vacuum to give (S)-4-(4-chloro-2-fluoroanilino)-7-(3-(2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazoline hydrochloride (86 mg, 32%).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C:7]2[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:38])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[C:31]([F:32])=[CH:30][CH:29]=[C:28]([O:33][CH2:34][CH3:35])[C:27]=4[F:36])=[CH:22][C:21]3=[O:37])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:11][CH:12]=2)[CH2:4][O:3]1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:6][C@@H:5]([C:7]1[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:38])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[C:28]([O:33][CH2:34][CH3:35])[C:27]=3[F:36])=[CH:22][C:21]2=[O:37])[CH2:16][CH:17]([CH3:18])[CH3:19])=[N:11][CH:12]=1)[CH2:4][OH:3]
Reactant: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3cnc([C@H]4COC(C)(C)O4)cn3)C2)c1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3cnc([C@H](O)CO)cn3)C2)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.1 %

Procedure:
A solution of (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-amide (prepared in Example 152, 0.251 g, 0.46 mmol) in tetrahydrofuran (25 mL) was treated with 1N aqueous hydrochloric acid (10 mL). The reaction mixture was stirred for 20 h at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 10% to 100% (9:1 dichloromethane:methanol)/hexanes) to afford (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-amide (0.210 g, 90%) as a fluffy white solid: HR-ES-MS m/z calculated for C24H28F2N4O6, [M+H]+ 507.2050 observed 507.2051; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.9 Hz, 3H), 1.35 (t, J=6.9 Hz, 3H), 1.40-1.56 (m, 1H), 1.56-1.73 (m, 1H), 1.75-1.93 (m, 1H), 3.42-3.62 (m, 1H), 3.61-3.74 (m, 1H), 4.13 (q, J=6.9 Hz, 2H), 4.31 (d, J=18.7 Hz, 1H), 4.51-4.69 (m, 2H), 4.73 (t, J=5.7 Hz, 1H). 5.02 (dd, J=10.6, 4.2 Hz, 1H), 5.08 (s, 1H), 5.55 (d, J=5.1 Hz, 1H), 7.12-7.23 (m, 1H), 7.23-7.33 (m, 1H), 8.45 (s, 1H), 9.17 (s, 1H), 11.16 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:38][C:39]([F:49])([F:48])[CH2:40][N:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1.CN1CCOCC1>CN(C)C(=O)C.O>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([NH:47][CH:44]3[CH2:45][CH2:46][N:41]([CH2:40][C:39]([F:49])([F:38])[F:48])[CH2:42][CH2:43]3)=[O:15])=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Reactant: NC1CCN(CC(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(NC1CCN(CC(F)(F)F)CC1)c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a 250 mL 3-necked flask containing 2-phenyl-5-pyridinecarboxylic acid (2.75 g, 13.8 mmol) in N,N-dimethylacetamide (DMA, 35 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC/EDC*HCl, 2.95 g, 15.2 mmol), 1-hydroxybenzotriazole (HOBt. 1.89 g, 13.8 mmol), 1-(2,2,2-trifluoroethyl)piperidin-4-amine (3.36 g, 15.2 mmol) and 4-methylmorpholine (NMM, 3.8 mL, 34.5 mmol). After stirring at room temperature for 1 hour, the reaction was diluted with water (˜200 mL) and the resulting solid collected by filtration. The solid was washed with H2O (3×100 mL), collected and dried in a vacuum oven (45° C.) overnight to give the desired product (4.24 g). LCMS (ES+) 4.30 min (TIC, 75%; 1H NMR purity >95%); 1H NMR (400 MHz, DMSO-d6) □ ppm 1.46-1.65 (m, 2H) 1.77 (d, J=10.80 Hz, 2 H) 2.31-2.54 (m, 4H) 2.90 (d, J=11.53 Hz, 2H) 3.65-3.86 (m, 1H) 7.36-7.56 (m, 3H) 8.01 (d, J=8.24 Hz, 1H) 8.09 (d, J=6.95 Hz, 2H) 8.22 (d, J=8.42 Hz, 1H) 8.38 (d, J=7.32 Hz, 1H) 9.02 (s, 1 H); MS(ES+) 364 (M+1); HRMS (TOF, ES+) calculated for C19H20F3N3O+H+: 364.1637; observed 364.1611.
Reaction SMILES: C([Al](CC(C)C)CC(C)C)C(C)C.[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2.[C:24](OC)(=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[OH:27].Cl>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.C(Cl)Cl>[OH:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[C:24]([NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2)=[O:32]
Reactant: COC(=O)c1ccccc1O
Reactant: Nc1cccc2[nH]ccc12
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1O
Temperature: 25 °C

