Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3Br)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:22]1(=[O:26])[CH2:25][CH2:24][CH2:23]1>O1CCCC1>[C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3[C:22]3([OH:26])[CH2:25][CH2:24][CH2:23]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(Br)c1
Reactant: O=C1CCC1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C2(O)CCC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a cooled (0° C.) stirred solution of 4-(adamantan-1-ylmethoxy)-3-bromobenzonitrile (3.20 g, 9.24 mmol) in tetrahydrofuran (40 mL) was added a solution of isopropylmagnesium chloride lithium chloride complex in tetrahydrofuran (1.3 M, 15.0 mL, 19.5 mmol) dropwise. The reaction mixture was stirred at 0° C. for 2 h and cyclobutanone (1.52 mL, 20.33 mmol) was added. Stirring was continued at 0° C. for 2 h and quenched with saturated ammonium chloride solution (30 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 10% to 25% gradient of ethyl acetate in hexanes to afford 4-(adamantan-1-ylmethoxy)-3-(1-hydroxycyclobutyl)benzonitrile as colorless solid (2.34 g, 69%): 1H NMR (300 MHz, CDCl3) δ 7.62-7.53 (m, 2H), 7.00-6.93 (m, 1H), 3.64 (s, 2H), 3.43 (s, 1H), 2.59-2.36 (m, 4H), 2.17-2.00 (m, 4H), 1.84-1.61 (m, 13H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].C([Li])CCC.[C:16]1(=[O:20])[CH2:19][CH2:18][CH2:17]1.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C:16]1([OH:20])[CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc(F)c(F)c1
Reactant: O=C1CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C1(O)CCC1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 3,4-difluoroanisole (2.47 g) in tetrahydrofuran (50 mL) was added n-butyllithium (2.64 mol/L n-hexane solution, 6.5 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a solution of cyclobutanone (1 g) in tetrahydrofuran (20 mL), and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give the title compound (2.69 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1>CN1C(=O)CCC1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:27][CH:28]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COc1cc2c(Oc3ccc(NC(C)=O)cc3)ccnc2cc1OCc1ccccc1
Temperature: 150 °C
Yield: 1328.7 %

Procedure:
Twelve carousel tubes were charged with 7-benzyloxy-4-chloro-6-methoxy-quinoline (12×2.00 g, 12×6.67 mmol) and N-(4-hydroxy-phenyl)-acetamide (12×3.03 g, 12×20.00 mmol, 3.0 eq) in NMP (12×2.00 ml) and heated under to nitrogen to 150° C. for 2.5 hours. The reaction mixtures were allowed to cool to room temperature, diluted with DCM (12×20 ml). The combined organic solutions were washed with 2N NaOH (3×200 ml), water (200 ml), brine (200 ml), dried (MgSO4), filtered and concentrated under reduced pressure to leave a brown oil. Purification by column chromatography (4% methanol in DCM) afforded the title compound as a beige solid (36.73 g).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][C@H:23]2[OH:36])=[CH:18][C:17]=1[F:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O=[C:58]1[C:63]([C:64]#[N:65])=[CH:62][CH:61]=[CH:60][NH:59]1>O1CCCC1.O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:24][C@@H:23]2[O:36][C:58]2[C:63]([C:64]#[N:65])=[CH:62][CH:61]=[CH:60][N:59]=2)=[CH:18][C:17]=1[F:37]
Reactant: N#Cc1ccc[nH]c1=O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@@H](Oc2ncccc2C#N)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.3 %

Procedure:
Diisopropyl azodicarboxylate (1.9 M in toluene, 0.69 mL) was added dropwise to a solution of tert-butyl (6R,7S)-7-(4-chloro-3-fluorophenyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (300 mg), triphenylphosphine (340 mg) and 2-oxo-1,2-dihydropyridine-3-carbonitrile (160 mg) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (250 mg).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[C:13](=O)[CH2:12][CH2:11][S:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:18]([NH:20][CH2:21][CH2:22][NH2:23])[CH3:19].C(O)C>Cl.O>[CH2:18]([NH:20][CH2:21][CH2:22][N:23]1[C:6]([C:5]2[CH:16]=[CH:17][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:7][C:8]2[CH2:9][S:10][CH2:11][CH2:12][C:13]1=2)[CH3:19]
Reactant: O=C(CC1CSCCC1=O)c1ccc(Br)cc1
Reactant: CCNCCN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCNCCn1c(-c2ccc(Br)cc2)cc2c1CCSC2
Temperature: -5 °C

