Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])([CH3:3])[CH3:2].N#C[Br:19]>CCOCC>[Br:19][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCOCOc1ccccc1C(C)C
Reactant: N#CBr
Solvent: CCOCC
Product: COCCOCOc1c(Br)cccc1C(C)C
Temperature: 7.5 °C
Reaction time: 5 h
Yield: 48.5 %

Procedure:
In dry ether (100 mL) was dissolved 5.18 g (23.1 mmol) of 1-isopropyl-2-[(2-methoxyethoxy)methoxy]benzene obtained in Example 18 (1), 22.3 mL (35.7 mmol) of n-butyl lithium-hexane solution (1.60M) was added dropwise to the solution in an ice bath (reaction solution temperature: 5-10° C.), and the mixture was stirred in an ice bath for 5 hours. To the reaction mixture was added 8.20 g (69.7 mmol) of 90% cyanogen bromide while maintaining the reaction solution temperature to 5-10° C. The reaction mixture was stirred in an ice bath for 2 hours, poured into ice-cold water (300 mL), and extracted with ether. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=100:1) to obtain 3.40 g (11.2 mmol, Yield: 48.5%) of 1-bromo-3-isopropyl-2-[(2-methoxyethoxy)methoxy]benzene.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])[S:3]1>[Pd].CN(C=O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])[S:3]1
Reactant: COC(=O)c1cc(C=C2SC(=O)NC2=O)ccc1OC
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CC2SC(=O)NC2=O)ccc1OC
Yield: 61.3 %

Procedure:
Methyl 5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxy-benzoate (9.52 g) was suspended into DMF (250 ml) and hydrogenated with 10% palladium/carbon (10.0 g) at room temperature under a hydrogen pressure of 3.5 kg/cm2. After the reaction, the solution was filtered and concentrated and water was added to the residue, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (developing solvent; methylene chloride:acetone=50:1) to obtain 5.88 g (61%) of aimed compound as an amorphous material. MS(m/z):295(M+)
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[N:16]=[CH:15]3)=[C:7]([CH:10]=1)[CH2:8][NH2:9].[C:22]([O-:25])(O)=O.[Na+]>CCOC(C)=O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[N:16]=[CH:15]3)=[C:7]([CH:10]=1)[CH2:8][NH:9][CH2:8][C:7]1[CH:10]=[CH:3][C:4]([O:25][CH3:22])=[CH:5][CH:6]=1
Reactant: O=C([O-])O
Reactant: Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(CNCc2cc(F)ccc2Oc2ccc3c(cnn3C)c2)cc1

