Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.[NH:53]1[CH:57]=[N:56][C:55]([C:58](O)=[O:59])=[N:54]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:58]([C:55]2[N:56]=[CH:57][NH:53][N:54]=2)=[O:59])[CH2:25]1
Reactant: O=C(O)c1nc[nH]n1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CN(C(=O)c2nc[nH]n2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 57 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 1H-1,2,4-triazole-3-carboxylic acid as the starting materials in 57% yield. LCMS for C25H24ClN10O2 (M+H)+: m/z=531.0.
Reaction SMILES: [CH:1]([N:4]([CH3:30])[C:5]1[C:6]([C:19]2[O:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([N:4]([CH3:30])[C:5]1[C:6]([C:19]2[O:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3cc(-c4ccccc4)co3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc(-c2ccccc2)co1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(4-phenylfuran-2-yl)quinoxaline-6-carboxylate (70 mg, 0.17 mmol) in MeOH (20 mL) was added sodium hydroxide (28 mg, 0.70 mmol) and water (2 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (3 mL) and adjusted to pH 6 with HCl (1N). The solids were collected by filtration to afford 3-(isopropyl(methyl)amino)-2-(4-phenylfuran-2-yl)quinoxaline-6-carboxylic acid (43 mg, 64%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][O:29][C:30]2[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=2[Cl:38])=[CH:22][CH:21]=1)[C:4]([N:6]([CH:16]1[CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[Cl:15])=[O:5].[CH2:39]=O>>[Cl:38][C:31]1[C:32]([F:37])=[CH:33][CH:34]=[C:35]([F:36])[C:30]=1[O:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:3]([CH2:2][NH:1][CH3:39])[C:4]([N:6]([CH:16]2[CH2:17][CH2:18]2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[O:5])=[CH:21][CH:22]=1
Reactant: C=O
Reactant: NCC(Cc1ccc(CCCOc2c(F)ccc(F)c2Cl)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Product: CNCC(Cc1ccc(CCCOc2c(F)ccc(F)c2Cl)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1

Procedure:
Prepared according to the procedure described in Example 19 but using instead 3-amino-2-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]benzyl}-N-cyclopropyl-N-(2,3-dichlorobenzyl)propanamide (Example 15) and paraformaldehyde. The title compound was obtained as a colorless oil. MS (ESI+): 595.3.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[C:14](Cl)=[O:15])[CH3:9]>>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:14](=[O:15])[C:2]([CH3:7])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:9]
Reactant: CCOc1ccc(C(=O)Cl)cc1OCC
Reactant: COC(=O)C(C)C
Product: CCOc1ccc(C(=O)C(C)(C)C(=O)OC)cc1OCC

Procedure:
Prepared analogously as described for the example D1 using methyl 2-methylproponate and 3,4-diethoxybenzoyl chloride as starting compounds.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH:8]([CH3:14])[C:9]([O:11]CC)=O)=[N:3][CH:2]=1.Cl.Cl.[NH:18]1[CH2:23][CH2:22][CH2:21][N:20]=[C:19]1[NH2:24]>>[CH3:14][C:8]1[C:9](=[O:11])[N:18]2[CH2:23][CH2:22][CH2:21][NH:20][C:19]2=[N:24][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][N:3]=1
Reactant: NC1=NCCCN1
Reactant: CCOC(=O)C(C)C(=O)c1ccncn1
Agent: Cl
Product: Cc1c(-c2ccncn2)nc2n(c1=O)CCCN2

Procedure:
A mixture of 10.72 g (51.48 mmol) of ethyl 3-(4-pyrimidinyl)-2-methyl-3-oxopropionate, (prepared by analogy to the method described in patent DE 2705641 and U.S. Pat. No. 4,110,450) 6.98 g (51.48 mmol) of 1,4,5,6-tetrahydro-2-pyrimidinamine dihydrochloride
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13](Cl)=[O:14].[OH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH3:27])[CH:18]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH3:27])[CH:18]=1)=[O:14]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: Cc1cc(O)c2ccccc2n1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(OC(=O)c2c(-c3ccccc3)noc2C)c2ccccc2n1
Temperature: 70 °C
Yield: 64.4 %

Procedure:
5-Methyl-3-phenylisoxazole-4-carbonyl chloride (100 mg) and 4-hydroxy-2-methylquinoline (250 mg) were dissolved in dichlorormethane (10 mL) and pyridine (0.2 mL). The reaction solution was heated at 70° C. overnight and then diluted with ethyl acetate (60 mL). The organic solution was washed with water (60 mL), dried, evaporated and purified by flash column chromatography (EtOAc/hexanes=1/2) to give 5-methyl-3-phenyl-4-isoxazolecarboxylic acid, 2-methyl-4-quinolinyl ester (100 mg). 1H NMR (CDCl3): δ 2.74 (s, 3H), 2.91 (s, 3H), 7.29 (s, 1H), 7.33-7.46 (m, 5H), 7.64-7.71 (m, 3H), 8.01 (td, J=0.9 and 8.4 Hz, 1H); LCMS: ret. time: 23.10 min.; purity: 100%; MS (m/e): 345.02 (MH+).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][NH2:15]>C1COCC1.O>[CH3:14][NH:15][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc2ccc([N+](=O)[O-])cc2s1
Yield: 88 %

