Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:18]Br.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.CN(C=O)C>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:18][N:3]1[CH:4]=[CH:5][N:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]1=[O:1]
Reactant: COC(=O)c1nccnc1O
Reactant: Fc1ccc(CBr)cc1F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C

Procedure:
Methyl 2-hydroxy-3-pyrazinecarboxylate (103 mg, 0.67 mmol) (obtained from Fulcrum Scientific Ltd.) was placed in a 25-mL RBF and placed under a nitrogen atmosphere. DMF (3 mL) was added, followed by NaH (33 mg, 0.83 mmol) and the reaction was allowed to stir for twenty minutes at room temperature. 3,4-Difluorobenzyl bromide (0.094 mL, 0.735 mmol) was added, and the reaction was allowed to stir at room temperature overnight, and the reaction was found to be complete by LC-MS. The reaction was added to a separatory funnel containing ethyl acetate (125 mL) and dilute aqueous NaHCO3 (75 mL); the phases were separated and the organic layer was washed with brine and dried over anhydrous Na2SO4, then concentrated in vacuo. The crude product was purified by silica gel chromatography using 10-100% EtOAc in n-heptane to afford methyl 4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydropyrazine-2-carboxylate as a yellow solid. 1H NMR (500 MHz, C2D6SO) δ 8.08 (d, 1H), 7.49 (t, 1H), 7.44 (d, 1H), 7.42 (t, 1H), 7.23 (m, 1H), 5.09 (s, 2H), 3.80 (s, 3H). LRMS (ESI) calc'd for (C13H11F2N2O3) [M+H]+, 281.1; found 281.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:20])[CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]([OH:19])=O)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=1[OH:30]>>[OH:30][C:24]1[CH:25]=[C:26]([OH:29])[CH:27]=[CH:28][C:23]=1[NH:22][C:17]([C:15]1[O:14][N:13]=[C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:20])[CH:16]=1)=[O:19]
Reactant: C[C@@H](COc1cc(C(=O)O)on1)NC(=O)OC(C)(C)C
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Product: C[C@@H](COc1cc(C(=O)Nc2ccc(O)cc2O)on1)NC(=O)OC(C)(C)C

Procedure:
Using 3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)isoxazole-5-carboxylic acid and 4-aminobenzene-1,3-diol hydrochloride, and in the same manner as in Example 2, step C, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39]OS1(=O)=O)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:39][CH2:40][NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][Si:16]([C:19]([CH3:21])([CH3:20])[CH3:22])([CH3:18])[CH3:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Reactant: CCOC(=O)c1cc2cc(O[Si](C)(C)C(C)(C)C)ccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(O[Si](C)(C)C(C)(C)C)ccc2n1CCNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 118.4 %

Procedure:
The solution of 7.0 g (21.9 mmol) 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole-2-carboxylic acid ethyl ester in 60 mL N,N-dimethylformamide was cooled down to 0° C. and 2.7 g (24.1 mmol) potassium tert-butoxide was added. After 30 min., 5.4 g (24.2 mmol) 2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (prepared according to WO 02/072584) was added and the cooling bath was removed. After 1.5 hours, 10% aqueous ammonium chloride solution was added and the two-phase mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The thus obtained crude product (brown oil; 12.0 g, 100%) was used without further purification for the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][C:25]=1[N+:32]([O-:34])=[O:33])[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[C:1]([O:5][C:6]([N:8]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][CH3:35])=[CH:26][C:25]=1[N+:32]([O-:34])=[O:33])[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(N(C(=O)OC(C)(C)C)c2ccc(CO)cc2[N+](=O)[O-])ncn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COCc1ccc(N(C(=O)OC(C)(C)C)c2cc(N(C)C(=O)OC(C)(C)C)ncn2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 17.6 %