Procedure:
Intermediate (5t) (136 mg, 0.442 mmol; prepared as in Example 106, Step A) was dissolved in EtOAc (100 mL) and neutralized with saturated NaHCO3 then washed with brine, dried over MgSO4 and evaporated under reduced pressure to obtain the free amine. The free amine was dissolved in 1,2-dichloroethane (5 mL) and p-anisaldehyde was added to the solution at room temperature. After 2 hours of stirring, the solution was evaporated under reduced pressure. The residue was dissolved in MeOH (5 mL) and cooled to 0° C. Sodium borohydride was added to the solution at 0° C. After 40 minutes of stirring at 0° C., the reaction mixture was quenched with several drops of acetic acid at 0° C., then the reaction mixture was evaporated under reduced pressure. The residue was diluted with EtOAc (50 mL) and neutralized with saturated NaHCO3 and washed with brine, dried over MgSO4 and evaporated to obtain a crude oil, which was purified on silica gel with EtOAc/hexane (1:1) with 1% Et3N to afford compound (29t) as a color less oil (139 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.34 (d, J=9.4 Hz, 1H), 7.28 (d, J=7.0 Hz, 1H), 7.23-7.15 (m, 2H), 7.13-7.06 (m, 2H), 6.92-6.85 (m, 2H), 6.84-6.78 (m, 2H), 4.61 (s, 1H), 4.06 (s, 3H), 3.82 (s, 2H), 3.77 (s, 3H), 3.72 (s, 2H) ppm.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1([OH:14])[CH3:13])(C)(C)C.[ClH:16].O1CCOCC1>ClCCl>[ClH:16].[NH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH3:13])[OH:14]
Reactant: CC(C)(C)OC(=O)NC1CCCC1(C)O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(O)CCCC1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl-2-hydroxy-2-methyl-cyclopentylcarbamate (25 g, 104.5 mmol) in dichloromethane (210 mL) is added hydrogen chloride in dioxane (156 mL, 6 mol, 4 M) and the reaction is stirred at room temperature for 3 h. The solvent is evaporated and the resulting material is dried under vacuum to a constant weight to obtain the title compound (20.4 g) as a dark brown oil which is used in the next step without further purification. GC-MS 115.1 (M+); GC-MS analysis shows a cis/trans mixture in about a 3/2 ratio.
Reaction SMILES: [NH2:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([Cl:23])=[CH:18][N:17]=1>>[Cl:15][C:16]1[N:21]=[C:20]([NH:1][C:2]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])[C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: C#CCNC(=O)c1cccc(F)c1N
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide was prepared from 2-amino-3-fluoro-N-prop-2-ynyl-benzamide and 2,4,5-trichloro-pyrimidine in an analogous manner to Example 308b. Product isolated as an orange solid (1.22 g, 28%). m.p.=209-213° C.; LCMS (m/e) 339 (M+H); 1H-NMR (CDCl3, 400 MHz); 9.07 (bs, 1H), 8.23 (s, 1H), 7.40-7.30 (m, 3H), 6.40-6.32 (m, 1H), 4.25-4.18 (m, 2H), 2.32-2.28 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.Cl>N1C=CC=CC=1>[C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1/[CH:1]=[CH:12]/[C:13]([OH:15])=[O:14])#[N:6]
Reactant: O=C(O)CC(=O)O
Reactant: N#Cc1ccccc1C=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: N#Cc1ccccc1/C=C/C(=O)O
Temperature: 0 °C
Yield: 69.9 %

Procedure:
A solution of 2-formylbenzonitrile (4.17 g, 31.8 mmol), malonic acid (7.61 g, 73.1 mmol), and piperidine (0.314 mL, 3.18 mmol) in pyridine (40 mL) was heated to reflux for 2 hr. The solution was cooled and poured into crushed ice (150 mL) and 12N HCl (30 mL). The white precipitate was filtered, washed with water, and air dried to give a tan powder (3.85 g, 70%). 1H NMR (500 MHz, DMSO-d6) δ 12.81 (br. s., 1H), 8.09 (d, J=7.9 Hz, 1H), 7.93 (dd, J=7.8, 0.9 Hz, 1H), 7.80-7.74 (m, 2H), 7.62 (td, J=7.6, 0.9 Hz, 1H), 6.80 (d, J=15.9 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22].[C:23](=O)([O-])[O-].[K+].[K+].CBr.Cl>CN(C=O)C.O>[Br:1][C:2]1[C:10]([O:11][CH3:23])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(O)c(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: CBr
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)O)cc(OCCc2ccc(Cl)cc2Cl)c1Br
Temperature: 0 °C
Reaction time: 16 h

Procedure:
0.2 g (0.49 mmol) of 4-Bromo-3-[2-(2,4-dichlorophenyl)-ethoxy]-5-hydroxy-benzoic acid was dissolved in 5 ml DMF and 0.272 mg (1.97 mmol) of potassium carbonate was added. The solution was cooled to 0° C. and 0.699 g (4.9 mmol) methyl bromide was added. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/1). The resulting compound was dissolved in 10 ml dioxan and 1 ml water. 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h. 5 ml water was added, followed by concentrated hydrochloric acid to give a pH of 1-2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.[NH:34]1[C:42]2[C:37](=[C:38]([C:43]3[CH:44]=[C:45]([NH2:58])[C:46]4[C:50]([CH:51]=3)=[N:49][N:48](C3CCCCO3)[CH:47]=4)[CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35]1>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:34]1[C:42]2[C:37](=[C:38]([C:43]3[CH:51]=[C:50]4[C:46]([CH:47]=[N:48][NH:49]4)=[C:45]([NH:58][C:7]([C:4]4[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=4)=[O:9])[CH:44]=3)[CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35]1
Reactant: Cc1cc(C(=O)O)n[nH]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n[nH]1
Reaction time: 0.08 h

