Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[NH:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:21]=[CH:20]1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=[C:2]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[N:21]=[CH:20]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: c1cc(-c2c[nH]cn2)ccn1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccncc3)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.1) (0.15 g, 0.5 mmol) and 4-(1H-imidazol-4-yl)-pyridine [CAS-No. 51746-87-3] (0.073 g, 0.5 mmol) according to the general procedure IVa. Obtained as a light red solid (0.15 g, 76%). MS (ISP) 402.3 [(M+H)+]; mp 269° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CO.O>[CH:19]1([CH2:18][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: CC(=O)c1ccc(OCC2CCCCC2)cc1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4′-hydroxyacetophenone (10.6 g, 77.7 mmol) in 600 mL MeOH and 15 mL H2O at room temperature was added Cs2CO3 (25.6 g, 1.01 eq). The reaction mixture immediately turned yellow and was then stirred for 40 min. The MEOH was removed in vacuo, and the remaining H2O was removed azetropically with 5×100 mL toluene. The resulting yellow solid was suspended in DMF (450 mL) and treated with (bromomethyl)cyclohexane (13.0 mL, 1.2 eq). The reaction mixture was heated to 90° C. and stirred overnight. The reaction mixture was then cooled to room temperature, poured into 500 mL of ice water and extracted with Et2O. The Et2O extract was dried over MgSO4 and concentrated in vacuo to a yellow oil, which smelled of the starting bromide. The bromide was distilled off at 50° C. under high vacuum until the bottoms reached a constant weight (13.96 g, 77%). This oil solidified to a white solid upon standing. 1H NMR (300 MHz CDCl3): 7.91 (2H, d, J=8.9 Hz), 6.90 (2H, d, J=8.8 Hz), 3.81 (2H, d, J=6.1 Hz), 2.55 (3H, s), 1.8 (6H, m), 1.2 (3H, m), 1.1 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[O:12]([CH2:19][CH2:20]CS([O-])(=O)=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[O:12]([CH2:19][CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=S(=O)([O-])CCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCOc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
1.19 g of 4-hydroxybenzaldehyde were dissolved in 30 ml of DMF, and 0.41 g of 60% NaH were further added to the resultant solution while cooling it with ice. The solution was then stirred for 1 hour after elevating the temperature of the solution up to room temperature. The solution was again cooled with ice, then added with 2.0 g of 2-phenoxyethyl-methane sulfonate, and stirred for 1 hour at room temperature and subsequently for a night at 50-60° C. The solution reacted was poured into ice-water and extracted with ethyl acetate, then the organic layer resulted was dried with anhydrous magnesium sulfate. The solvent used was then removed by distillation under reduced pressure, and the residue obtained was washed with a mixture of ether and hexane, thereby affording 1.45 g of 4-(2-phenoxyethyloxy)benzaldehyde.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([F:27])=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:7]=2[CH:26]=1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[F:2][C:3]1[C:4]([F:27])=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH:25][C:34]([CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)=[O:35])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:7]=2[CH:26]=1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3noc4cc(F)c(F)cc34)CC2)CC1
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3noc4cc(F)c(F)cc34)CC2)CC1)C1CCOCC1

Procedure:
The title compound, MS: m/e=476.3 (M+H+), was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine hydrochloride (example 62, step 1) and tetrahydro-pyran-4-carboxylic acid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)([OH:3])=[O:2].[C:19](OCC)(=[O:23])[C:20]([CH3:22])=O>>[C:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:12]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:18]=[C:20]([CH3:22])[C:19]2=[O:23])=[CH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1ccccc1Nc1ccc(CC(=O)O)cc1
Product: Cc1nc2ccccc2n(-c2ccc(CC(=O)O)cc2)c1=O

