Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38])#[N:33].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[C:34]([C:32]#[N:33])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1
Yield: 96.2 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4a with 69 mg (0.514 mmol) of 3-cyanobenzoic acid, 143 mg (0.561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (250 mg, 96%) is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.53, FD-MS: M+ =556.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][C:5](=[O:8])[NH:4][CH2:3][CH2:2]1.S(OC)(O[CH3:13])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:13][O:8][C:5]1=[N:4][CH2:3][CH2:2][O:1][CH2:7][CH2:6]1
Reactant: COS(=O)(=O)OC
Reactant: O=C1CCOCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC1=NCCOCC1
Temperature: 150 °C
Yield: 97.6 %

Procedure:
To a solution of 1,4-oxazepan-5-one (0.091 g, 0.793 mmol) in DCM (2 mL) in a screw-cap vial was added dimethyl sulfate (0.1 g, 0.793 mmol) to give a colorless solution. The reaction was heated to 150° C. for 5 minutes. Potassium carbonate (200 mg) was added and the vial was capped and shaken. The reaction was filtered through a glass frit and solvent was removed under reduced pressure to give a clear oil (100 mg) that was used without further purification. LCMS (+ESI) m/z: 130.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:5]=[C:4]([NH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[N:3]=1.[NH3:27]>CC(O)C.O1CCOCC1>[NH2:27][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:5]=[C:4]([NH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[N:3]=1
Reactant: N
Reactant: Cc1cc(C)c(Nc2nc(Cl)nc(Nc3ccc(C#N)cc3)n2)c(C)c1
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cc1cc(C)c(Nc2nc(N)nc(Nc3ccc(C#N)cc3)n2)c(C)c1
Yield: 66.1 %

Procedure:
A mixture of 4-[[4-chloro-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]-amino]benzonitrile (*A9c) (0.00137 mol) and NH3 in 1,4-dioxane (0.5 M; 0.00548 mol) was heated in a pressure vessel at 100° C. for 6 days. The solvent was evaporated and the residue was dissolved in CH2Cl2, washed with a saturated aqueous NaHCO3 solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0, 99/1 and 98/2). The desired fractions were collected and the solvent was evaporated. The residue was recrystallized from toluene. The precipitate was filtered and dried, yielding 0.29 g (61.4%) of 4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile. b) As an alternative for the preparation of this compound, a mixture of 4-[[4-chloro-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile (0.0230 mol) in NH3 in 2-propanol (2.0 M; 60 ml) and NH3 in 1,4-dioxane (0.5 M; 20 ml) was heated at 95° C. for 21 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate, washed with 1 N NaOH, water and brine, dried, filtered and the filtrate was evaporated. The residue was recrystallized with acetonitrile, yielding 5.25 g (66.1%) of 4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:30]([CH3:33])=[N:31][N:32]=3)[N:18]=[C:19]([N:21]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:22])[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:23]([N:21]([CH3:22])[C:19]1[CH:20]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:16]2[N:17]([C:30]([CH3:33])=[N:31][N:32]=2)[N:18]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nnc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)cc(N(C)Cc3ccccc3)nn12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc2c(NC3CCNCC3)cc(N(C)Cc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[6-(Benzyl-methyl-amino)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (4.08 g; 9.04 mmol) was dissolved in 20.0 ml of DCM and treated with 5.0 ml TFA. It was stirred at ambient temperature for 1 hour. The solution was concentrated under reduced pressure and the residue taken up in DCM and washed with half concentrated NaHCO3 solution. The organic phase was dried over MgSO4 and concentrated.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([C:21](=[O:23])[NH2:22])=[CH:16][C:15]=1[CH3:24])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.[C:35]1([C:41]2[N:42]=[C:43]([CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][NH:47]3)[NH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C)CCCCN=C=NCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([C:21](=[O:23])[NH2:22])=[CH:16][C:15]=1[CH3:24])[C:10](=[O:11])[N:47]1[CH2:48][CH2:49][CH2:50][CH2:51][CH:46]1[C:43]1[NH:44][CH:45]=[C:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:42]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: c1ccc(-c2c[nH]c(C3CCCCN3)n2)cc1
