Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.[Cu]I.[Cu]>[F:11][C:12]([F:20])([F:21])[C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccnc1Oc1cccc(C(F)(F)F)c1
Temperature: 140 °C
Yield: 29.5 %

Procedure:
To a solution of 2-chloro-nicotinic acid (1.0 g, 6.35 mmol, 1.0 equiv; [CAS RN 2942-59-8]) and 3-trifluoromethyl-phenol (1.03 g, 6.35 mmol, 1.0 equiv; [CAS RN 98-17-9]) in anhydrous DMF (5 mL) was added potassium carbonate (1.75 g, 12.69 mmol, 2.0 equiv; [CAS RN 584-08-7]), copper(I) iodide (0.12 g, 0.64 mmol, 0.1 equiv; [CAS RN 7681-65-4]) and copper(0) nanopowder with an averaged particle size of 100 nm (0.12 g, 1.90 mmol, 0.3 equiv; [CAS RN 7440-50-8]). The reaction mixture was heated by microwave irradiation to 140° C. for 30 min. The solvent was evaporated under reduced pressure and the crude reaction product taken up in water (25 mL) and filtered. The solution was adjusted to pH 4 by addition of acetic acid and the formed white precipitate filtered, washed with little cold water and dried under high vacuum providing 0.53 g (28%) of the title compound. 1H NMR (300 MHz, DMSO): δ7.26-7.30 (m, 1H), 7.43-7.50 (m, 2H), 7.57-7.66 (m, 2H), 8.26-8.29 (m, 2H). 19F NMR (282 MHz, DMSO): δ−61.0. MS (ISN): 282.1 [M−H]−.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1([C:17]([NH:19][CH:20]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23][OH:24])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[C:33]1[C:34]2[CH:41]=[CH:40][NH:39][C:35]=2[N:36]=[CH:37][N:38]=1>C(O)C>[NH2:10][C:11]1([C:17]([NH:19][CH:20]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23][OH:24])=[O:18])[CH2:16][CH2:15][N:14]([C:33]2[C:34]3[CH:41]=[CH:40][NH:39][C:35]=3[N:36]=[CH:37][N:38]=2)[CH2:13][CH2:12]1
Reactant: NC1(C(=O)NC(CCCO)c2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC1(C(=O)NC(CCCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
DIPEA (2.85 mL, 16.0 mmol) was added to 4-amino-N-(1-(4-chlorophenyl)-4-hydroxybutyl)piperidine-4-carboxamide (Intermediate 72) (1.04 g, 3.19 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.490 g, 3.19 mmol) in ethanol (15.96 mL) at 25° C. The resulting solution was stirred at 65° C. overnight. The crude product was analysed by LCMS and evaporated to dryness. The crude solid was then purified by ion exchange chromatography, using an SCX-2 column. The product was eluted from the column using 20% 7N ammonia in methanol/DCM. The crude mixture was then re-purified by flash silica chromatography (eluent 0-10% 7N ammonia/MeOH in DCM) and pure fractions evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-4-hydroxybutyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (63.9%) (racemate) as a fine white solid. The racemate was chirally resolved by supercritical flow chromatography (SFC) to afford the pure enantiomers in yields of 272 mg (19%) and 245 mg (17%) respectively. The NMR spectra for both enantiomers were identical.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[CH:10][O:11]C)=[CH:4][CH:3]=1.CC1C=CC(C=O)=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: COC=CCc1ccc(C)cc1
Agent: Cc1ccc(C=O)cc1
Product: Cc1ccc(CCC=O)cc1

