Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)([O-:3])=[O:2].[C:21](=[O:24])([O-])[O-].[K+].[K+].[CH2:27]=[O:28]>C1(C)C=CC=CC=1>[N+:1]([C:4]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=1)([CH2:21][OH:24])[CH2:27][OH:28])([O-:3])=[O:2]
Reactant: CCCCCCCCc1ccc(CCC[N+](=O)[O-])cc1
Reactant: O=C([O-])[O-]
Reactant: C=O
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc(CCC(CO)(CO)[N+](=O)[O-])cc1
Temperature: 2.5 °C

Procedure:
3-nitro-1-(4-octylphenyl)propan-1-one (20 g) and dichloromethane (100 mL) are charged into a round bottom flask at 25-30° C. and stirred. The mixture is cooled to −10° C. to 0° C. and triethylsilane (19.9 g) is added. A solution of titanium tetrachloride (19.57 g) in dichloromethane (100 mL) is added over a period of 15 minutes and the obtained reaction mixture is maintained at −10 to 0° C. for 5 hours. Water (200 mL) precooled to 0-10° C. is slowly added to the reaction mixture over a period of 20 minutes and the temperature is allowed to raise to 25-30° C. The reaction mixture is stirred for about 1 hour, organic layer is separated, washed with 5% sodium bicarbonate solution (100 mL), followed by 20% brine solution (100 mL), the organic layer is concentrated under vacuum at 45° C. to obtain 38.2 g of crude 1-(3-nitropropyl)-4-octylbenzene. Toluene (200 mL) and crude 1-(3-nitropropyl)-4-octylbenzene (38.2 g) are charged into the round bottom flask at 25-30° C. and stirred. Potassium carbonate (18.96 g) and paraformaldehyde (7.21 g) are charged and the reaction mixture is stirred at the same temperature for about 6 hours. The reaction mixture is filtered and washed with toluene (40 mL). The obtained filtrate, water (200 mL) and ethyl acetate (60 mL) are charged into a round bottom flask and stirred for 2 hours. The organic layer is separated, washed with 5% hydrochloric acid solution (100 mL), 5% sodium bicarbonate solution (100 mL) and followed by 5% brine solution (100 mL). The resultant organic layer is concentrated under vacuum at below 45° C. n-Hexane (100 mL) is added to the obtained compound and stirred. The obtained mixture is cooled to 0 to 5° C., maintained at the same temperature for about 60 minutes, filtered and washed with n-hexane (20 mL). The obtained wet compound and toluene (80 mL) are charged into a round bottom flask, heated to 40-45° C. and maintained at the same temperature for about 15 minutes. The reaction mixture is cooled to 0-5° C., maintained for about 45 minutes, filtered and washed the product with toluene (40 mL) precooled to 0-5° C. and the product obtained is dried under vacuum at 25-30° C. to give the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=3)[N:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:57]([N:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][CH2:68]O)[CH2:62][CH2:61]1)(=[O:59])[CH3:58]>C(Cl)Cl>[C:57]([N:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][CH2:68][O:34][C:31]2[CH:32]=[C:33]3[C:28](=[CH:29][C:30]=2[O:35][CH3:36])[N:27]=[CH:26][N:25]=[C:24]3[O:23][C:22]2[C:14]([F:13])=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([CH3:37])=[CH:16]3)[CH2:62][CH2:61]1)(=[O:59])[CH3:58]
Reactant: CC(=O)N1CCN(CCCO)CC1
Reactant: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
Diethyl azodicarboxylate (0.178 g, 1.02 mmol) was added to a solution of 4-(4-fluoro-2-methylindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.267 g, 0.787 mmol), triphenylphosphine (0.31 g, 1.188 mmol) and 3-(4-acetylpiperazin-1yl)propan-1-ol (0.176 g, 0.945 mmol) in methylene chloride (10 ml). After stirring for 15 minutes at ambient temperature, further triphenylphosphine (0.062 mg, 0.236 mmol) and diethyl azodicarboxylate (0.041 mg, 0.3 mmol) were added. After stirring for 1 hour at ambient temperature, the mixture was poured onto a column of silica and eluted with increasingly polar mixtures of ethyl acetate and methylene chloride followed by methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and the solid was filtered, washed with ether and dried under vacuum to give 6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline 0.210 g, 60%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]1([N:28]([CH3:44])[C:29]2[CH:30]=[N:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[CH2:27][CH2:26][CH2:25]1>>[CH:24]1([N:28]([CH3:44])[C:29]2[CH:34]=[C:33]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)[CH:32]=[N:31][CH:30]=2)[CH2:25][CH2:26][CH2:27]1
Reactant: CN(c1cncc(B2OC(C)(C)C(C)(C)O2)c1)C1CCC1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(N(C)C5CCC5)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and Cyclobutyl-methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 174.1.1) to give the title compound as a white solid. (HPLC: tR 2.39 min (Method A); M+H=454 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.15-8.04 (m, 4H), 7.96-7.92 (m, 1H), 7.60-7.57 (m, 11-1), 7.06-7.03 (m, 1H), 4.17 (qt, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 2.89 (s, 3H), 2.28-2.02 (m, 4H), 1.97 (s, 3H), 1.81-1.63 (m, 2H))
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[NH:29][N:28]=[N:27][N:26]=3)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: N#CCCCCCc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)o1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc(CCCCCc3nnn[nH]3)oc2-c2ccc(Cl)cc2)cc1
Reaction time: 48 h
Yield: 45 %

