Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:33])[C:15]([C:17]3[C:22]([C:23]#[C:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=4)=[CH:21][N:20]=[C:19]([NH2:32])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:34])=O)(C)(C)C.[ClH:35]>O1CCOCC1>[ClH:35].[NH2:32][C:19]1[N:18]=[C:17]([C:15]2[N:14]([CH3:33])[C:11]3[CH2:12][CH2:13][NH:8][C:9](=[O:34])[C:10]=3[CH:16]=2)[C:22]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[CH:21][N:20]=1.[ClH:35]
Reactant: Cn1c(-c2nc(N)ncc2C#Cc2cccc(O)c2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(-c2nc(N)ncc2C#Cc2cccc(O)c2)cc2c1CCNC2=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2-[2-Amino-5-(3-hydroxy-phenylethynyl)-pyrimidin-4-yl]-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (22 mg, 0.048 mmol) was suspended in dry dioxane (1 mL) under nitrogen atmosphere and 4 N HCl solution in dioxane (0.120 mL, 0.48 mmol, 10 eq) was added. After stirring for 45 minutes at room temperature the suspension was evaporated to dryness, taken up with methanol and evaporated to dryness (3×2 mL). The residue was diluted with ethyl ether and evaporated to dryness (3×2 mL). The desired product was obtained as hydrochloride (21 mg, yellow solid).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+].O.C(O)C>C1COCC1.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cnc(OCC2CC2)c(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1cnc(OCC2CC2)c(Br)c1
Temperature: 50 °C
Yield: 59.9 %

Procedure:
A mixture of 3-bromo-2-(cyclopropylmethoxy)-5-nitropyridine (1 g, 3.7 mmol), ammonium chloride (600 mg, 11.1 mmol), and iron powder (1.05 g, 19 mmol) suspended in THF (6.2 mL), water (2.3 mL) and ethanol (6.2 mL) was heated to 100° C. using microwave irradiation (normal) for 5 h. The crude reaction mixture was filtered through a short plug of celite; the celite plug was washed with warm (50° C.) MeOH (50 mL). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (100 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound, (539 mg, 60%). LCMS (M+H)+=244.
Reaction SMILES: COCCN(S(F)(F)F)CCOC.F[C:15]1[CH:16]=[C:17]([Br:24])[CH:18]=[C:19]([CH:21]([F:23])[F:22])[CH:20]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=1.CC(C)([O-])C.[K+]>C1COCC1.C(Cl)Cl>[Br:24][C:17]1[CH:16]=[C:15]([O:32][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH:20]=[C:19]([CH:21]([F:23])[F:22])[CH:18]=1
Reactant: Fc1cc(Br)cc(C(F)F)c1
Reactant: COc1ccc(CO)cc1
Agent: CC(C)(C)[O-]
Agent: COCCN(CCOC)S(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(Br)cc(C(F)F)c2)cc1

Procedure:
In a fourteenth embodiment of the present invention there is provided a process for the preparation of a compound according to formula 2 which process comprises the steps of: (a) contacting 3,5-dibromo-fluoro-benzene (25) with iso-propyl magnesium chloride to afford a 3-bromo-5-fluoro-phenylmagnesium halide (26); (b) contacting 26 with DMF followed by aqueous acid and MTBE to afford 3-bromo-5-fluoro-benzaldehyde (28); (c) contacting 28 with DEOXO-FLUOR and DCM to a afford 3-fluoro-5-difluoromethyl-1-bromo-benzene (30); (d) contacting 30 with p-methoxy-benzyl alcohol and potassium tert-butoxide in THF to afford 1-bromo-3-difluoromethyl-5-(4-methoxy-benzyloxy)-benzene (32); (e) contacting a solution of 32 and NMP with potassium ferrocyanide, Na2CO3, Pd(OAc)2 and DPPF at about 130° C. to afford 34; (f) treating a solution of 34 and anisole with TFA at temperatures sufficient to cleave the O-benzyl linkage and afford 36; (g) treating a solution of 36 and THF with 1,2,3-trifluoro-4-nitrobenzene (37) and K2CO3 to afford 3-difluoromethyl-5-(2,3-difluoro-6-nitro-phenoxy)-benzonitrile (38); (h) contacting 4 with a strong base in an inert solvent said strong base capable of forming the conjugate base of 4 and contacting said conjugate base with 6 to afford 