Procedure:
4-Methyl 1-(3-methoxy-2-propen-1-yl)benzene was similarly prepared as described in Examples I and II. First, 4-methyl benzaldehyde (140 g, commercially available from Mitsubishi Gas Chemical Company, Inc.) was used to obtain 3-(4-methyl-phenyl)-propionaldehyde (130 g) with a boiling point of 120° C. at a pressure of 21 mmHg. 3-(4-Methyl-phenyl)-propionaldehyde (225 g) was consequently used to provide 4-methyl 1-(3-methoxy-2-propen-1-yl)benzene (139 g) with a boiling point of 117° C. at a pressure of 35 mmHg
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[O:16]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2ccccc2Oc2ccccc2)c1C(=O)OC
Yield: 73 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 2-phenoxyaniline (0.57 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.86 g of the product at 80:20 hexanes-ethyl acetate, in 73% yield: 1H NMR (CDCl3) δ 3.75 (s, 3H), 3.86 (s, 3H), 6.93-7.03 (m, 4H), 7.06-7.12 (m, 2H), 7.17 (dd, J=7.3 Hz, J=1.0 Hz, 1H), 7.29-7.38 (m, 4H), 7.46 (d, J=8.4 Hz, 1H), 7.89 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]1[C:11]2[CH2:12][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[OH:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:14][CH2:15][C:10]=2[CH:9]=[CH:8]1.C(N(CC)CC)C>ClCCl.CS(C)=O>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:13]2[CH2:14][CH2:15][C:10]3[CH:9]=[CH:8][O:7][C:11]=3[CH2:12]2)(=[O:17])=[O:18])=[CH:20][CH:21]=1)(=[O:26])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S(=O)(c1ccc(C(O)c2ccccc2)cc1)N1CCc2ccoc2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc(S(=O)(=O)N2CCc3ccoc3C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.04 ml (0.5 mmol) of oxalyl chloride in 30 ml of dichloromethane, 0.07 ml (1.0 mmol) of dimethyl sulfoxide was added dropwise at -78° C., followed by stirring for 5 minutes. To this solution, a solution of 0.122 g (0.330 mmol) of 4-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-ylsulfonyl)phenylphenylmethanol in 10 ml of dichloromethane and 1 ml of dimethyl sulfoxide was added at -78° C., followed by stirring for 15 minutes. To this mixture, 0.28 ml (2.0 mmol) of triethylamine was added; the mixture was allowed to warm to room temperature. After the reaction mixture was washed with water, the water layer was re-extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2.[CH3:30][NH2:31]>CS(C)=O>[OH:29][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([CH2:4][CH2:3][CH2:2][NH:31][CH3:30])[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]4[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=4[C:12]=3[C:11]=2[CH:10]=1
Reactant: CN
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCBr
Solvent: CS(C)=O
Product: CNCCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4)cc21)C(=O)NC3=O
Yield: 61.2 %

Procedure:
Bromide (204) (40 mg, 0.09 mmol) prepared as described in example 173 was reacted with aqueous methylamine solution (10 mol equiv.) according to the procedure described in example 179 except that the reaction was performed in dimethylsulfoxide at room temperature for 3 h, to give amine (214) (22 mg, 61%) as an orange/yellow powder, mp 265–268° C. 1H NMR δ [(CD3)2SO] 9.33 (br s, 1H), 8.41 (d, J=2.5 Hz, 1H), 7.80 (s, 1H), 7.64 (m, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.47 (m, 3H), 7.14 (dd, J=8.8, 2.5 Hz, 1H), 4.51 (t, J=6.8 Hz, 2H), 2.40 (t, J=6.5 Hz, 2H), 2.20 (s, 3H), 1.88 (m, 2H). FABMS found [M+H]+:400.1659. C24H22N3O3 requires 400.1661.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][CH3:10].O[CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:3]=1[CH2:9][CH3:10]
Reactant: CCc1cc(O)ccc1Cl
Reactant: COC(=O)C(C)(C)CO
Product: CCc1cc(OCC(C)(C)C(=O)OC)ccc1Cl
Yield: 85.3 %