Procedure:
To a solution of tert-butyl (6-((tert-butoxycarbonyl)(4-(hydroxymethyl)-2-nitrophenyl)amino)pyrimidin-4-yl)(methyl)carbamate (1.5 g, 3.488 mmol) in acetone (20 mL) under an argon atmosphere at 0° C., was added potassium carbonate (0.48 g, 6.97 mmol) followed by dimethyl sulfate (0.87 g, 6.97 mmol). The resulting reaction mixture was then refluxed for 24 h and then allowed to cool to rt. The reaction mixture was concentrated under vacuum to obtain a crude residue. The residue was purified by silica gel column chromatography to afford the title compound (0.3 g, yield: 19%) as a solid. MS (ESI): 490.55 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:39][CH3:40])[C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32])[CH2:6][O:7]/[N:8]=[C:9](/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)\[CH2:10][CH2:11][C:12]([O:14]C)=[O:13].CO.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:39][CH3:40])[C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32])[CH2:6][O:7]/[N:8]=[C:9](/[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)\[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)CC/C(=N\OCc1cc(OC)c(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(CO/N=C(\CCC(=O)O)c2ccccc2)cc(OC)c1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A mixture of methyl E-4-[3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (970 mg), methanol (5 ml), tetrahydrofuran (10 ml) and 1N aqueous sodium hydroxide (5 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), and concentrated to give E-4-[3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (880 mg, yield 93%) as crystals. Recrystallization from ethyl acetate-isopropyl ether gave colorless needles. m.p. 8990° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[N:13][CH:12]=1)[NH2:7].[C:18](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:19]>ClCCl>[N:7]([C:6]1[CH:8]=[CH:9][C:10]([C:11]2[CH:16]=[C:15]([CH3:17])[N:14]=[N:13][CH:12]=2)=[C:4]([O:3][CH3:2])[CH:5]=1)=[C:18]=[S:19]
Reactant: COc1cc(N)ccc1-c1cnnc(C)c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Agent: Cl
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-c1cnnc(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
Step L (4): Dichloromethane (20 mL) was added to a flask charged with 3-methoxy-4-(6-methylpyridazin-4-yl)aniline hydrochloride (900 mg, 3.58 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (913 mg, 3.93 mmol). The resulting mixture was stirred for 16 h at rt. The reaction mixture was concentrated in vacuo. The crude products were purified using silica gel chromatography (0-50% EtOAc/dichloromethane to afford 5-(4-isothiocyanato-2-methoxyphenyl)-3-methylpyridazine (650 mg, 2.53 mmol, 70.7% yield). LC-MS (M+H)+ 258.0. 1H NMR (500 MHz, chloroform-d) δ ppm 9.18 (d, J=2.44 Hz, 1 H) 7.43 (d, J=2.14 Hz, 1 H) 7.32 (d, J=7.93 Hz, 1 H) 6.95 (dd, J=8.09, 1.98 Hz, 1 H) 6.83 (d, J=2.14 Hz, 1 H) 3.85 (s, 3 H) 2.75 (s, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:12](=[NH:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:19]1([C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:25][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)c1cncc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
Add 3-bromo-5-(trifluoromethyl)pyridine (600 mg, 2.67 mmol), benzophenone imine (701 mg, 4.0 mmol), Cs2CO3 (2.17 g, 6.68 mmol), BINAP (25 mg, 0.040 mmol), Pd2(dba)3 (24 mg, 0.027 mmol) in 1,4-dioxane (10 mL), stir at 110° C. for 16 hrs. Cool to room temperature, add water (100 mL), extract with EtOAc (15 mL×3), wash the combined organic layers with brine, dry over anhydrous Na2SO4, concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=6:94) affords the target compound (850 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([S:9][CH2:10][C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15][CH2:14]3)=[O:12])[S:8][C:4]=2[CH:3]=1.[CH3:25][C:26](OC(C)=O)=[O:27].CCN(CC)CC>C(Cl)Cl>[N:13]1([C:11](=[O:12])[CH2:10][S:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([NH:1][C:26](=[O:27])[CH3:25])[CH:24]=[CH:23][C:5]=3[N:6]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2nc(SCC(=O)N3CCCc4ccccc43)sc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2nc(SCC(=O)N3CCCc4ccccc43)sc2c1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a 0° C. solution of compound 49 (0.16 g, 0.45 mmol) in dry CH2Cl2 (5 mL) was added Ac2O (0.25 mL, 2.70 mmol) followed by dropwise addition of Et3N (0.25 mL, 1.80 mmol). The reaction was stirred for 2 h under N2. The reaction mixture was diluted with CH2Cl2 (40 mL), washed with saturated NaHCO3 (10 mL), water (2×10 mL), and saturated NaCl (2×10 mL). Dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the product was purified by column chromatography (EtOAc/hexanes 3:7) to afford 51 as a white solid (154 mg, 86%); MS m/z: 398 (M+H)+. Anal. Calcd. For, C20H19N3O2S2: C, 60.43; H, 4.82; N, 10.57; S, 16.13. Found: C, 60.54; H, 4.91; N, 10.41; S, 15.87.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]([O:14][CH3:15])=[C:9]([CH2:11][S:12][CH3:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl>C(O)C>[C:1]([C:5]1[CH:10]=[C:9]([CH2:11][S:12][CH3:13])[C:8]([O:14][CH3:15])=[C:7]([CH:6]=1)[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(CSC)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1c(N)cc(C(C)(C)C)cc1CSC