Procedure:
92 ml of a solution of 1.1 mol/l of triisobutylaluminum in toluene were added slowly with stirring under an inert atmosphere to a solution of 6.6 g of 4-aminoindole in 250 ml of chloroform. 9.6 ml of methyl salicylate were then added and the mixture was refluxed for 20 hours and then cooled to room temperature. 300 ml of N hydrochloric acid and 300 ml of methylene chloride were added and the organic phase was washed with water, dried, and evaporated to dryness under reduced pressure at 50° C. The residue was made into a paste with ether, filtered and dried at 60° C. under reduced pressure to obtain 9.4 g of 2-hydroxy-N-(1H-indol-4-yl)benzamide melting at ≃232° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:25](OC)([O:28]C)[O:26]C>O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:25]([OH:28])[OH:26])[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]=2[O:9][CH2:8]1
Reactant: CCc1cc(Br)cc2c1OCC2(C)C
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCc1cc(B(O)O)cc2c1OCC2(C)C

Procedure:
Following General Procedure A and using 5-bromo-3,3-dimethyl-7-ethyl-2,3-dihydro-benzofuran (Intermediate 14, 0.76 g, 3 mmol), 15 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (3.53 mL, 6 mmol) and trimethyl borate (0.75 mL, 7 mmol), the title compound was obtained as a foam that was used as such for the next step without purification and characterization.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=4)[CH:17]3[C:27]([O:29][CH3:30])=[O:28])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37]O)[CH3:34].FC1C=CC(OC2C=CC(S(N3CCC4C(=CC=C(OCCCN5CCN(C)CC5)C=4)C3C(OC)=O)(=O)=O)=CC=2)=CC=1>>[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][O:26][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[CH:17]([C:27]([O:29][CH3:30])=[O:28])[N:16]([S:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:32][CH:31]=3)=[CH:12][CH:11]=1)(=[O:14])=[O:15])[CH2:25][CH2:24]2)[CH3:34]
Reactant: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: CCN(CC)CCO
Agent: COC(=O)C1c2ccc(OCCCN3CCN(C)CC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Product: CCN(CC)CCOc1ccc2c(c1)CCN(S(=O)(=O)c1ccc(Oc3ccc(F)cc3)cc1)C2C(=O)OC

Procedure:
Methyl 2-[4-(4-fluorophenoxy)benzenesulfonyl]-6-hydroxy-1,2,3,4-tetrahydro-isoquinoline-1-carboxylate (3B) is reacted with 2-diethylaminoethanol by the method described under 3C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][N:6]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)[CH:7]=1.[CH2:13]([OH:15])[CH3:14]>>[Cl:2][C:3]1[CH:4]=[N:5][N:6]([C:8]2([C:11](=[NH:12])[O:15][CH2:13][CH3:14])[CH2:9][CH2:10]2)[CH:7]=1
Reactant: CCO
Reactant: N#CC1(n2cc(Cl)cn2)CC1
Agent: Cl
Product: CCOC(=N)C1(n2cc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dry hydrogen chloride gas was bubbled through a solution of 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbonitrile (1.2 g, 0.75 mmol) in ethanol (10 mL) at 0° C. for 15 min. The mixture was then stirred at room temperature for 1 h. The solvent was removed under reduced pressure to afford ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate. The crude material was used without further purification.