Procedure:
By using 4-chloro-3-ethylphenol (2000 mg) and methyl hydroxypivalate (2025 mg), the procedure was carried out in the same manner as in Example 1-1) to obtain methyl 3-(4-chloro-3-ethylphenoxy)-2,2-dimethylpropanoate (2951 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:6]=1[CH2:7][N:8]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[F:17][C:2]([F:1])([F:16])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:6]=1[CH2:7][NH2:8]
Reactant: [N-]=[N+]=NCc1cc(Cl)ccc1OCC(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2,2,2-trifluoroethoxy)-5-chlorobenzyl azide (1.76 g, 6.63 mmol) in THF (20 mL) was added triphenylphosphine (2 g, 7.63 mmol). After stirring at room temperature for 2 h, water (0.5 mL) was added and the reaction mixture then heated at 65° C. for 2 h. After cooling back to room temperature the solvents were removed under reduced pressure. Following azeotroping with benzene, the residue was dissolved in ether and treated with an excess of cold 1M HCl in ether. The hydrochloride salt of the title compound was filtered off and washed well with ether and dichloromethane. Drying gave a white powder: 1H NMR (CD3OD) δ7.46 (m, 2H), 7.18 (d, J=8.4 Hz, 1H), 4.70 (q, J=8.4 Hz, 2H), 4.14 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:9][NH2:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.OO.[O-]Cl.[Na+]>O.CO>[CH2:9]1[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2][N:1]=[N:10]1
Reactant: NCC1(CN)CCOCC1
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CO
Product: C1CC2(CCO1)CN=NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
C-(4-Aminomethyl-tetrahydro-pyran-4-yl)-methylamine (1.0 g) was taken up in a mixture of H2O (10 mL) and MeOH (2.5 mL), and cooled in an ice bath. Simultaneously, H2O2 (4.8 mL of a 30% solution, 6 equiv.) and NaClO (12.4 mL of a 10% solution, 2.4 equiv.) were added dropwise, the ice bath was removed, and the mixture was stirred overnight at room temperature. Extraction with DCM, drying over Na2SO4 and evaporation under reduced pressure yielded 380 mg of a clear, light-yellow liquid containing 85% of the anticipated product and 15% of the diamine starting material. This material was used in subsequent steps without further purification. 1H NMR (400 MHz, CDCl3) δ 1.49 (t, 4H), 3.65 (t, 4H), 4.28 (s, 4H).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:33]5[CH:32]=[CH:31][CH:30]=[C:29]([N+:26]([O-:28])=[O:27])[CH:34]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cccc([N+](=O)[O-])c4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 3-nitrophenyl boronic acid. Mass spectrum (ESI) 437.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5]1[S:6][C:7]([CH3:12])=[CH:8][C:9]=1[C:10]#[N:11].[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1>>[CH3:12][C:7]1[S:6][C:5]2[NH:4][C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[N:1]=[C:10]([N:11]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:9]=2[CH:8]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(C#N)c(Nc2ccccc2N)s1
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1

Procedure:
The process disclosed herein comprises reaction of 2-(2-aminoanilino)-5-methylthiophene-3-carbonitrile [10] with N-methylpiperazine in conjunction with N-methyl piperazine acid salt to give Olanzapine. The reaction is carried out at 90-138° C., preferably at 110-125° C. in 6-12 hours.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30]C(=O)OC(C)(C)C)[N:17]=[CH:16]2.Cl>O1CCOCC1.ClCCl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH2:30])[N:17]=[CH:16]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3c2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
A mixture of tert-butyl ((1S,2R)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)cyclohexyl)carbamate (1.14 g, 2.1 mmol) and 4N HCl in Dioxane (5.2 mL) in dichloromethane (10 mL) was stirred at room temperature for 30 minutes. LC-MS indicated complete consumption of SM. The reaction mixture was concentrated to give (1R,2S)—N1-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)cyclohexane-1,2-diamine (0.94 g, 100%) which was used without further purification in the next step.
Reaction SMILES: I[CH:2]([CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].C([O-])(=O)C.[Na+]>[Pd].C(O)C>[F:19][C:14]([F:20])([C:15]([F:16])([F:17])[F:18])[CH2:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: OCCCCCCCCCC(I)CC(F)(F)C(F)(F)F
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCCCCCCCCCCC(F)(F)C(F)(F)F
Yield: 53.4 %

Procedure:
The reaction mixture containing 16.5 grams (0.04 mole) of the 10-iodo-12,12,13,13,13-pentafluorotridecanol of step (A), 2.0 grams of palladium/charcoal catalyst, and 3.3 grams (0.04 mole) of sodium acetate in 100 ml of ethanol was hydrogenated using a Parr hydrogenator. Upon completion of the uptake of the theoretical amount of hydrogen the reaction mixture was concentrated under reduced pressure and stirred with 125 ml of pentane. The mixture was filtered and the filtrate was concentrated under reduced pressure to a residual semi-solid. The residue was distilled under vacuum to yield 6.2 grams of 12,12,13,13,13-pentafluorotridecanol; b.p. 112° C./1.4 mm, which solidified on standing; m.p. 41°-43° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([CH3:31])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:32][C@@H:33]1[CH2:38][CH2:37][O:36][C:34]1=[O:35]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][C@@H:3]([CH3:31])[CH2:2][NH:1][C:34](=[O:35])[C@H:33]([OH:32])[CH2:38][CH2:37][OH:36])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: C[C@@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C1OCC[C@H]1O
Product: C[C@@H](CNC(=O)[C@H](O)CCO)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 62 %