Procedure:
A mixture of 1.00 g 5-tert-butyl-2-methoxy-1-methylsulphanylmethyl-3-nitro-benzene, 4.20 g tin dichloride dihydrate and 15 ml of ethanol is refluxed for 2 h. Then the solvent is removed, and water and dichloromethane are added to the residue. The mixture is filtered through Celite, and the aqueous part of the filtrate is separated off and extracted twice with dichloromethane. The combined organic phases are dried (Na2SO4), and the solvent is removed. The residue is chromatographed on aluminium oxide with cyclohexane/ethyl acetate (4:1→1:4) as eluant.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][C:9]([NH:11][C:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([CH3:15])[CH2:13][OH:14])=[O:10]>C(O)(CC)(C)C.CO.O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:12]2([CH3:15])[NH:11][C:9](=[O:10])[CH2:8][O:14][CH2:13]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(C(C)(CO)NC(=O)CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Solvent: CO
Solvent: O
Product: COc1ccc(C2(C)COCC(=O)N2)cc1
Reaction time: 3 h

Procedure:
A solution of 129.1 mmol of potassium tert-butoxide in 100 ml of tert-amyl alcohol is mixed at room temperature with 51.6 mmol of 2-chloro-N-[2-hydroxy-1-(4-methoxyphenyl)-1-methylethyl]acetamide and stirred for 3 hours. The reaction mixture is diluted with 50 ml of methanol and 3 ml of water and evaporated. The title compound is obtained as a white solid from the residue by flash chromatography (SiO2 60 F). Rf=0.10 (ethyl acetate-heptane 2:1), Rt=2.81 (gradient I).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][C:25]=3[F:26])[N:22]([CH3:27])[N:21]=[CH:20]4)[CH3:16])=[CH:13][N:14]=2)[N:11]=1)=[CH2:5])C.Cl>C(O)(=O)C>[F:26][C:25]1[CH:24]=[C:23]2[C:19]([CH:20]=[N:21][N:22]2[CH3:27])=[CH:18][C:17]=1[CH:15]([C:12]1[N:10]2[N:11]=[C:6]([C:4](=[O:3])[CH3:5])[CH:7]=[CH:8][C:9]2=[N:14][CH:13]=1)[CH3:16]
Reactant: C=C(OCC)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a solution of the 6-(1-ethoxyvinyl)-3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)-imidazo[1,2-b]pyridazine (450 mg, 0.985 mmol) in acetic acid (8 mL), was added 3N HCl (0.5 mL). The solution was stirred at rt for 2 h and the solvents were removed under reduced pressure. The residue was diluted with water and its pH was adjusted to basic with aqueous NaHCO3, extracted with DCM. The organic layer was washed with NaHCO3(aq) and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give yellow solid 1-(3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (300 mg, 81%). LCMS (method B): [MH]+=338, tR=2.49 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([NH2:15])([CH3:14])[CH3:13].[Cu](C#N)[C:17]#[N:18]>CN1CCCC1=O>[C:17]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([NH2:15])([CH3:14])[CH3:13])#[N:18]
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Br)cc12
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Product: CC(C)(N)Cc1c[nH]c2ccc(C#N)cc12