Procedure:
Place 2-chloro-6-nitro-benzothiazole (5.82 g, 27.1 mmol) in THF (130 mL). Add 40% methylamine in water (7 mL) and stir until the product precipitates out. Concentrate in vacuo and then triturate with methanol. Filter off the product and wash with methanol, Dry thoroughly to yield 4.99 g (88%) of the title compound: mass spectrum (ion-spray): (m/z)=210.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:26].O>CN(C)C=O>[CH3:26][N:7]([CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:14][CH:15]=1)[CH3:9])[C:6](=[O:22])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(OCC(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccc(OCC(F)(F)F)nc1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 86 %

Procedure:
To a stirred solution of tert-butyl(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)carbamate (221 mg, 0.69 mmol, Step-1, single enantiomer) and sodium hydride (61 mg, 1.52 mmol, 60% in oil) in N,N-dimethylformamide (7 mL) is added dropwise iodomethane (0.065 mL, 1.04 mL) at room temperature. After stirring at room temperature for 3.5 hours, the reaction mixture is slowly poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer is washed with water (30 mL) and dried over sodium sulfate. After concentration in vacuo, the residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (9:1) to give 198 mg (86% yield) of the title compound as colorless oil.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1.C(N(CC)CC)C>C(#N)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:16][CH:17]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cn2)CC1
Yield: 36.9 %

Procedure:
Tert-butyl piperazine-1-carboxylate (300 mg, 1.611 mmol) and 2-bromo-5-chloropyridine (465 mg, 2.416 mmol) were dissolved in acetonitrile (3 ml), followed by addition of triethylamine (0.45 ml, 3.222 mmol), and then the resulting liquid was subjected to microwave irradiation at 150° C. for 2 hours. The resulting reaction liquid was concentrated under reduced pressure, followed by addition of a saturated aqueous ammonium chloride solution (10 ml), and extracted with MC (15 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (20% EtOAc/Hexanes), to obtain 177 mg of colorless oil (37%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7]1>C(O)(=O)C.C(OC(=O)C)(=O)C>[N+:1]([C:13]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7][C:6]([CH3:18])([CH3:5])[C:15]=2[CH:14]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 8 h

Procedure:
77.2 ml of glacial acetic acid and 20.8 ml of nitric acid (98% strength) were mixed while cooling and then added dropwise within 2 hours to a solution of 65.8 g (0.35 mol) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 154 ml of glacial acetic acid and 257 ml of acetic anhydride in a salt/ice bath. After the addition was complete, the reaction mixture was washed to room temperature and stirred overnight. The solution was then poured into water, and the precipitate was filtered off with suction, washed with water and dried. 79.7 g of crude 2-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene of melting point 46°-50° C. were obtained.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.C([O:12][C:13](=[O:25])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:23]#[CH:24])(C)(C)C.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]([OH:25])=[O:12])=[C:17]([C:23]#[C:24][C:2]2[S:3][C:4]([Cl:7])=[CH:5][CH:6]=2)[CH:18]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Clc1ccc(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccc(Cl)s1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 2-bromo-5-chlorothiophene (Aldrich, 163 mg; 0.82 mmol), tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3, 200 mg; 0.75 mmol), dichlorobis(triphenylphosphine)palladium(II) (33 mg; 0.04 mmol), copper(I) iodide (8.6 mg; 0.04 mmol) was degassed during two minutes under nitrogen then THF (3 mL) and triethylamine (208 μL; 1.50 mmol) were added and reaction mixture was stirred at 60° C. for 16 hours. The solvent was evaporated and the residue was treated with an HCl solution (4 N in dioxane, 3.7 mL). After stirring for 16 hours, the solvents were removed under vacuum and the crude product purified by preparative HPLC. The title compound was obtained as a brown sticky solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])=[O:17])#[N:12].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>>[C:11]([C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:17])#[N:12]
Reactant: N#Cc1cccc(C(=O)Nc2ccccc2O)c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccccc2NC(=O)c2cccc(C#N)c2)cc1