Procedure:
Preparation as in Example 1 but using N-(4-carboxymethylphenyl)benzene-1,2-diamine and ethyl pyruvate gave the title compound mp 179°-181.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[CH2:13]2)=[CH:6][C:7]=1[Br:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1C(=O)CC(c2ccc(N)cc2)CC1=O
Solvent: ClCCl
Product: CN1C(=O)CC(c2ccc(N)c(Br)c2)CC1=O
Yield: 67 %

Procedure:
A solution of 289 mg (1.32 mmol) of 4-(4-amino-phenyl)-1-methyl-piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (15 mL) was treated portionwise with 224 mg (1.29 mmol) of solid NBS for 20 min. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (2×30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue with 25-50% EtOAc-hexane afforded 265 mg (67%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C12H13N2O2Br, 297.0/299.0 (M+H), found 297.0/299.0.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:6]2[N:5]=1)=O.[N:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH2:32])=[CH:31][C:26]=2[NH:25][CH:24]=1>>[N:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=5)[N:6]4[N:5]=3)=[CH:31][C:26]=2[NH:25][CH:24]=1
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: Nc1ccc2nc[nH]c2c1
Product: CS(=O)(=O)c1ccc(-c2ccc3cnc(Nc4ccc5nc[nH]c5c4)nn23)cc1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 2-methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.22 mmol) was coupled with 3H-benzimidazol-5-ylamine (51 mg, 0.38 mmol) at 105° C. in a for 86 h to afford the title compound. Yield of TFA salt: 46 mg (40%) of brown powder; LC/MS: 405 (M+H); HPLC: 90% pure, RT=2.14 min; 1H NMR: (DMSO, δ) 9.96 (s, 1H), 9.48 (s, 1H), 9.13 (s, 1H), 8.51 (d, J=8.6, 2H), 8.18 (s, 1H), 8.07 (d, J=8.6, 2H), 7.86 (m, 2H), 7.42 (d, J=4.8, 1H), 7.07 (d, J=4.8, 1H), 3.28 (s, 3H)-benzimidazole NH presumably underwent rapid exchange with residual water.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[C:13](Cl)(=O)C>CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH3:13])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(OC)c(N)c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
A 1 L 3-necked round bottomed flask equipped with a nitrogen inlet, stirbar, addition funnel and thermocouple was charged with 3-amino-4-methoxy benzoic acid (50 g, 0.299 mol) and methanol (300 mL). The system was cooled to 0 C and acetyl chloride (30 mL, 0.42 mol) was added dropwise. The system was warmed to room temperature, the addition funnel was replaced with a reflux condenser, and was heated to reflux for 1.5 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCO3, and extracted with ethyl acetate. The organic extract was washed with brine, dried with Na2SO4 and concentrated in vacuo to give methyl 3-amino-4-methoxybenzoate as a dark solid (47.9 g, 88%). 1H NMR (400 MHz, CD3OD) δ 7.40 (t, J=268 Hz, 1H), 7.37 (t, J=2.0 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 3.98 (s, 3H), 3.81 (s, 3H) ppm. ES-HRMS m/z 182.0826 (M+H calcd for C9H12ClNO3 requires 182.0812).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:3]=1.[C:26](OCC)(=O)[CH3:27]>CN(C=O)C.[F-].[K+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:8]([F:11])([F:10])[C:6]1[N:5]=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:3]=[C:2]([CH:26]=[CH2:27])[N:7]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)nc(C(F)(F)F)n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)n1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-{[6-chloro-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate (0.742 g, 1.94 mmol) in DMF (8.7 mL) was added (2-ethenyl)tri-n-butyltin (0.682 mL, 2.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (112 mg, 0.0972 mmol). The reaction solution was stirred at 65° C. overnight. The reaction solution was diluted with ethyl acetate and saturated KF solution. The aqueous layer was extracted with ethyl acetate three times. The combined organic solutions were dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel column to give the desired product as light brown oil. LCMS (M+H)+: 374.2.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.O>CS(C)=O>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:1]2[CH2:5][CH2:4][NH:3][C:2]2=[O:6])=[CH:16][CH:15]=1
Reactant: O=C1NCCN1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN1Cc1ccc(Br)cc1
Reaction time: 1.8 h
Yield: 100 %