Procedure:
A solution of 4.0 g (0.012 mole) of 3-(4-bromophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one [Example 2 (a)], 1.3 g of ethylaminoethylamine, 14 ml. of ethanol, and one drop of concentrated hydrochloric acid is heated under reflux for 2.5 hours, cooled to -5°C, and diluted with water. The oil which separates is collected and triturated with water to provide a solid. The resultant solid is recrystallized from ethanol to give off-white crystals of 1-(2-ethylaminoethyl)-2-(4-bromophenyl)-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole, m.p. 84° to 85°C.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([N:28]2[CH2:27][CH:26]=[C:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:31])[F:32])[CH:20]=3)[CH2:30][CH2:29]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C(c1ccccc1)c1ccccc1)N1CC=C(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 1 h
Yield: 34.2 %

Procedure:
8 g of α,α-diphenylacetyl chloride in 50 ml of methylene chloride were added dropwise to a mixture of 8 g (0.035 mole) of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, 50 ml of methylene chloride and 4.96 ml of triethylamine at the temperature of 0/+5° C. Stirring is effected for one hour at room temperature, the solvent is evaporated off under reduced pressure, the residue is taken up into ethyl ether, washing is effected with a 0.2M aqueous solution of hydrochloric acid, with water, with an aqueous solution of sodium carbonate and then with water. Drying is effected over sodium sulphate, the solvent is evaporated off under reduced pressure. 5 g of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+].CN(C)C=O>O>[N:16]([CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1CN(Cc2ccccc2)CCO1
Temperature: 130 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of 4-benzyl-2-chloromethylmorpholine (15.0 g), sodium azide (8.6 g), and dimethylformamide (150 ml) is stirred at 130° C. for 2 hours. The reaction mixture is diluted with water and extracted with diethyl ether. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give 2-azidomethyl-4-benzylmorpholine (15 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:12])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>O1CCOCC1>[O:9]1[C:5]2[CH:4]=[C:3]3[NH:12][C:13](=[O:14])[NH:1][C:2]3=[CH:11][C:6]=2[NH:7][C:8]1=[O:10]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc2[nH]c(=O)oc2cc1N
Solvent: C1COCCO1
Product: O=c1[nH]c2cc3[nH]c(=O)oc3cc2[nH]1
Temperature: 25 °C
Yield: 65 %

Procedure:
3.3 g. (0.02 mole) 5,6-diaminobenzoxazolin-2-one and 5.5 g. (0.034 mole) 1,1'-carbonyldiimidazole are dissolved in 150 ml. dioxan and heated to the boil for 3 hours. After cooling to ambient temperature, the brownish crystalline substance obtained is filtered off with suction, boiled with dimethylformamide, filtered with suction and washed with methanol. There is obtained a yield of 65% of theory of the desired compound; m.p. >360° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc1

Procedure:
The 4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-cinnamic acid ethyl ester (126 g, 0.33 mol) obtained in Example 8 (1) was dissolved in ethanol (1 L), and 10% Pd—C (48.5 g) was added, followed by stirring in a hydrogen atmosphere for 18 hours. The insoluble material was filtered with Celite, and the filtrate was evaporated under reduced pressure, thereby obtaining 4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-dihydrocinnamic acid ethyl ester (107 g, 85%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].Br[CH:20]([CH2:26][CH2:27][CH2:28][CH3:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22].CCO>CO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH:20]([CH2:26][CH2:27][CH2:28][CH3:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CCCCC(Br)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCCCC(Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)OCC
Temperature: 140 °C
Yield: 98.8 %