Agent: CCN=C=NCCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N1CCCCC1c1nc(-c2ccccc2)c[nH]1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid (0.42 g, 1.25 mmol) was dissolved in DMF (5 mL) followed by 1-hydroxybenzotriazole (0.34 g, 1.75 mmol), and the resulting solution was cooled to 0° C. To this reaction mixture was added 2-(4-phenyl-1H-imidazol-2-yl)-piperidine (0.31 g, 1.75 mmol) followed by (4-dimethylamino-butyl)-ethyl-carbodiimide (0.34 g, 1.75 mmol). The reaction was then warmed to room temperature and stirred for 16 hours. The reaction mixture was then combined with 2N citric acid and washed multiple times with ethyl acetate. The combined organics were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 600 mg of desired product {1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-carbamic acid tert-butyl ester as a glass which was used as is without further purification. (TLC: 5:1 CHCl3: MeOH Rf=0.6)
Reaction SMILES: [Cl:1][Ta:2]([Cl:6])(Cl)(Cl)Cl.[CH:7]([OH:10])([CH3:9])[CH3:8]>C1(C)C=CC=CC=1>[Cl:1][Ta:2]([Cl:6])([O:10][CH:7]([CH3:9])[CH3:8])([O:10][CH:7]([CH3:9])[CH3:8])[O:10][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)O
Reactant: Cl[Ta](Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)O[Ta](Cl)(Cl)(OC(C)C)OC(C)C
Temperature: 45 °C

Procedure:
20.7 g of pentachlorotantalum was dispersed in 100 ml of toluene, to which 88.5 ml of isopropyl alcohol was added dropwise in a nitrogen gas atmosphere. The resultant solution was stirred at room temperature for 1.5 hours, and was then heated to 45° C. to remove the solvent therefrom by distillation. As a result, 24.8 g of dichlorotriisopropoxytantalum [TaCl2 (OCH(CH3)2)3 ] was obtained as a residue in the form of white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21]Br)=[O:4].[N:23]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21][N:32]1[CH2:33][CH2:34][CH:29]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:30][CH2:31]1)=[O:4]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2ccccc2)nc2ccccc12
Temperature: 50 °C
Yield: 56.4 %

Procedure:
5 g (14 mmol) of 3-bromomethyl-2-phenyl-quinoline-4-carboxylic acid methyl ester (compound of Description 2), 2.9 g, (15.4 mmol) of 90% [1,4′]Bipiperidinyl (Aldrich), 2.7 ml (15.4 mmol) of ethyl-diisopropyl-amine were dissolved in 100 ml of dry THF and the mixture was stirred for one night at 50° C. The solvent was concentrated, the residue was dissolved in CH2Cl2, washed with water, and the organic phase was dried over MgSO4. After concentration of the solvent, the residue was purified by flash chromatography over 160 g of silicagel (eluting with CH2Cl2/MeOH/NH4OH:95/5/0.5) affording 3.5 g (yield 56%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([F:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)CC>CC(C)=O>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][C:12]([C:13]([OH:28])=[O:14])=[C:11]([F:25])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)cc1F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCCO
Product: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)cc1F
Temperature: 0 °C
Reaction time: 19 h
Yield: 81 %

Procedure:
To a cold (0° C.) solution of 4,5-bis-benzyloxy-2-fluoro-benzaldehyde (2.15 g, 6.39 mmol) in acetone (86.0 mL) was slowly added Jones reagent (4.3 mL). The reaction mixture was stirred 19 h at 0° C. Propanol (0.43 mL) was added and the reaction mixture was stirred 40 min at 20° C. The crude mixture was filtered, washed with acetone and poured into water (50 mL). The solid was filtered, washed with water and dried in vacuo, yielding the title compound (1.82 g, 81%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([O:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[C:22]2[C:29]([CH3:30])=[C:28]([C:31](O)=[O:32])[S:27][C:23]=2[N:24]=[CH:25][N:26]=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.N>CN(C=O)C>[C:31]([C:28]1[S:27][C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][CH:10]([CH3:11])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C:22]=2[C:29]=1[CH3:30])(=[O:32])[NH2:35]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC(C)CNC(=O)OC(C)(C)C)c12
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC(C)CNC(=O)OC(C)(C)C)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(2-(1-(tert-Butoxycarbonylamino)propan-2-yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (250 mg) and TBTU (170 mg) was dissolved in DMF (3 ml) and triethylamine (1900) was added. The mixture was stirred at room temperature for 10 min, then 0.5 ml conc. ammonia was added. The reaction was stirred for 2 h. Then the reaction mixture was concentrated in vacuo and purified by RP-chromatography (water with 0.2% trifluoroacetic acid/methanol 72-100%) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][PH:32](=[O:34])[OH:33])=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1.[CH2:39]([Sn:43]([CH2:57][CH2:58][CH2:59][CH3:60])([CH2:53][CH2:54][CH2:55][CH3:56])[C:44]1[N:45]=[N:46][N:47]([CH2:49][CH2:50][CH2:51]O)[CH:48]=1)[CH2:40][CH2:41][CH3:42].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][PH:32](=[O:33])[O:34][CH2:51][CH2:50][CH2:49][N:47]4[CH:48]=[C:44]([Sn:43]([CH2:53][CH2:54][CH2:55][CH3:56])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:57][CH2:58][CH2:59][CH3:60])[N:45]=[N:46]4)=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CCCO)nn1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1cn(CCCO[PH](=O)CCCCc2ccc(Nc3ncc(C(F)(F)F)c(Nc4ccc(Br)nc4C(=O)NC)n3)c(OC)c2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
A solution of (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)propylphosphinic acid (Compound 74B, 0.370 g, 0.599 mmol), 3-[4-(tributylstannanyl)-1H-1,2,3-triazol-1-yl]propan-1-ol (Compound 64B, 0.299 g, 0.719 mmol) and DIPEA (0.313 mL, 1.80 mmol) in 1,2-dichloroethane (10.0 mL) was charged with (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (0.936 g, 1.80 mmol). The resulting mixture was stirred at rt for 16 hours. The reaction mixture was quenched with sat. aq. NaHCO3 (10 mL) and extracted with DCM (20 mL). The organic layer was washed with sat. aq. NaHCO3 (10 mL), washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a brown oil. The crude material was purified using a Teledyne ISCO Combiflash® Rf system using 1:1 DCM-EtOAc/MeOH (100:0→90:10) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield an off-white solid (352.1 mg, 57.8%). MS (ESI): m/z 1016.90 [M+H]+. UPLC: tR=1.44 min (UPLC-SQD: analytical_non-polar 2 min).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([C:6]1[C:7]2[C:8]3[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=S)[C:9]=3[CH:16]=[CH:17][CH:18]=2)(=[O:5])=[O:4].[N:20]1([CH:25]([CH3:29])[CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][N:22]=[CH:21]1>C(O)C>[N:20]1([CH:25]([CH3:29])[CH2:26][CH2:27][NH:28][C:10]2[C:9]3[CH:16]=[CH:17][CH:18]=[C:7]4[C:8]=3[C:12](=[CH:13][CH:14]=[C:6]4[S:3]([N:2]([CH3:19])[CH3:1])(=[O:5])=[O:4])[N:11]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: CC(CCN)n1ccnc1
Reactant: CN(C)S(=O)(=O)c1ccc2c3c(cccc13)C(=S)N2
Solvent: CCO
Product: CC(CCNC1=Nc2ccc(S(=O)(=O)N(C)C)c3cccc1c23)n1ccnc1
Yield: 55.4 %

Procedure:
A mixture of 7.3 g of 1,2-dihydro-N,N-dimethyl-2-thioxobenz(cd)indole-6-sulfonamide, 4.2 g of 3-(1H-imidazol-l-yl)butanamine, 150 ml of ethanol and 9.6 g of mercuric acetate was reacted as described in Example 1, giving 5.5 g of the desired product, mp 221° C.-222° C.