8; (i) exposing 8 to reaction conditions which are capable of hydrolyzing the ester and decarboxylating the resulting carboxylic acid 8a, (j) contacting 2 with a reducing agent capable of selective reduction of the nitro group to afford 12; (k) contacting 12 with a diazotizing reagent and either Cu(I)Br/LiBr or Cu(I)Cl/LiCl to afford 14, (1) exposing 14 to an oxidizing agent capable of oxidation of the sulfide to a sulfone 18; and (m) contacting 18 with acetic acid/acetic anhydride under conditions which result in cleavage of the S-heteroaryl bond and hydrolysis of the resulting acetate to afford 20 wherein R2 is bromo and chloro respectively, Ar is phenyl substituted with 2 or 3 groups independently selected from halogen, cyano and C1-6 haloalkyl, and R1 and R3 are C1-10 alkyl.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[B-](F)(F)F.[O:18]=[N+:19]=[O:20].S1(CCCC1)(=O)=O>COCCOC>[N+:19]([C:6]1[CH:5]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=[CH:8][C:7]=1[OH:10])([O-:20])=[O:18]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O=S1(=O)CCCC1
Solvent: COCCOC
Product: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1O
Temperature: -50 °C
Reaction time: 6 h

Procedure:
To a mixture of 4-(trifluoromethoxy)phenol (4 g, 0.0225 mol) in ethylene glycol dimethyl ether (90 mL) was added a 0.5 M solution of nitronium tetrafluoroborate in sulfolane (46 mL, 0.0229 mol) at −50° C. The mixture was stirred at −50° C. under an atmosphere of nitrogen for 6 hours. The mixture was filtered through silica gel pad, and the pad was washed with 25% ethyl acetate/n-heptane. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography on silica using 0%-50% ethyl acetate/n-heptane as a mobile phase to give 2-nitro-4-(trifluoromethoxy)phenol (2.5 g, 0.011 mol). TLC (ethyl acetate/n-heptane=25:75) Rf 0.50 MS: MH−: 222.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
N-tert-Butyl-3-{4-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.46) (0.29 g, 0.83 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.26 g, 1.0 mmol) according to the general procedure VI. Obtained as a light brown solid (0.23 g), which was subsequently deprotected.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([F:33])[CH:26]=1>O.CO>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[O:11][CH3:12])=[C:27]([F:33])[CH:26]=1
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: Fc1cc(Br)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
1-(4-hydroxy-3-methoxyphenyl)ethanone (25.0 g, 0.15 mol) and potassium carbonate (15.4 g, 0.11 mol) were added to DMF (80 mL). 4-bromo-1-(bromomethyl)-2-fluorobenzene (50.2 g, 0.19 mol) was added to the mixture, and the mixture was stirred at room temperature for 2 hours and then stirred at 60° C. for 16 hours. Methanol (40 mL) was added to this reaction solution, which was stirred at 60° C. for 1 hour and then blended with water (200 mL). The precipitated crystals were filtered and washed with water and hexane. The crystals were vacuum-dried at 60° C. for 3 hours, yielding 1-[4-(4-bromo-2-fluorobenzyloxy)-3-methoxyphenyl]ethanone (52.7 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[CH2:28][CH2:29]Br.[H-].[Na+]>O1CCCC1>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]=[C:14]([C:22]4([C:23]([O:25][CH3:26])=[O:24])[CH2:29][CH2:28]4)[CH:13]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: BrCCBr
Reactant: COC(=O)Cc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2cc(OC3CCC4(CC3)OCCO4)nc(C(F)(F)F)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