Procedure:
Using a procedure similar to Example 32A except starting from 4-methoxybenzyl chloride and N1-(3-cyanobenzoyl)-2-hydroxyaniline and using K2CO3/DMF in place of potassium t-butoxide/THF, the title compound was obtained as a solid (27%); MS(FD): 359.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:14])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[C:12]#[N:13].C[O-].[Na+].CN(C)[CH:20]=[O:21]>CO>[C:12]([C:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([CH3:14])=[N:3][C:2]=1[O:21][CH3:20])#[N:13]
Reactant: Cc1nc(Cl)c(C#N)c2c1CCCC2
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)c2c(c1C#N)CCCC2

Procedure:
3-Chloro-4-cyano-1-methyl-5,6,7,8-tetrahydroisoquinoline (10.0 g) was refluxed with sodium methoxide (1.1 equiv) in a mixture of methanol (150 ml) and anhydrous dimethylformamide (20 ml) for 24 hr. The bulk of the solvent was evaporated under reduced pressure, water was added to the residue and the resulting mixture was extracted with ether. The dried (MgSO4) organic fraction was evaporated and the residue was purified by column chromatography over silica gel with dichloromethane elution to give 4-cyano-3-methoxy-1-methyl-5,6,7,8-tetrahydroisoquinoline as white crystals, mp 116° C. Pmr spectrum (CDCl3 ; δ in ppm): 1.81 (4H,m); 2.39 (3H,s); 2.50-2.94 (4H,m); 3.98 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[H][H]>CCOC(C)=O>[NH2:15][C:12]1[CH:13]=[CH:14][C:2]([F:1])=[C:3]([CH:11]=1)[NH:4][C:5](=[O:10])[C:6]([F:7])([F:8])[F:9]
Reactant: [H][H]
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1F)C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(NC(=O)C(F)(F)F)c1
Reaction time: 4 h

Procedure:
A Schlenk-flask (250 mL) was evacuated and flushed with argon two times. Then 10% Pd/C (0.74 g, VWR International, oxidized form) and EtOAc (30 mL) were placed into it, and the flask was closed with a septum. The mixture was flushed with hydrogen and stirred vigorously to activate the catalyst. Then 32-NO2—H (5.14 g, 20.4 mmol) in 20 mL of EtOAc was added by syringe through a septum. (Addition was accompanied by the exothermic reaction). The solution was hydrogenated for 4 h at 20° C. Then hydrogen was replaced by argon and the mixture was filtered through Celite®. The filter-cake was washed with EtOAc (2×50 mL) and the solvent was evaporated in vacuo to yield the title compound as a brownish solid with m.p. 116-118° C.; yield—4.35 g (96%). 1H NMR (CDCl3, 300 MHz, ppm): δ=3.30 (br. s, 3H, NH2), 6.44 (ddd, 3JHH=8.8, 4JHF=4.1, 3JHH=2.8, 1H, H-4), 6.92 (dd, 3JHH=8.9, 3JHF=10.4, 1H, H-3), 7.63 (dd, 4JHH=2.8, 4JHF=6.4, 1H, H-6), 8.01 (s, 1H, NH); 13C NMR (75 MHz, CDCl3): δ=107.8 (s, C-4/6), 112.2 (d, 3JCF=7.1, C-6/4), 115.4 (q, 1JCF=289, CF3), 115.5 (d, 2JCF=28, C-3), 124.0 (d, 2JCF=11.2, C-1), 143.3 (s, C-5), 144.6 (d, 1JCF=236, C-2), 154.5 (q, 2JCF=37.5, CO); ESI-MS, negative mode: m/z (rel. int., %)=221 (100) [M−H]−; elemental analysis (%): C, 43.16; H, 2.85; N, 12.86 (found); C, 43.25; H, 2.72; N, 12.61 (calc.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][N:18]([CH2:20][CH2:21][CH2:22][N:23]([CH2:33][CH2:34][F:35])[CH2:24][C:25]([CH2:30][O:31][CH3:32])([CH3:29])[CH2:26][O:27][CH3:28])[CH3:19])([OH:15])[CH2:6][CH2:5]2.CCN(CC)CC.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:13])[CH3:14])[C@@:7]([O:15][C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])([CH2:16][CH2:17][N:18]([CH2:20][CH2:21][CH2:22][N:23]([CH2:33][CH2:34][F:35])[CH2:24][C:25]([CH2:26][O:27][CH3:28])([CH3:29])[CH2:30][O:31][CH3:32])[CH3:19])[CH2:6][CH2:5]2
Reactant: CC(C)C(=O)Cl
Reactant: COCC(C)(COC)CN(CCF)CCCN(C)CC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(C)(COC)CN(CCF)CCCN(C)CC[C@@]1(OC(=O)C(C)C)CCc2cc(F)ccc2[C@@H]1C(C)C
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of 398 mg of (1S,2S)-6-fluoro-2-[2-({3-[(2-fluoro-ethyl)-(3-methoxy-2-methoxymethyl-2-methyl-propyl)-amino]-propyl}-methyl-amino)-ethyl]-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-ol and 0.44 mL of NEt3 in 8 mL of DCM 0.25 mL of isobutyrylchloride was added at 0° C. The mixture was stirred for 25 min at 0° C. and then for 3 h at rt. It was quenched with sat. aqueous NaHCO3 and extracted with DCM. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude was purified by CC using EtOAc/Hept 3/1 as eluant to yield 411 mg of isobutyric acid (1S,2S)-6-fluoro-2-[2-({3-[(2-fluoro-ethyl)-(3-methoxy-2-methoxymethyl-2-methyl-propyl)-amino]-propyl}-methyl-amino)-ethyl]-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl ester as orange oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH:55]1([C:58]2[O:62][N:61]=[CH:60][C:59]=2[C:63](O)=[O:64])[CH2:57][CH2:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:63]([C:59]2[CH:60]=[N:61][O:62][C:58]=2[CH:55]2[CH2:57][CH2:56]2)=[O:64])[CH2:49][CH2:48]1
Reactant: O=C(O)c1cnoc1C1CC1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2cnoc2C2CC2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 18 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-cyclopropylisoxazole-4-carboxylic acid as starting materials in 18% yield. LCMS for C31H32ClN8O3 (M+H)+: m/z=599.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[OH:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[C:22]([CH3:27])[N:23]2[CH3:26])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:31]([NH:30][C:28]([C:21]1[C:20]2[C:24](=[CH:25][C:17]([O:16][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[S:12][CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:18][CH:19]=2)[N:23]([CH3:26])[C:22]=1[CH3:27])=[O:29])([CH3:33])[CH3:32]
Reactant: Cc1c(C(=O)NC(C)C)c2ccc(O)cc2n1C
Reactant: Clc1ccnc2cc(-c3nccs3)sc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)NC(C)C)c2ccc(Oc3ccnc4cc(-c5nccs5)sc34)cc2n1C
Yield: 38 %