Procedure:
The procedure described in Example 63 was repeated using 5-[(1S)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 36, preparation of starting materials) and (R)-(+)-α-hydroxy-γ-butyrolactone to give the title compound in 62% yield; NMR spectrum (DMSO-d6) 1.31-1.47 (m, 4H), 1.64-1.77 (m, 1H), 3.33-3.50 (m, 3H), 3.71-3.84 (m, 1H), 3.90-4.00 (m, 1H), 4.32 (t, 1H), 4.87-4.98 (m, 1H), 5.29 (s, 2H), 5.48 (d, 1H), 7.18-7.27 (m, 2H), 7.28-7.40 (m, 2H), 7.54-7.64 (m, 2H), 7.87 (dt, 1H), 8.10-8.21 (m, 2H), 8.47 (s, 1H), 8.59 (d, 1H), 9.95 (s, 1H); Mass spectrum MH+ 537.9.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:11]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([N:8]=[C:10]=[S:11])=[N:6][CH:7]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1cc(N)ncc1Cl
Solvent: ClCCl
Product: Cc1cc(N=C=S)ncc1Cl
Temperature: 40 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To 5-chloro-4-methylpyridin-2-amine (0.41 g, 2.88 mmol) in dichloromethane (25 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.70 g, 3.0 mmol). The reaction was stirred at 40° C. for 3 hours. The reaction was cooled to room temperature. The crude mixture was purified by chromatography (Biotage: 25-100% ethyl acetate/hexane) to yield 5-chloro-2-isothiocyanato-4-methylpyridine (0.45 g, 2.44 mmol, 85% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.45 (s, 1H), 7.47 (s, 1H), 2.37 (s, 3H). LC/MS RT=2.79; [M+H]+=184.9.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([NH2:30])[CH3:29])[CH:23]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>[Cl-].[Na+].O.CN(C=O)C>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([NH:30][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=3)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=2)=[O:13])[CH3:29])[CH:23]=1
Reactant: CC(N)c1cccnc1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)c1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
2-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (300 mg, 0.81 mmol), 1-(pyridin-3-yl)ethanamine (148 mg, 1.21 mmol) and DIPEA (0.42 mL, 2.42 mmol) were combined with DMF (5 mL) to give a yellow solution. Then HATU (306 mg, 0.81 mmol) was added and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was diluted with brine and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water and brine then dried over MgSO4, filtered and concentrated in vacuo to afford 350 mg (91%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-3-yl-ethyl)-amide as a yellow oil. MS: (M+H)+=477.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=O)[CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:53]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)=[O:21])[CH:18]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(C(=O)O)cs2)C1
Reactant: C1CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(C(=O)N3CCCCCC3)cs2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
3-(4-Carboxy-thiophen-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.075 g, 0.24 mmol) was dissolved in DMF (2 mL). Triethylamine (0.72 mmol), HATU (0.26 mmol) and homopiperidine (0.26 mmol) were added and the reaction stirred at room temperature overnight. The reaction mixture was purified directly by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.066 g). LCMS m/z 393.26 [M+H]+ RT=4.05 min (Analytical Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:55][C:56]([F:68])([F:67])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[C:63]1([NH2:66])[CH2:65][CH2:64]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:66][C:63]3([C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=4[C:56]([F:55])([F:67])[F:68])[CH2:65][CH2:64]3)=[O:21])=[CH:17][CH:16]=2)[N:10]=1
Reactant: O=C(O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: NC1(c2ccccc2C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(c2ccccc2C(F)(F)F)CC1)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 13.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoic acid (Intermediate-9, 0.100 g, 0.290 mmol), THF (10 mL), di-isopropyl ethyl amine (10.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[2-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-12, 0.035 g, 0.350 mmol) to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.23 (s, 2H), 1.31 (s, 2H), 7.59 (d, J=7.2 Hz, 2H), 7.65-7.68 (m, 4H), 7.82 (d, J=12.0 Hz, 2H), 7.88-8.02 (m, 3H), 8.77 (s, 1H), 12.60 (br s, 1H); MS (m/z): 517.03 (M+).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15](=[O:17])[NH2:16])[CH:7]=1)C.[OH-].[Na+]>CO.O>[C:15]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:5][C:4]([OH:18])=[O:3])=[CH:7]1)(=[O:17])[NH2:16]
Reactant: CCOC(=O)Cc1cn(C(N)=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)n1cc(CC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of (1-carbamoyl-1H-indol-3-yl)-acetic acid ethyl ester in methanol (61 mL) and water (6.1 mL) was added an 1N aqueous solution of NaOH (12.2 mL, 12.2 mmol) and the resulting yellow solution was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was suspended in HCl 1N. The aqueous mixture was extracted with EtOAC (3×), the combined organic extracts were dried (phase separator) and concentrated in vacuo. The crude product was used directly in the next step without any further purification. MS: 219 [M+H]+, 437 [2M+H]+; tR (HPLC conditions b) 2.16 min.