Procedure:
A mixture of 6.45 g of 2-(5-bromo 3-indolyl)1,1-dimethyl ethylamine and 3.25 g of copper cyanide in 40 ml of N-methylpyrrolidone is heated to reflux for 5 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[C:6](I)[CH:7]=1.[CH3:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[C:6]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][C:28]=2[CH3:27])[CH:7]=1
Reactant: Cc1ccncc1B(O)O
Reactant: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(F)cc(I)c1)CC2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(F)cc(-c3cnccc3C)c1)CC2

Procedure:
A mixture of 1-(3-fluoro-5-iodophenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline (D17, 0.31 g, 0.65 mmol), 4-methyl-3-pyridylboronic acid (88 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (O) (23 mg, 0.02 mmol) and sodium carbonate (0.31 g, 3.0 mmol) in 1,2-dimethoxyethane (20 mL) and water (2 mL) was heated under reflux for 24 h, then cooled and poured into water. The aqueous mixture was extracted with dichloromethane/methanol, and the organic extract was washed with brine, dried and evaporated. The residue was chromatographed on silica gel eluted with 2-3% methanol/dichloromethane to give the title compound, which was recrystallised from dichloromethane/petrol (80 mg, 28%), Mp 191-5° C.
Reaction SMILES: Cl.[OH:2][C:3]1[C:8]2[C:9]([CH3:21])=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[O:11][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:22]N(C)C.C(Br)C.[CH2:29]([OH:31])[CH3:30]>>[OH:2][C:3]1[C:8]2[C:9]([CH3:21])=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[O:11][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:22][O:31][CH2:29][CH3:30]
Reactant: COc1ccc(Cc2oc3ccc(CN(C)C)c(O)c3c2C)cc1
Reactant: CCO
Agent: Cl
Solvent: CCBr
Product: CCOCc1ccc2oc(Cc3ccc(OC)cc3)c(C)c2c1O

Procedure:
A mixture of (177) (Example 45) (0.1 g, 0.28 mmol), ethyl bromide, (1 mL) and ethanol (5 mL) was refluxed for 6 h. The solvent was evaporated, the residue was chromatographed on preparative tlc to give the title compound.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:9]2[N:10]=[C:11]([CH2:13][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[NH:12][C:8]=2[CH:7]=[C:6]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=2)[N:5]=1)#[N:3].[Cl:46][CH2:47][CH:48]=O.N12CCCN=C1CCCCC2.C(O)C>C1COCC1>[Cl:46][CH2:47][CH:48]=[CH:13][C:11]1[NH:12][C:8]2[CH:7]=[C:6]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[C:35]([C:42]([F:44])([F:45])[F:43])[CH:34]=3)[N:5]=[C:4]([C:2]#[N:3])[C:9]=2[N:10]=1
Reactant: CCOc1ccc(-c2cc3[nH]c(C[P+](c4ccccc4)(c4ccccc4)c4ccccc4)nc3c(C#N)n2)cc1C(F)(F)F
Reactant: O=CCCl
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccc(-c2cc3[nH]c(C=CCCl)nc3c(C#N)n2)cc1C(F)(F)F

Procedure:
A solution of [4-cyano-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-triphenyl-phosphonium chloride (167.2 mg, 0.26 mmol), chloroacetaldehyde (50% in water) (32,6 mg, 0.41 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (62.4 mg, 0.41 mmol) was dissolved in a 1:1 mixture of THF:ethanol (4 ml) at room temperature overnight. The mixture was concentrated and purified on preparative HPLC to afford the title compound. MS m/z 407.5 (m+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]2[O:19][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ti]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]([O:5][CH:1]([CH3:3])[CH3:2])[C@@H:10]1[OH:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H]2O[C@H]12
Agent: [Ti]
Solvent: CO
Product: CC(C)O[C@@H]1c2ccccc2C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O
Temperature: 96 °C
Yield: 94.9 %