Procedure:
A 12.4 g (0.14 mole) portion of 2-imidazolidinone in 125 ml of dimethylsulfoxide treated with 19.9 g (0.14 mole) of K2CO3, 11.5 g (0.069 mole) of KI and 36.0 g (0.14 mole) of 4-bromobenzylbromide. The reaction mixture was heated to 105° over 0.3 hours, held at 105° with stirring for 1.8 hours, and poured into 1.51 of cold water. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 500 ml of water, dried over MgSO4 overnight and filtered. The filtrate was concentrated under reduced pressure to give 36 g (100%) of a light yellow semisolid. The crude product was crystallized using 150 ml of ether, filtered, air dried and dried at 60° for 4 hours to give 15 (42%) of a white solid m.p. 163°-167°. Recrystallization from acetonitrile gave an analytical sample, m.p. 166°-168°.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[CH:40]=[C:39]([S:44]([N:47]1[CH2:52][CH2:51][N:50]3[CH:53]=[CH:54][CH:55]=[C:49]3[CH:48]1[CH2:56][C:57](O)=[O:58])(=[O:46])=[O:45])[CH:38]=[CH:37]2.[N:60]1([CH2:66][C:67]2[CH:68]=[C:69]3[C:74](=[CH:75][CH:76]=2)[CH2:73][CH:72]([NH2:77])[CH2:71][CH2:70]3)[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>C(Cl)Cl>[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[CH:40]=[C:39]([S:44]([N:47]1[CH2:52][CH2:51][N:50]3[CH:53]=[CH:54][CH:55]=[C:49]3[CH:48]1[CH2:56][C:57]([NH:77][CH:72]1[CH2:71][CH2:70][C:69]3[C:74](=[CH:75][CH:76]=[C:67]([CH2:66][N:60]4[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]4)[CH:68]=3)[CH2:73]1)=[O:58])(=[O:45])=[O:46])[CH:38]=[CH:37]2
Reactant: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)O)ccc2c1
Reactant: NC1CCc2cc(CN3CCCCC3)ccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)NC3CCc4cc(CN5CCCCC5)ccc4C3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
DIPEA (2.5 eq.), HOAt (1.0 eq.) and EDCl (1.5 eq.) were added to a solution of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid S2 (0.2325 mmol, 1.0 eq.) in DCM (3 ml) at 0° C. and the mixture was stirred for 15 min at RT. Then 6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-amine A5 (0.2325 mmol, 1.0 eq.) in DCM (2 ml) was added at 0° C. and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and extracted with aqueous NaHCO3 solution, aqueous NH4Cl solution, water and saturated sodium chloride solution. The organic phase was dried (Na2SO4), concentrated to small volume and purified by column chromatography (alox). Yield: 58%; m/z=627.4 [MH]+
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([O:14][CH3:15])=[C:8]([CH2:16][CH3:17])[N:7]=1)=O)C.[NH2:18][NH2:19]>O1CCOCC1>[CH2:16]([C:8]1[N:7]=[C:6]([C:4]([NH:18][NH2:19])=[O:3])[C:11]([O:12][CH3:13])=[CH:10][C:9]=1[O:14][CH3:15])[CH3:17]
Reactant: CCOC(=O)c1nc(CC)c(OC)cc1OC
Reactant: NN
Solvent: C1COCCO1
Product: CCc1nc(C(=O)NN)c(OC)cc1OC
Yield: 71.4 %