Procedure:
206 g (1 mol) of 2,4-di-tert-butylphenol were melted and heated to 140° C. under nitrogen. 185 g (1.03 mol) of a 30% strength NaOMe solution in MeOH and 245 g (1.1 mol) of ethyl 2-bromocaproate were metered in simultaneously in the course of 1 hour. During the addition, a mixture of MeOH and EtOH was distilled off. After the addition, the reaction to give the ester mixture was complete. The mixture was cooled to 80° C., 20 g of NaOMe solution were added and 750 ml of ethanol were then added in the course of 4 hours. A methanol/ethanol mixture distilled off at an overhead temperature of initially 74° to 76° C. At the end, the temperature was increased to 90° C. and pure ethanol distilled over at 78° to 79° C. For isolation, 250 ml of water were added. After separation of the phases and renewed washing with 200 ml of water, 351 g of a viscous yellow oil of the following composition (0.3% of ethyl bromocaproate, 0.7 g of residual phenol, 98% of ethyl 2-(2,4-di-tert-butylphenoxy)caproate and 0.3% of methyl 2-(2,4-ditert-butylphenoxy)caproate, remained. This corresponds to a yield of 98.8% of theory, based on the phenol employed.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)/[C:7]1=[O:24])=[O:5])[CH3:2].[CH3:25][C:26]1[CH:27]=[C:28]([CH:32]=[N:33][C:34]([O:36][Si](C)(C)C)=[CH2:35])[CH:29]=[CH:30][CH:31]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:35][C:34](=[O:36])[NH:33][CH:32]2[C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=2)[C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cccc(C)c1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cccc(C)c1
Yield: 86 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.4 g, 1.10 mmol) prepared in example 4b was reacted with 1-(3-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 10a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(3-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 0.5 g, 86%).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[CH3:23][CH:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[F:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([F:22])[C:15]=1[C:8]1[N:9]([CH3:14])[C:10](=[O:13])[C:11]([OH:12])=[C:6]([C:4]([NH:31][CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:23])=[O:5])[N:7]=1
Reactant: CC(N)c1ccccc1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Product: CC(NC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O)c1ccccc1

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and α-methylbenzylamine (61 mg, 0.5 mmol). The title product was obtained as an off-white solid (24.6 mg, 64% yield). 1HNMR (500 MHz, CDCl3) δ: 12.39 (1H, s), 7.71 (1H, d, J=7.94 Hz), 7.54–7.48 (1H, m), 7.36–7.25 (5H, m), 7.06 (2H, dd, J=14.65, 8.54 Hz), 5.22 (1H, qt, J=7.02 Hz), 3.40 (3H, s), 1.58 (3H, d, J=7.02 Hz). HRMS (ESI) calcd for C20H16F2N3O3 (M−H): 384.1160; found: 384.1161.
Reaction SMILES: O=[CH:2][C@H:3]([C@H:5]([C@H:7]([CH3:9])[OH:8])[OH:6])[OH:4].[NH2:10][NH2:11]>>[CH:2](=[N:10][NH2:11])[C@H:3]([C@H:5]([C@H:7]([CH3:9])[OH:8])[OH:6])[OH:4]
Reactant: NN
Reactant: C[C@H](O)[C@H](O)[C@H](O)C=O
Product: C[C@H](O)[C@H](O)[C@H](O)C=NN