Methyl [6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl]acetate (0.46 g, 1.2 mmol) was dissolved in tetrahydrofuran (23 mL), then 1,2-dibromoethane (300 μL, 3.4 mmol) was added and the reaction mixture cooled to 0° C. NaH in mineral oil (136 mg, 3.4 mmol) was then added and the reaction mixture was heated to 67° C. for 18 h. LCMS showed 50% reaction. The reaction was quenched with saturated NH4Cl and was partitioned between EtOAc and water. The EtOAc extract was washed with brine, dried (Na2SO4), and stripped in vacuo. The ester was purified by automatic silica gel chromatography on a 40 g silica gel column, using solvent A=hexane; solvent B=EtOAc; flow 40 mL/min; A, 2 min; Gradient to 30% B in 30 min; detector set at 254 nm; collected 47 mL fractions; retention time starting ester, 26 min; product, 19 min. The solvent was removed by rotary evaporation to give 0.17 g of product. 1H NMR (300 MHz, CDCl3) δ 7.35 (s, 1H); 5.30 (m, 1H); 3.97 (s, 4H); 3.74 (s, 3H); 1.8-2.0 (m, 6H); 1.6-1.8 (m, 6H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:13][N:12]([CH3:14])[C:11](=[O:15])[N:10]([CH3:16])[CH2:9]2)[CH2:4][CH2:3]1.Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[OH-].[Na+]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:22]([O:21][C:19]([CH2:18][O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:9][N:10]([CH3:16])[C:11](=[O:15])[N:12]([CH3:14])[CH2:13]2)[CH2:6][CH2:7]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN1CN([C@H]2CC[C@H](O)CC2)CN(C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CN([C@H]2CC[C@H](OCC(=O)OC(C)(C)C)CC2)CN(C)C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
trans-5-(4-Hydroxycyclohexyl)-1,3-dimethylhexahydro-2-oxo-1,3,5-triazine (1.00 g, 4.40 mmol) and t-butyl bromoacetate (1.29 g, 6.60 mmol) were dissolved in toluene (13 ml), and tetra-n-butylammonium hydrogensulfate (45 mg, 0.13 mmol) was added to the mixture. A solution of sodium hydroxide (13.2 g, 330 mmol) dissolved in water (13.2 ml) was dropwise added, and the mixture was stirred at room temperature for 15 hours. The organic layer was partitioned, washed with water and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to give 680 mg of trans-5-[4-[(t-butoxycarbonyl)methyloxy]cyclohexyl]-1,3-dimethylhexahydro-2-oxo-1,3,5-triazine as a colorless solid
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:25][CH2:24][CH2:23][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:21][CH2:20][CH2:19][N:18](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:17][CH2:16][CH2:15][N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C>C(OCC)C>[NH:10]1[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCCN(S(=O)(=O)c3ccc(C)cc3)CCCN(S(=O)(=O)c3ccc(C)cc3)CCC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCO
Product: C1CNCCCNCCCNCCCNC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 47 %

Procedure:
A mixture of 1,5,9,13-tetra(p-toluenesulfonyl)-1,5,9,13-tetraazacyclohexadecane prepared as in Example 10E (33.7 g, 0.0399 mole) and concentrated H2SO4 (100 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 72 h. To the resulting brown solution, ethanol (200 mL) was added dropwise with stirring at 0° C, followed by ethyl ether (500 ml). The tan solid was filtered and washed thoroughly with ethyl ether. The solid was then dissolved in H2O (50 ml), the pH was adjusted to 11 with solid NaOH, and the solvent was removed in vacuo. The resulting brown oily solid was extracted with hot THF (4×100 ml) and the extracts were filtered. The filtrates were combined and filtered to remove cloudiness. The solvent was removed in vacuo and the crude product was purified by recrystallization from CHCl3 -ethyl ether to give 4.29 g (47% yield) of the product as colorless prisms: mp 84-6° C.; 1H NMR (CDCl3) δ 1.54 (br s, 4 H), 1.70 (quint, J=6.0 Hz,8 H), 2.72 (t, J=6.1 Hz, 16 H); Exact mass (M+H)+ : calcd., 229.2391; Found, 229.2417 (C12H29N4).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][O:25]C(=O)C)[N:19]=2)=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([CH3:42])[N:12]2[C:29](=[O:41])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1.[NH4+].[Cl-].O>CO>[F:40][C:37]([F:38])([F:39])[C:33]1[CH:32]=[C:31]([NH:30][C:29]([N:12]2[C:13]3[C:9](=[C:8]([F:7])[C:16]([O:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][OH:25])[N:19]=4)=[CH:15][CH:14]=3)[CH:10]=[C:11]2[CH3:42])=[O:41])[CH:36]=[CH:35][CH:34]=1