Procedure:
A flask was charged with 6-ethyl-3,5-dimethoxy-pyridine-2-carboxylic acid ethyl ester (50 mg.; 0.21 mmol), dioxane (4 mL) and hydrazine (64 mg; 2 mmol). The reaction was heated at reflux for one hour, and all solvents were removed by evaporation. To the dried cake was added ethyl acetate (10 mL) and a 10% aqueous sodium carbonate solution (1 mL). The organic layer was isolated, dried with magnesium sulfate, and evaporated to give 6-ethyl-3,5-dimethoxy-pyridine-2-carboxylic acid hydrazide (34 mg.; 0.15 mmol).
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[CH:6]=[C:7]([NH:8][C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:2]=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1cc(-c2ccc(Cl)cc2)cnc1Br
Product: C[Si](C)(C)C#CNc1cncc(-c2ccc(Cl)cc2)c1

Procedure:
The product was obtained analogously to Example 7.1b starting from 2-bromo-5-(4-chlorophenyl)pyridin-3-ylamine (Example 16.1c) and trimethylsilylacetylene. Yield: 1.09 g (51% of theoretical); C16H17ClN2Si (M=300.858); calc.: molpeak (M+H)+: 301/303 (Cl); found: molpeak (M+H)+: 301/303 (Cl).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C@@H:13]([NH:20][C:21]([C:23]2[CH:27]=[C:26]([OH:28])[N:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:24]=2)=[O:22])[CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:42]([O:44][C:45]([C:47]1(Br)[CH2:50][CH2:49][CH2:48]1)=[O:46])[CH3:43]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C@@H:13]([NH:20][C:21]([C:23]2[CH:27]=[C:26]([O:28][C:47]3([C:45]([O:44][CH2:42][CH3:43])=[O:46])[CH2:50][CH2:49][CH2:48]3)[N:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:24]=2)=[O:22])[CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCS(C)(=O)=O)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCS(C)(=O)=O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 100 mg of 4-{(S)-2-[(5-Hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-4-methanesulfonyl-butyryl}-piperazine-1-carboxylic acid ethyl ester in 2 ml of DMF, 127 mg of cesium carbonate and 81 mg of 1-Bromo-cyclobutanecarboxylic acid ethyl ester was added and heated to 100° C. for 2 h. Then, the reaction mixture was diluted with water and filtered through a Chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[C:5]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7](=[O:16])[C:6]=2[CH:17]=1.C(O)=O>[Pd].CN(C)C=O>[N+:18]([C:4]1[C:5]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7](=[O:16])[C:6]=2[CH:17]=[CH:2][CH:3]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)c1cc(=O)c2cc(Br)cc([N+](=O)[O-])c2o1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: O=CO
Product: CCOC(=O)c1cc(=O)c2cccc([N+](=O)[O-])c2o1
Temperature: 145 °C
Reaction time: 5.75 h
Yield: 55 %