Procedure:
5-Methyl-1H-pyrazole-3-carboxylic acid (10 mg) in DMF (0.2 ml) was treated with N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (27 mg) in DMF (0.2 ml) and DIPEA (0.03 ml). The reaction mixture was shaken for five min prior to treatment with 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (20 mg) in DMF (0.2 ml). The reaction mixture was shaken for five min and left to stand at 22° C. for 18 h. The solvent was removed in vacuo and the product re-dissolved in methanol (1 ml) prior to application on to an SCX SPE cartridge (1 g). The product was eluted after 1 h with 2M ammonia in methanol (2×3 ml), the fractions were combined and concentrated under a stream of nitrogen using blow down apparatus. Purification by mass directed preparative HPLC (Method C) afforded the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)([O-:3])=[O:2].[N:16]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>O.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH2:16])=[O:15])=[CH:9]2)([O-:3])=[O:2]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reaction time: 0.33 h
Yield: 73.3 %

Procedure:
To a mixture of 7-nitro-1H-indole-2-carboxylic acid (4.40 g), 1H-1,2,3-benzotriazol-1-ol (3.45 g) and N,N-dimethylformamide (80 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (4.90 g) at room temperature, and the mixture was stirred for 20 min and 28% aqueous ammonia (7.8 mL) was added. The reaction mixture was stirred at room temperature for 1 hr, and water was added. The resulting crystals were filtrated, washed with water, and dried to give the title compound (3.21 g, yield 73%) as yellow crystals. melting point 297-298° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1COCC1.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]>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(N2CCN(C)CC2)ccc1O
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 48.8 %