Procedure:
The procedure is as in Example 2, heating for 48 hours 2.4 g of 6-[4,5-bis(4-chlorophenyl)-2-oxazolyl]hexanenitrile, 1.2 g of sodium azide and 1 g of ammonium chloride in 45 cm3 of dimethylformamide. Sodium azide and ammonium chloride are added (in the same quantities as before) and the mixture is brought again to 105° C. for 48 hours. The reaction product is extracted as in the abovementioned example and crystallised in 80 cm3 of diisopropyl ether. 1.2 g of 5-{5-[4,5-bis(4-chlorophenyl)-2-oxazolyl]pentyl}tetrazole, white crystals, melting point 100° C., are obtained.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])[C:6]=2[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:3]=1.C[O:28][B:29](OC)[O:30]C>>[Cl:20][C:14]1[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:7]1[C:6]2[CH:5]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:3]=[C:2]([B:29]([OH:30])[OH:28])[C:10]=2[N:9]=[C:8]1[CH3:11]
Reactant: COB(OC)OC
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Product: Cc1nc2c(B(O)O)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl

Procedure:
The titled compound was prepared from 4-(4-bromo-1-(2,3-dichlorobenzyl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.9 g, 1.977 mmol) using Method A with trimethylborate to give the product (82 mg, 10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H) 2.97-3.12 (m, 4H) 3.69-3.77 (m, 4H) 5.57 (s, 2H) 6.32 (dd, J=7.83, 1.01 Hz, 1H) 7.12 (d, J=2.02 Hz, 1H) 7.26 (t, J=7.96 Hz, 1H) 7.36 (d, J=2.02 Hz, 1H) 7.61 (dd, J=8.08, 1.26 Hz, 1H) 8.66 (s, 2H); MS (ES+) m/z 420.1 [M+H]+.
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=C(F)C=1.COC1C=CC(CN2C(=O)C(C)NC2=O)=CC=1.[CH3:42][C:43]1[C:44]([N:50]2[CH2:55][CH2:54][N:53]([C:56]([C:58]3[CH:63]=[CH:62][C:61]([N:64]4[CH:68]([CH3:69])[C:67](=[O:70])[N:66](CC5C=CC(OC)=CC=5)[C:65]4=[O:80])=[CH:60][C:59]=3[F:81])=[O:57])[CH2:52][CH2:51]2)=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=1>>[CH3:42][C:43]1[C:44]([N:50]2[CH2:51][CH2:52][N:53]([C:56]([C:58]3[CH:63]=[CH:62][C:61]([N:64]4[CH:68]([CH3:69])[C:67](=[O:70])[NH:66][C:65]4=[O:80])=[CH:60][C:59]=3[F:81])=[O:57])[CH2:54][CH2:55]2)=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=1
Reactant: COc1ccc(CN2C(=O)C(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(F)c3)C2=O)cc1
Agent: COc1ccc(CN2C(=O)NC(C)C2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)cc3F)CC2)c(C)c1

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (314 mg) described in Preparation Example 114 and 3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione (225 mg) described in Preparation Example 51 and by the reaction and treatment in the same manner as in Example 508, the title compound (184 mg) was obtained via 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([N+:21]([O-])=O)=[N:10][CH:11]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=2)[CH2:4][CH2:3]1.[C:24]([C:26]1[O:30][C:29]([C:31](Cl)=[O:32])=[CH:28][CH:27]=1)#[N:25].C(C1OC(C(O)=O)=CC=1)#N>CN(C=O)C>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([NH:21][C:31]([C:29]3[O:30][C:26]([C:24]#[N:25])=[CH:27][CH:28]=3)=[O:32])=[N:10][CH:11]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: CC1CCN(c2cc(N3CCN(C)CC3)cnc2[N+](=O)[O-])CC1
Agent: N#Cc1ccc(C(=O)O)o1
Solvent: CN(C)C=O
Product: CC1CCN(c2cc(N3CCN(C)CC3)cnc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 4 %