Reaction SMILES: C([O:3][C:4]([CH:6]=[N:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:18]([F:32])=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1)=[O:5])C.[Li+].[OH-].Cl>CO.O>[C:4]([CH:6]=[N:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:18]([F:32])=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C=Nc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
The reaction of N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (0.1 g) and LiOH (10 equivalents) in MeOH:water (1:1, v/v) for 1 h at room temperature followed by treatment with aqueous HCl gave the solid. The resulting solid was filtered, washed with water and dried to give N2-(3-carboxymethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 18.23 min.; purity: 87.6%; MS (m/e): 412.01 (Mg).
Reaction SMILES: [CH3:1][C:2]([OH:20])([CH3:19])[CH2:3][NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:10]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH3:19][C:2]1([CH3:1])[O:20][C:29](=[O:31])[N:4]([C:5]2[N:6]=[N:7][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH2:3]1
Reactant: CC(C)(O)CNc1ccc(C#Cc2ccccc2)nn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CN(c2ccc(C#Cc3ccccc3)nn2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
A solution of 2-methyl-1-(6-(phenylethynyl)pyridazin-3-ylamino)propan-2-ol (Example 152, step 1) (90 mg, 337 μmol) and triethylamine (102 mg, 141 μl, 1.01 mmol, 3 equiv.) in 4 ml of THF was cooled to 0-5° C. and then triphosgene (99.9 mg, 337 μmol, 1 equiv.) was added and the reaction was stirred for 1 hour at 0-5° C. The mixture was quenched with 5 ml of 5% sodium bicarbonate solution and worked up with ethyl acetate/water. The crude material was adsorbed onto silicagel and purified by flash chromatography over a heptane to 50% ethyl acetate in heptane gradient to yield the title compound (51 mg, 52% yield) as a crystalline light yellow solid, MS: m/e=294.2 (M+H+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1.[CH3:15]I.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH3:15])[C:8]=2[CH:14]=1
Reactant: CI
Reactant: O=C1COc2ccc(Br)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)COc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.10 g, 2.6 mmol) was added to a solution of 6-bromo-2H-1,4-benzoxazin-3(4H)-one (0.49 g, 2.1 mmol) in N,N-dimethylformamide (3 mL) under nitrogen. After the mixture was stirred at r.t. for 10 min, methyl iodide (0.27 mL, 4.3 mmol) was added. The reaction mixture was stirred at r.t. for 1 h. Then 10 mL of water was added to the mixture, and a white precipitate was removed by filtration, washed with water, and dried under vacuum to afford the product which was directly used in next step reaction without further purification. LCMS (M+H)+=242.2/244.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH:6]1[CH2:9][NH:8][CH2:7]1.O=[C:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]#[N:30])[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH:6]1[CH2:9][N:8]([C@@H:14]2[CH2:15][CH2:16][C@H:17]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:29]#[N:30])[CH:27]=4)[NH:22][CH:21]=3)[CH2:18][CH2:19]2)[CH2:7]1
Reactant: N#Cc1ccc2[nH]cc(C3CCC(=O)CC3)c2c1
Reactant: Fc1cccc(OC2CNC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc2[nH]cc([C@H]3CC[C@@H](N4CC(Oc5cccc(F)c5)C4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
To a solution of 0.170 g of 3-(3-fluoro-phenoxy)-azetidine in 10 mL of CH2Cl2 was added 0.180 g of 3-(4-oxo-cyclohexyl)-1H-indole-5-carbonitrile followed by 0.420 g of sodium triacetoxyborohydride. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH and the product was extracted with ether. The organic phase was washed with water, dried over magnesium sulfate, filtered, and concentrated. The product was filtered through 150 mL of silica gel using 50% ethyl acetate/hexane, 75% ethyl acetate/hexane and finally 100% ethyl acetate to give 0.095 g of the desired product: mp 187-190° C. 1H NMR (300 MHz, CDCl3) δ 1.51-1.65 (m, 2H), 1.69-1.75 (m, 4H), 1.77-1.90 (m, 2H), 2.45 (m, 1H), 2.90 (m, 1H), 3.03 (dd, 2H), 3.81 (dd, 2H), 4.77 (m, 1H), 6.53-6.59 (m, 2H), 6.66 (m, 1H), 7.13-7.22 (m, 2H), 7.39 (dd, 2H), 8.00 (s, 1H), 8.28 (s, 1H); MS (ES) m/z (relative intensity): 390 (M++H).