Procedure:
This material was prepared by the reaction 7-chloro-2-(1,3-thiazol-2-yl)thieno[3,2-b]pyridine 41a (0.084 g, 0.33 mmole) with 6-hydroxy-N-isopropyl-1,2-dimethyl-1H-indole-3-carboxamide 66b (0.082 g, 0.33 mmole) and Cs2CO3 (0.116 g, 0.33 mmole) to give a off-white solid (0.058 g, 38%). 1H NMR (300 MHz, CDCl3) δ 8.46 (1H, d, J=5.4 Hz), 7.93 (1H, s), 7.88 (1H, d, J=3.2Hz), 7.73 (1H, d, J=8.6 Hz), 7.42 (1H, d, J=3.2 Hz), 7.17 (1H, d, J=2.1 Hz), 7.07 (1H, dd, J=2.1, 8.6 Hz), 6.54 (1H, d, J=5.4 Hz), 5.71 (1H, d, J=7.7 Hz), 4.36 (1H, m), 3.66 (3H, s), 2.72 (3H, s), 1.31 (6H, d, J=6.6 Hz); ESIMS (MH+): 463.10.
Reaction SMILES: [ClH:1].CCOC(C)=O.C(OC(=O)[NH:14][C:15]1[C:20]([C:21]2([OH:33])[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[CH:19][CH:18]=[CH:17][N:16]=1)(C)(C)C>>[ClH:1].[NH2:14][C:15]1[C:20]([C:21]2([OH:33])[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ncccc1C1(O)CCC(c2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ncccc1C1(O)CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4N HCl-EtOAc (5 ml) was added to tert-butyl[3-(1-hydroxy-4-phenylcyclohexyl)pyridin-2-yl]carbamate (450 mg) and the mixture was stirred at room temperature overnight. The resulted precipitates were collected and dried in vacuo to give 1-(2-aminopyridin-3-yl)-4-phenylcyclohexanol hydrochloride.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][N:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:40][N:41]([CH3:46])[CH2:42][C:43](O)=[O:44]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][N:30]5[CH2:35][CH2:34][N:33]([C:43](=[O:44])[CH2:42][N:41]([CH3:46])[CH3:40])[CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CC(=O)O
Reactant: COc1cc(C(=O)NN2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)NN2CCN(C(=O)CN(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperazin-1-yl)benzamide using a procedure that is analogous to that described in connection with amide formation except that N,N-dimethylglycine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.89 (m, 10H) 2.19 (s, 6H) 2.89 (br. s., 2H) 2.94 (br. s., 2H) 3.31 (s, 3H) 3.54 (br. s., 2H) 3.63 (br. s., 2H) 3.93 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 4.46 (m, 1H) 7.42 (d, J=8.0 Hz, 1H) 7.44 (s, 1H) 7.91 (s, 1H) 8.21 (s, 1H) 8.28 (d, J=8.33 Hz, 1H) 9.52 (s, 1H). [M+H] calculated for C30H41F2N9O4, 630. found 630.