Procedure:
4-Methy-5′-(4-methyl-piperazin-1-yl)-2′-nitro-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl (as prepared in the previous step) (319 mg, 1.00 mmol) was converted to corresponding amine according to the procedure in Example 55, step (c) and coupled with 5-cyano-furan-2-carbonyl chloride as prepared in Example 4, step (c) (obtained from 137 mg, 1.00 mmol of 5-cyano-furan-2-carboxylic acid as prepared in Example 1) in DMF (2 mL) at 0° C. The product was isolated by flash chromatography on silica (20% EtOAc/hexane-10% MeOH/EtOAc) to obtain the title compound (16 mg, 4%). 1H-NMR (CDCl3; 400 MHz): δ 9.35 (br s, 1H), 7.95 (br s, 1H), 7.33 (d, 1H, J=3.5 Hz), 7.22 (d, 1H), J=3.5 Hz), 7.06 (br s, 1H), 3.21 (m, 4H), 3.06 (m, 2H), 2.71 (m, 2H), 2.58 (m, 4H), 2.37 (s, 3H), 1.84 (m, 2H), 1.7-1.5 (m, 3H), 1.07 (d, 3H, J=6.3 Hz). LC-MS (ESI, m/z); Calcd. for C22H28N6O2, 409.2 (M+H), found 409.2.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][NH2:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:13][NH:14][C:15](=NC)[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[CH3:13][N:14]1[C:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:10][N:11]=[C:15]1[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]
Reactant: C=CCCCC(=NC)NC
Reactant: NNC(=O)Cc1ccccc1
Agent: Cl
Product: C=CCCCc1nnc(Cc2ccccc2)n1C

Procedure:
The title compound was prepared in analogy to Preparation 11 in 0.18 g yield starting from phenylacetic hydrazide (0.5 g) and N,N′-dimethyl-5-hexenimidamide hydrochloride (0.62 g). MS (m/z): 242 [MH]+.
Reaction SMILES: [Cl:1][C:2](OCC(Cl)(Cl)Cl)=[O:3].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1>ClCCCl>[ClH:1].[Br:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]=[C:2]=[O:3])=[N:12][CH:13]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(Br)cn1
Solvent: ClCCCl
Product: Cl
Product: O=C=Nc1ccc(Br)cn1
Temperature: 25 °C
Yield: 72 %

Procedure:
78.0 ml (0.64 mol) of trichloroethyl chloroformate are added dropwise to a stirred solution of 100 g (0.58 mol) of 2-amino-5-bromopyridine in 400 ml of 1,2-dichloroethane at the boiling point. After the addition, the mixture is boiled under reflux for 2 hours and is then allowed to cool to room temperature. The precipitate formed is separated off by filtration, washed thoroughly with 100 ml of 1,2-dichloroethane and dried under a high vacuum over sodium hydroxide. 98.3 g (72%) of the title compound are obtained as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:20][C@H:21]1[CH2:26][O:25][CH2:24][CH2:23][NH:22]1>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][C@@H:21]2[CH3:20])[CH:7]=1
Reactant: C[C@H]1COCCN1
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1nc(Cl)cc(N2CCOC[C@@H]2C)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 109.1 %

Procedure:
To a solution of 4,6-dichloro-2-(methylthio)pyrimidine (585 mg, 3.0 mmol) in DCM (5 mL) was added DIPEA (1.5 mL, 9.0 mmol), followed by 3-(S)-methylmorpholine (909 mg, 9.0 mmol) dropwise. The reaction mixture was stirred at 40° C. overnight whereupon it was washed with water (10 mL), passed through a PTFE hydrophobic frit and the solvent removed in vacuo to yield a colourless oil (850 mg) used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[N:4]([CH2:8][C:9](=O)[CH3:10])[N:3]=1.[CH3:12][NH:13][NH2:14].C(O)(=O)C(O)=O>CC(O)C.O>[CH3:12][N:13]1[C:5](=[O:7])[N:4]([NH:3][C:2](=[O:6])[CH3:1])[CH2:8][C:9]([CH3:10])=[N:14]1
Reactant: CNN
Reactant: CC(=O)Cn1nc(C)oc1=O
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(C)O
Product: CC(=O)NN1CC(C)=NN(C)C1=O
Yield: 53.6 %