Procedure:
reacting 5-deoxy-L-ribose with a hydrazine compound to form a 5-deoxy-L-ribose hydrazone compound; and
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@:8]2([CH3:20])[CH2:13][O:12][C@@:11]([CH3:18])([C:14]([F:17])([F:16])[F:15])[C:10]([NH2:19])=[N:9]2)[C:5]([F:21])=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:25]=[C:26]([CH3:33])[C:27]([C:30]([NH2:32])=[O:31])=[N:28][CH:29]=1)#[N:23].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(OC)(C)C.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]>[NH2:19][C:10]1[C@:11]([CH3:18])([C:14]([F:17])([F:16])[F:15])[O:12][CH2:13][C@:8]([C:6]2[N:7]=[C:2]([NH:32][C:30]([C:27]3[C:26]([CH3:33])=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:21])([CH3:20])[N:9]=1
Reactant: C[C@@]1(c2nc(Br)ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Reactant: Cc1cc(C#N)cnc1C(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(N)=N2)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
A mixture of (2R,5R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (80 mg, 0.216 mmol), 5-cyano-3-methyl-pyridine-2-carboxylic acid amide (34.8 mg, 0.216 mmol, see Intermediates Amide 1), xantphos (11.26 mg, 0.019 mmol) and cesium carbonate (99 mg, 0.303 mmol) in dioxane (2 ml) was degassed for 5 minutes with argon. Pd2(dba)3 (5.94 mg, 6.48 μmol) was added, the microwave vial was sealed and stirred at 80° C. for 18 hours. The reaction mixture was diluted with water and TBME. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. 173 mg orange solid. Silica gel chromatography (applied on two 20×20 cm plate, 1 mm, dichloromethane:methanol 9:1, rechromatographed with dichloromethane:methanol 95:5 with double evolution of the plates) afforded the title compound: 15 mg and 21 mg. Combined amount: 36 mg (37% yield). TLC (dichloromethane/methanol 9:1) Rf=0.53; API ES+ MS 451. LCMS RtH4=0.87 min. (100%, ES+ 451), 1H-NMR (400 MHz, CDCl3): 10.80 (br s, 1H), 8.83 (br s, 1H), 8.41 (dd, 1H), 7.93 (br s, 1H), 7.55 (t, 1H), 5.8-4.6 (very broad, 2H), 4.23 (br s, 2H), 2.83 (s, 3H), 1.75 (s, 3H), 1.66 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17]3)[CH:10]=2)[CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[N:16]1([CH2:15][C:11]2[CH:10]=[C:9]([NH:8][C:4]3[CH:3]=[C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH3:25])[N:7]=[CH:6][N:5]=3)[CH:14]=[CH:13][CH:12]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cc(Nc2cccc(Cn3ccc4ccccc43)c2)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1cc(Nc2cccc(Cn3ccc4ccccc43)c2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
234 mg (6-Chloro-pyrimidin-4-yl)-(3-indol-1-ylmethyl-phenyl)-amine (pre-pared in Example 90) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 152 mg 2-methoxyphenyl-boronic acid (1 mmol), 318 mg anhydrous Na2CO3 (3 mmol) and 6 ml water were added. The mixture was ferluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (90 mg, 32% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18]([NH2:21])(=[O:20])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)=[O:23])[CH:7]=1.[C:38](O)(=[O:40])[CH3:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18]([NH:21][C:38](=[O:40])[CH3:39])(=[O:19])=[O:20])=[C:13]3[N:12]=[CH:11][C:10]=2[C:22]([N:24]2[CH2:25][CH2:26][CH:27]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH2:28][CH2:29]2)=[O:23])[CH:7]=1
Reactant: CC(=O)O
Reactant: NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: CC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 87.7 %

Procedure:
Using 7-(5-chloro-2-fluorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.091 mmol) obtained in step 5 and acetic acid (0.026 mL, 0.457 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.047 g, 87%) was obtained.
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.[F:55][C:56]1[CH:61]=[CH:60][C:59]([N:62]=[C:63]=[O:64])=[CH:58][CH:57]=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]([NH:62][C:59]2[CH:60]=[CH:61][C:56]([F:55])=[CH:57][CH:58]=2)=[O:64])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)Nc2ccc(F)cc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 32 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H 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 1-fluoro-4-isocyanatobenzene as starting materials in 32% yield. LCMS for C31H31ClFN8O2 (M+H)+: m/z=601.2.
Reaction SMILES: FC1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=CC2NC=C3C(=O)N(C4C=CC=CC=4)N=C3C=2C=1.F[C:29]1[C:30]([F:50])=[CH:31][C:32]2[C:33]3[C:34]([C:39](=[O:49])[N:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=4[F:48])[N:41]=3)=[CH:35][NH:36][C:37]=2[CH:38]=1.CN1CCNCC1>>[F:50][C:30]1[C:29]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[CH:38][C:37]2[NH:36][CH:35]=[C:34]3[C:39](=[O:49])[N:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=4[F:48])[N:41]=[C:33]3[C:32]=2[CH:31]=1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1F
Agent: CN1CCNCC1
Product: CN1CCN(c2cc3[nH]cc4c(=O)n(-c5ccccc5F)nc-4c3cc2F)CC1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27c and 1-methylpiperazine. 1H-NMR (CD3OD) δ (ppm): 2.23 (3H, s), 2.48 (4H, brm), 2.68 (4H, brm), 7.05 (1H, d, J=7.7 Hz), 7.16 (2H, m), 7.31 (1H, m), 7.40 (1H, m), 7.66 (1H, d, J=13.1 Hz), 8.44 (1H, s). m/z 396.2