Procedure:
A mixture of ethyl 6-bromo-8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate (5.0 g, 14.6 mmol), 10% palladium-on-charcoal (0.541 g), formic acid (7.90 ml) and N,N-dimethylformamide (42 ml) was stirred at 145° C. for 5.75 h under inert atmosphere. After this time the mixture was left to cool and the catalyst was removed by filtration, washing it with N,N-dimethylformamide. The resulting filtrate was evaporated to dryness and the obtained residue was purified by chromatography through a silica gel column. Eluting with hexane:chloroform, 85:15, 2.109 g of the title product were recovered (55% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][C@H:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[N:15]=2)[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]([O:34]CC)=[O:33].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:1][C:2]1[CH:7]=[C:6]([S:8][C@H:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[N:15]=2)[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]([OH:34])=[O:33]
Reactant: CCCC[C@H](Sc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC[C@H](Sc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
To a solution of ethyl ({2-methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)thio]phenyl}oxy)acetate (34 mg, 0.07 mmol) in THF (1 mL) and MeOH (1 mL) was added aqueous NaOH (2M, 1 mL) and the resulting mixture agitated for 1.5 hours at rt. The mixture was then reduced under vacuum, acidified with aqueous HCl (2M) and extracted with DCM (2 mL) and reduced to afford the title compound as a colourless oil (31 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:9]=2)=[C:4]([O:45][CH3:46])[CH:3]=1.[N-:47]=[C:48]=[O:49].[K+]>O.C(O)(=O)C>[CH3:46][O:45][C:4]1[CH:3]=[C:2]([NH:1][C:48]([NH2:47])=[O:49])[CH:7]=[CH:6][C:5]=1[C:8]1[C:16]2[C:15]([NH:17][C@H:18]([C:20]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:24](=[O:32])[C:23]4=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]4[N:21]=3)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=2[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[CH:9]=1
Reactant: [N-]=C=O
Reactant: COc1cc(N)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(NC(N)=O)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a suspension of (S)-2-(1-((5-(4-amino-2-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) in water (0.40 mL) and acetic acid (0.20 mL) was added potassium isocyanate (19 mg, 0.23 mmol) according to the method described in Preparation 181 but stirring at 60° C. overnight. The residue was purified using SP1® Purification System (0% to 100% n-hexane-ethyl acetate) to obtain 34 mg (61% yield) of the title compound.
Reaction SMILES: CO[CH:3]=[C:4]([C:9]([O:11]C)=O)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][O:14][CH:15]([O:26][CH3:27])[CH2:16][NH:17][C:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[NH:19].CO>C(OCC)C>[CH3:27][O:26][CH:15]([O:14][CH3:13])[CH2:16][N:17]1[C:9](=[O:11])[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][N:19]=[C:18]1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: COC(CNC(=N)c1cccnc1)OC
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cnc(-c2cccnc2)n(CC(OC)OC)c1=O

Procedure:
Dimethyl methoxymethylenemalonate and N-(2,2-dimethoxy-ethyl) -3-pyridinecarboxamidine were subjected to a procedure similar to that described in Example 1.b. Chromatography, with methanol:diethyl ether (gradient, 0:100, 10:90) as the eluent, gave methyl 1-(2,2-dimethoxy-ethyl)-2-(3-pyridyl)pyrimidin-6(1H)-one-5-carboxylate as an oil; MS: m/z=320(M+1); TLC: Rf =0.4, methanol:diethyl ether (5:95).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Fc1cccc(CBr)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc(F)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[C:13]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=4)=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:26][NH2:27]>C1COCC1.CC(O)C>[Cl:25][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[N:5]=[CH:4][N:3]=[C:2]4[NH:27][CH3:26])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: Fc1ccc(-c2ncccc2-c2ccc3ncnc(Cl)c3c2)cc1Cl
Reactant: CN
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CNc1ncnc2ccc(-c3cccnc3-c3ccc(F)c(Cl)c3)cc12

Procedure:
4-Chloro-6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)quinazoline (75 mg), 2M MeNH2 in THF (2 mL) and i-PrOH (3 mL) were heated and stirred in a screw capped vial for 12 h at 65° C. The heterogeneous reaction mixture was cooled and filtered. The solid on the funnel was washed with water and dried to obtain 6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)-N-methylquinazolin-4-amine (53 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.72 (dd, J=4.7, 1.7 Hz, 1H), 8.47 (s, 1H), 8.31 (q, J=4.7 Hz, 1H), 8.25 (d, J=1.9 Hz, 1H), 7.95 (dd, J=7.8, 1.7 Hz, 1H), 7.61-7.50 (m, 3H), 7.36 (dd, J=8.6, 1.9 Hz, 1H), 7.24 (t, J=8.9 Hz, 1H), 7.13 (ddd, J=8.6, 4.8, 2.2 Hz, 1H), 2.98 (d, J=4.4 Hz, 3H). 19F NMR (282 MHz, DMSO-d6): δ −117.17 (td, J=8.6, 5.1 Hz). LCMS: rt 4.68 min (A), purity 99%, MS (m/e) 365 MH+.