Reactant: CC(=O)OCc1nccc(Oc2ccc3c(cc(C)n3C(=O)Nc3cccc(C(F)(F)F)c3)c2F)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc2c(F)c(Oc3ccnc(CO)n3)ccc2n1C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (289 mg, 2.09 mmol) is added to a solution of acetic acid 4-[4-fluoro-2-methyl-1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-2-ylmethyl ester (1.05 g, 2.09 mmol) in MeOH (40 mL) at 23° C. The resulting mixture is stirred at 23° C. for 1 h. Saturated aqueous NH4Cl (50 mL) and water (20 mL) are added and the mixture is extracted with EtOAc (3×50 mL). The organic layers are combined, washed with brine (30 mL), dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (10-100% EtOAc/heptane) to provide 4-fluoro-5-(2-hydroxymethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 461.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.02 (s, 1 H) 8.69 (d, J=5.56 Hz, 1 H) 8.12 (s, 1 H) 7.91 (s, 1 H) 7.66 (t, J=7.96 Hz, 1 H) 7.52 (t, J=8.34 Hz, 2 H) 7.17 (dd, J=8.84, 7.83 Hz, 1 H) 7.05 (d, J=5.56 Hz, 1 H) 6.63 (s, 1 H) 5.14 (t, J=6.19 Hz, 1 H) 4.38 (d, J=6.32 Hz, 2 H) 2.59 (s, 3 H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25]Br)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(CBr)nc1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccccc4)c3)cn2)CC1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-(bromomethyl)nicotinamide (0.11 mmol) was used in general procedure 5 with 1-methylpiperazin (0.12 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(4-methylpiperazin-1-ylmethyl)nicotinamide. MS (Q1) 464.0 (M)+
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>>[C:21]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:24])[CH:22]=[CH2:23]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)N=C(OCC)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and acryloyl chloride, there is obtained ethyl N-(acryloyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 320 (11), 291 (19), 194 (100), 55 (15);
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CO.N>CN(C=O)C>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][S:25][CH2:24][CH2:23]3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: ClCCCN1CCSCC1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Yield: 39.7 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (1000 mg, 4.25 mmol), 4-(3-chloro-propyl)-thiomorpholine (764 mg, 2,13 mmol), DMF (20 ml), and K2CO3 (2.34 g, 17 mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant DCM:MeOH:NH3 (95:5:1) to give the title compound (320 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 6.86 (d, 2H), 3.99 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.79-2.64 (m, 8H), 2.55 (t, 2H), 2.40 (s, 2H), 2.16-2.04 (m, 2H), 2.01-1.82 (m, 4H), 1.97 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(C(C)C)CC)(C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)c1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1C
Temperature: 130 °C
Yield: 8.5 %

Procedure:
2,4-Dichloro-5-methylpyrimidine (28.1 g, 4172 mmol), ethyl 2-aminobenzoate (26.7 mL, 181 mmol), diisopropylethylamine (33 mL, 190 mmol) and ethanol (200 mL) were mixed together then equally divided and placed in two 350 mL pressure vessels. They were then capped and heated to 130° C. for three days. Upon cooling to room temperature, the precipitated product was collected and washed with ethanol followed by hexanes and then dried to give 4.5 g (9%) of ethyl 2-[(2-chloro-5-methyl-4-pyrimidinyl)amino]benzoate as an off-white solid. MS: M(C14H14ClN3O2)=291.7, (M+H)+=292.2 and 294.2.