Reaction SMILES: [NH3:1].[CH3:2][C:3]1([CH2:10][CH2:11][C:12]([O:14]C)=O)[C:7](=[O:8])[CH2:6][CH2:5][C:4]1=[O:9]>O1CCCC1>[CH3:2][C:3]1([CH2:10][CH2:11][C:12](=[O:14])[NH2:1])[C:7](=[O:8])[CH2:6][CH2:5][C:4]1=[O:9]
Reactant: COC(=O)CCC1(C)C(=O)CCC1=O
Reactant: N
Solvent: C1CCOC1
Product: CC1(CCC(N)=O)C(=O)CCC1=O
Yield: 41 %

Procedure:
A 1 ml quantity of 25% aqueous ammonia solution was added to 1.6 g of 2-methyl-2-(β-carbomethoxyethyl)cyclopentan-1,3-dione which was known and disclosed for example in J. Org. Chem., 31, 1489 (1966). The mixture was reacted at room temperature for 5 hours. After reaction, 10 ml of tetrahydrofuran (THF) was added. The insolubles were filtered and recrystallized from ethanol to obtain 0.6 g of Compound mentioned above (yield: 41%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:12])=[C:5]([CH2:10][OH:11])[C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[CH3:13][C:14]1([CH3:22])[C:16]([CH3:18])([CH3:17])[CH:15]1[C:19](Cl)=[O:20]>>[CH3:13][C:14]1([CH3:22])[C:16]([CH3:18])([CH3:17])[CH:15]1[C:19]([O:11][CH2:10][C:5]1[C:6]([CH3:9])=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[C:4]=1[CH3:12])=[O:20]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: Cc1ccc(C#N)c(C)c1CO
Product: Cc1ccc(C#N)c(C)c1COC(=O)C1C(C)(C)C1(C)C

Procedure:
In a similar manner, (3-cyano-2,6-dimethylphenyl)methanol is reacted with other 3-(2-halo-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylic acid chlorides and others 3-(2,2-dihaloethenyl)-2,2-dimethylcyclopropanecarboxylic acid chlorides, or 2,2,3,3-tetramethylcyclopropanecarboxylic acid chloride to give other (3-cyano-2,6-dimethylphenyl)methyl 3-(2-halo-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylates and 3-(2,2-dihaloethenyl)-2,2-dimethylcyclopropanecarboxylates within the scope of this invention, or (3-cyano-2,6-dimethylphenyl)methyl 2,2,3,3-tetramethylcyclopropanecarboxylate, respectively.
Reaction SMILES: [C:1](O[K])(C)(C)C.O=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[CH2:1]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)O[K]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A solution of methyltriphenylphosphonium bromide (2.15 g, 6.02 mmol) in hexane (15 mL) was added with tert-butoxypotassium (0.676 g, 6.02 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added portionwise with tert-butyl 4-oxopiperidine-1-carboxylate (1.10 g, 5.52 mmol), and the mixture was stirred overnight at room temperature. The solid was removed by filtration, the concentrated filtrate was added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-methylenepiperidine-1-carboxylate (0.731 g, 67%).