Procedure:
1-(5-bromo-2-hydroxyphenyl)ethanone 1.0 g (4.65 mmol) in THF (10 ml), N-methylpiperazine 0.83 ml (7.45 mmol), LiHMDSA 16.2 ml (16.2 mmol), Pd2(dba)3 68 mg (0.074 mmol) and 2-dicyclohexylphosphino-2′-N,N-dimethylaminobiphenyl 29.3 mg (0.074 mmol) were combined under argon in a capped vial and stirred at 70° C. for 40 minutes. The volatiles were removed in vacuo, the obtained residue was dissolved with water and 1 N HCl (pH=6) and portioned with DCM. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM gradient to 10% MeOH/DCM) to provide 532 mg (51%) of desired product as a brown solid. LC/MS (254 nm) HPLC method 2 Rt 3.34 min. 1H NMR (401 MHz, DMSO-d6) δ 11.45 (s, 1H), 7.21-7.28 (m, 2H), 6.80-6.93 (m, 1H), 2.98-3.10 (m, 4H), 2.63 (s, 3H), 2.44-2.48 (m, 4H), 2.23 (s, 3H). HRMS (ESI) calcd for C13H18N2O2 [M+H]+ 235.1441 Found 235.1448.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([F:22])[C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:23])[CH2:3][CH2:2]1.O[CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH3:25])[CH:18]=[C:17]([F:22])[C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:23])[CH2:2][CH2:3]1
Reactant: Oc1cc(F)c2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](COc1cc(F)c2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4-fluoro-1,3-benzoxazol-6-ol (110 mg), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (91.0 mg) and triphenylphosphine (136 mg) in THF (5 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 0.274 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (159 mg).
Reaction SMILES: C[Si](C)(C)[O-].[K+].[F:7][CH2:8][O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([O:18]C)=[O:17])=[N:14][CH:15]=1.O.CCOC(C)=O>C1COCC1>[F:7][CH2:8][O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[N:14][CH:15]=1
Reactant: COC(=O)c1cnc(OCF)cn1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cnc(OCF)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium trimethylsilanolate (18.6 mg) was added to a solution of methyl 5-fluoromethoxypyrazine-2-carboxylate obtained in Preparation Example 15-(1) (18.0 mg) in THF (1.0 mL). The reaction solution was stirred at RT for 1 h. Water and EtOAc were added to the reaction solution, and the aqueous layer was separated. The aqueous layer was made acidic with 1 M hydrochloric acid, followed by extraction with EtOAc. The organic layer was dried over anhydrous MgSO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a crude product of the title compound (10.2 mg). The compound was used for the next reaction without further purification. 1H-NMR (400 MHz, CDCl3) δ (ppm): 6.16 (d, J=50.8 Hz, 2H), 8.34 (d, J=1.4 Hz, 1H), 9.05 (d, J=1.4 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>O1CCCC1>[C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=1[O:19][CH3:18])#[N:2]
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1I
Reactant: COc1ccc(CN)c(OC)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(NCc2ccc(OC)cc2OC)c(C#N)c1I
Temperature: 60 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
Ethyl 4-cyano-3-iodo-5-(methylsulfonyl)thiophene-2-carboxylate (5.60 g, 0.0145 mol) and 2,4-dimethoxybenzylamine (3.51 mL, 0.0234 mol) were combined in tetrahydrofuran (100 mL) and stirred at 60° C. for 3 days. The reaction was concentrated in vacuo, diluted with dichloromethane and hexanes and the resultant precipitate was filtered to yield the title compound (5.56, 81%) as a yellow solid. LCMS: (FA) ES+, 473. 1H NMR (400 MHz, d6-DMSO) δ: 9.05 (s, 1H) 7.10 (d, 1H, J=8.57 Hz), 6.60-6.50 (m, 2H), 4.30 (s, 2H), 4.22-4.14 (m, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 1.26-1.21 (m, 3H).
Reaction SMILES: FC(F)(F)[C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][CH:4]=1.F[C:13](F)(F)[C:14]([OH:16])=O>C(#N)C>[CH:5]1[CH2:6][CH:8]=[CH:9][CH:3]=1.[CH:14](=[O:16])[C:13]1[CH:8]=[CH:9][CH:3]=[CH:4][CH:5]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: CC#N
Product: C1=CCC=C1
Product: O=Cc1ccccc1
Yield: 200 %

Procedure:
4.84 g (30 mmol) of 4-trifluoromethylaniline are dissolved in 20 ml of acetonitrile, and 3.42 g (2.3 ml, 30 mmol) of trifluoroacetic acid are added (gives mixture A) 1.98 g (2.47 ml, 30 mmol) of freshly distilled cyclopentadiene and 3.18 g (3.05 ml, 30 mmol) of benzaldehyde are initially introduced with ice-cooling. Mixture A, pre-cooled to 5° C., is added to this solution, the mixture is allowed to come to room temperature and is stirred for 16 h. The mixture is then evaporated in vacuo. Purification by column chromatography gives the desired product.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]=O)=[CH:30][CH:29]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:38][O:39][C:40](=[O:42])[CH3:41])(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.[CH3:50][O:51][NH2:52]>C(O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]=[N:52][O:51][CH3:50])=[CH:30][CH:29]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:38][O:39][C:40](=[O:42])[CH3:41])(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C#N)c(Cc3ccc(OCC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2C#N)cc1
Temperature: 80 °C
Yield: 57.8 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-cyano-3-(4-(2-oxoethoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (100.0 mg, 0.17 mmol) in ethanol (4 mL) under nitrogen atmosphere, was added pyridine (0.07 mL, 0.86 mmol) and O-methylhydroxylamine hydrochloride (28.7 mg, 0.34 mmol). The reaction mixture was heated at 80° C. for 2 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was diluted with ethyl acetate (40 mL). The organic layer was separated, washed with 5% HCl (10 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:49 EtOAc:Pet Ether) to afford title compound (60 mg, 43%) as solid.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:19][C:20]4[N:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][CH:21]=4)[S:16][C:17]=3[CH3:18])[CH:10]=[N:9]2)=CC=1.C(Cl)Cl.CO>C(O)(C(F)(F)F)=O>[CH3:18][C:17]1[S:16][C:15]([NH:19][C:20]2[N:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][CH:21]=2)=[N:14][C:13]=1[C:11]1[CH:12]=[N:8][NH:9][CH:10]=1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4cccc(C#N)n4)sc3C)cn2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1sc(Nc2cccc(C#N)n2)nc1-c1cn[nH]c1
Yield: 13 %