Reaction SMILES: C([Li])CCC.C(NCC)C.[CH2:11]([CH:14]([CH2:17][CH2:18][CH3:19])[C:15]#[N:16])[CH2:12][CH3:13].Br[CH2:21][CH2:22][Cl:23]>CCCCCC.CCOCC.O>[Cl:23][CH2:22][CH2:21][C:14]([CH2:17][CH2:18][CH3:19])([CH2:11][CH2:12][CH3:13])[C:15]#[N:16]
Reactant: ClCCBr
Reactant: CCCC(C#N)CCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCNCC
Solvent: CCOCC
Product: CCCC(C#N)(CCC)CCCl
Reaction time: 1 h

Procedure:
To the solution (245 ml) of 1,6M n butyllithium in hexane is added, drop by drop in an atmosphere of nitrogen and with stirring, the solution of 28.8 g of diethylamine in 100 ml of anhydrous ether. After 1 hour, the solution of 49.2 g of 2-propyl pentane nitrile in 100 ml of anhydrous ether is added at ambient temperature then, after return to ambient temperature, the solution of 49.1 g of 1-bromo 2-chloro ethane in 700 ml of anhydrous ether is added. The mixture is taken to reflux for 15 hours then, whilst cooling the reaction mixture in an ice bath, water is added. The organic phase is separated, washed with water, then with a dilute solution of hydrochloric acid and again with water. It is dried over sodium sulfate and the solvent is evaporated. The residue is distilled and a liquid is obtained; b.p./20 mm Hg: 140°-150° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:13]=3[N:14]=2)=[CH:5][CH:4]=1)[CH3:2].[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH:19][C:27](=[O:28])[CH2:26][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(Nc2nc3cc(N)ccc3o2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(Nc2nc3cc(NC(=O)Cc4ccccc4)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound 1 prepared in Example 1 (1 mmol, 1 eq) was dissolved with DMF (dimethylformamide, 3 mL), and 2-phenylacetyl chloride (1 mmol, 1 eq) and N,N-diisopropylethylamine (1 mmol, 1 eq) were added together thereto. The mixture was then stirred at room temperature for 16 hours. To the reaction solution was added 10% aqueous HCl solution, and the mixture was extracted with 30 mL of EtOAc. The organic layer was washed with 10% aqueous HCl solution, and then two times with saturated NaHCO3 solution and two times with saturated aqueous NaCl solution. After drying with anhydrous MgSO4 and filtering under reduced pressure, the organic solvent was removed under reduced pressure to prepare the title compound.
Reaction SMILES: [Mg].Cl[Si:3]([CH3:6])([CH3:5])[CH3:4].[F:7][C:8](F)([F:17])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>O1CCCC1>[F:7][C:8]([F:17])=[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:10][Si:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: C[Si](C)(C)Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C[Si](C)(C)OC(=C(F)F)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a dry 250 ml Schlenk flask the following compounds were added: magnesium turnings (1.45 g, 60 mmol), dry tetrahydrofuran (THF, 120 ml) and chlorotrimethylsilane (TMSCl, 13.0 g, 120 mmol). The flask was cooled to 0° C. 2,2,2-Trifluoroacetophenone (non-radioactive) 2a (5.2 g, 30 mmol) was added drop wise into the flask with a syringe. After addition of the 2,2,2-Trifluoroacetophenone, the reaction mixture was stirred for an additional 1 h. The completion of the reaction was monitored by 19F NMR spectroscopy. The solvent and excess TMSCl were removed under vacuum, and hexane (50 ml) was added to the residue. Solid impurities were removed by suction filtration, and the solvent was evaporated to yield 2,2-difluoro-1-phenyl-1-trimethylsiloxyethene 1a (6.8 g, 99% yield).