Procedure:
Under argon to a solution of (±)-(1S,2R,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-1,2,3,4-tetrahydro-naphthalene (96 mg) in methanol (4 ml) was added titanium isopropoxyde (0.19 ml). The mixture was warmed for 14 hours in an oil bath maintained at 96° C. Evaporation of the warm mixture under an argon flow gave a residue which was purified on a silica gel column (22 g, elution with ethyl acetate:cyclohexane, 1:4). After evaporation of solvents was recovered an oil which was crystallized from a pentane/diethyl ether mixture to afford the title compound as a white solid (56 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([OH:22])=O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][C:56]1[CH:57]=[C:58]([NH:62][C:63](=[O:75])[C@@H:64]([N:66]([CH3:74])[C:67](=[O:73])[O:68][C:69]([CH3:72])([CH3:71])[CH3:70])[CH3:65])[CH:59]=[CH:60][CH:61]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:55][C:56]3[CH:57]=[C:58]([NH:62][C:63](=[O:75])[C@@H:64]([N:66]([CH3:74])[C:67](=[O:73])[O:68][C:69]([CH3:70])([CH3:72])[CH3:71])[CH3:65])[CH:59]=[CH:60][CH:61]=3)=[O:22])=[CH:12][N:11]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)O
Reactant: C[C@@H](C(=O)Nc1cccc(N)c1)N(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 56.8 %

Procedure:
To 2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (C5, 297 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (383 mg) and 1-hydroxybenzotriazole monohydrate (270 mg), N,N-dimethylformamide (7.5 mL) was added at room temperature, and the mixture was stirred at 50° C. for 1 hour and 20 minutes. The reaction mixture was cooled to room temperature, and then N,N-diisopropylethylamine (697 μL) and (S)-tert-butyl (1-((3-aminophenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (B9, 323 mg) were added to the mixture at room temperature, and the mixture was stirred at the same temperature for 30 minutes, and then further stirred at 50° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the mixture. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 40 to 10% hexane in ethyl acetate) to obtain (S)-tert-butyl (1-((3-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (C8, 325 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.S(O)(O)(=O)=O.[CH3:15][O:16][C:17](=[NH:19])[NH2:18].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:19][C:17](=[NH:18])[O:16][CH3:15])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: COC(=N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=N)Nc1nc(Cl)cc(Cl)n1
Temperature: 110 °C
Reaction time: 10 h
Yield: 142.6 %

Procedure:
45.9 g (0.25 mol) of 2,4,6-trichloropyrimidine, 30.8 g (0.125 mol) of O-methyl-isourea sulphate and 51.8 g (0.375 mol) of ground potassium carbonate are suspended in 800 ml of toluene and stirred at 110° C. for 10 hours. After cooling, the crystalline solid is filtered off with suction, stirred with water for 15 minutes and again filtered off with suction. 39.4 g of N-(4,6-dichloro-pyrimidin-2-yl)-O-methylisourea are obtained (GC purity 98%: 38.6 g; yield: 69 of theory), melting point 178° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].Br[CH2:26][C:27]1[CH:31]=[CH:30][S:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:14])=[O:15])[CH2:26][C:27]1[CH:31]=[CH:30][S:29][CH:28]=1
Reactant: BrCc1ccsc1
Reactant: COC(=O)c1cccc(C=O)c1NS(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)c1cccc(C=O)c1N(Cc1ccsc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 86 %

Procedure:
Following the procedure of Example 322, 1.0 g (2.865 mmol) of the product of Example 321 is reacted with 3-bromomethyl thiophene to give 1.10 g (86%) of the product as a white solid after chromatography on silica gel eluting with EtOAc/Hexanes (1:3). Electrospray Mass Spec: 446.1 (M+H)+.