Procedure:
According to Scheme 4 Step 2: A solution of 6-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-methylthiazol-2-ylamino)picolinonitrile (0.69 mmol, 277 mg) in TFA (4 mL) was microwaved for 7 minutes at 100° C. After evaporation of the solvent, the resulting residue was neutralized with a saturated solution of Na2CO3. The compound precipitated and after filtration, the solid was washed with water and dried. The solid was finally triturated in Et2O, DCM and MeOH to yield 6-(5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-ylamino)picolinonitrile (90 μmol, 25 mg, 12%) as a beige solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:29][N:28]([CH3:30])[CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][C@@H:34]1[CH2:42][OH:43]>CS(C)=O>[CH3:30][N:28]1[CH2:27][CH2:26][C:9]2[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[CH:23][N:22]=[C:21]4[CH3:25])=[CH:16][CH:15]=3)[N:12]=[C:7]([N:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35][C@@H:34]3[CH2:42][OH:43])[C:8]=2[CH2:29]1
Reactant: OC[C@H]1Cc2ccccc2N1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C)CC3)cc1
Solvent: CS(C)=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N4c5ccccc5C[C@@H]4CO)n2)CN(C)CC3)cc1
Yield: 47.4 %

Procedure:
6-Methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (65 mg, 0.14 mmol, Example 9a) and (R)-indolin-2-ylmethanol (20.70 mg, 0.14 mmol) in DMSO (3 mL) were heated to 80° C. in a microwave reactor for 2 h. The reaction mixture was filtered and purified by preparative HPLC, yielding (R)-(1-(6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)indolin-2-yl)methanol (31.0 mg, 47.8%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][CH2:17][CH2:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)=[O:20]>>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][C:19]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)=[O:20])[CH2:11][CH2:10]1
Reactant: O=C(CCCCl)N1CCc2ccccc21
Reactant: Clc1ccccc1N1CCNCC1
Agent: Cl
Product: O=C(CCCN1CCN(c2ccccc2Cl)CC1)N1CCc2ccccc21

Procedure:
from 1-(2-chlorophenyl)piperazine, hydrochloride and 4-chloro-1-(2,3-dihydro-1H-indol-1-yl)butan-1-one. Mp 119–121° C. 1H NMR (DMSO-d6): 1.75–1.85 (m, 2H); 2.35–2.50 (m, 4H); 2.55 (s, 4H); 3.95 (s, 4H); 3.15 (t, 2H); 4.10 (t, 2H); 6.95 (t, 1H); 7.05 (t, 1H); 7.10 (d, 1H); 7.15 (t, 1H); 7.20 (d, 1H); 7.25 (t, 1H); 7.40 (d, 1H); 8.10 (d, 1H). MS m/z: 384 (MH+), 265, 188.
Reaction SMILES: [CH2:1]([C:3]([CH2:9][CH3:10])=[C:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:2].[CH3:11][Li].O>CCOCC>[CH2:1]([C:3]([C:4]1[CH2:8][CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH2:9][CH3:10])[CH3:2]
Reactant: CCC(CC)=C1C=CC=C1
Reactant: [Li]C
Solvent: CCOCC
Solvent: O
Product: CCC(C)(CC)C1=CC=CC1
Temperature: 25 °C
Yield: 61 %

Procedure:
To a solution of 8.00 g (59.6 mmol) of 6,6-diethylfulvene in 35 ml of ether, 60.0 ml (68.4 mmol) of an ether solution of methyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. Then, 30 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (92° C./40 mmHg) to obtain 5.50 g (36.6 mmol) of a light yellow liquid (yield: 61%). The analyzed values are given below.