Procedure:
To a solution of 5-methyl-3-(2-oxo-propyl)-3H-1,3,4-oxadiazol-2-one (1.518 g, 9.72 mmol) in a mixture of 2-propanol (8.8 mL) and water (0.22 mL) is added methyl hydrazine (0.79 mL, 14.6 mmol). The reaction mixture is heated to reflux under N2 for 4 h, and then a solution of oxalic acid (0.273 g, 2.92 mmol) in 2-propanol (4 mL) is added. The resulting precipitate is removed by filtration. The filtrate is concentrated in vacuo and the residue dissolved in 2-propanol (25 mL). The solution is chilled and Et2O is added. The precipitate is collected by filtration and dried to afford N-(2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-acetamide (0.96 g, 54%) as a crystalline solid. MS: 185 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 4.18 (s, 2H), 3.28 (s, 3H), 2.02 (s, 3H), 1.95 (s, 2H).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[N:8]=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1.[OH:14][CH2:15][C:16](C)([CH3:19])[CH:17]=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O>[Cl:6][C:7]1[N:8]=[N:9][C:10]([Cl:13])=[CH:11][C:12]=1[C:16]([CH2:15][OH:14])([CH3:19])[CH3:17]
Reactant: CC(C)(C=O)CO
Reactant: Clc1ccc(Cl)nn1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(CO)c1cc(Cl)nnc1Cl
Reaction time: 1 h

Procedure:
Ten ml. of water and 0.33 ml. of sulfuric acid were heated to 80°, and to it were added 0.75 g. of 3,6-dichloropyridazine and 2.55 g. of 3-hydroxy-2,2-dimethylpropanaldehyde. Then a solution of 5.7 g. of ammonium persulfate in 15 ml. of water was added dropwise over 10 minutes. The temperature of the mixture reached 100° during the addition. The mixture was stirred for one hour, and then 0.51 g. of the aldehyde and 1.1 g. of ammonium persulfate were added, and the mixture was stirred one hour more at 90°. It was then cooled and extracted twice with 30 ml. portions of dichloromethane. The organic layers were combined, washed with 30 ml. of water and then with 30 ml. of saturated aqueous sodium bicarbonate, and dried with sodium sulfate. The solvent was removed under vacuum to obtain 1.38 g. of oil, which was chromatographed on 100 g. of silica gel, eluting with one liter of 3:7 ethyl acetate:hexane and then with 2:3 ethyl acetate:hexane. The product-containing fractions were combined and evaporated under vacuum to obtain 0.43 g. of the desired product in crude form, about 80% pure by nuclear magnetic resonance analysis. The spectrum, taken in CDCl3 on a 90 mmHz instrument, showed the following characteristic features: δ7.59 (s, 1H); 4.02 (broad s, 3H); 1.46 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-fluoro-5-trifluoromethylpyridine. ESI-MS (m/z): 460 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:12])[N:3]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19]CC)=[O:18].[F:22][C:23]1[CH:24]=[C:25]([CH2:30][OH:31])[CH:26]=[CH:27][C:28]=1[F:29]>O1CCCC1>[F:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:30][O:31][C:2]1[CH:11]=[C:6]2[N:7]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:12])[N:3]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: O=c1nc(Cl)cc2n1CCCN2
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.8 %

Procedure:
To a solution of 8-chloro-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (5 g, 26.9 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (2.59 g, 108 mmol) at r.t. stirred for 10 minutes at r.t., then was added ethyl 2-bromoacetate (4.50 g, 26.9 mmol) and stirred for 2 h, and followed by addition of (3,4-difluoro phenyl)methanol (3.88 g, 26.9 mmol). The reaction mixture was stirred for 1 h at r.t., quenched by addition of water, and extracted by EtOAc. The aqueous phase was acidified to pH˜1 with HCl (1N), washed by EtOAc, then the aqueous phase was concentrated in vacuum, and the residual was washed by methanol and filtrated. The filtrate was concentrated to afford the title compound (3.1 g)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]([O:11][CH:12]1[C:13]([O:55][CH:56]([O:58][CH2:59][CH3:60])[CH3:57])([CH3:54])[CH2:14][CH2:15][CH:16]([O:48][CH:49]([O:51][CH2:52][CH3:53])[CH3:50])[CH2:17][C:18]([O:20][CH:21](/[C:26](/[CH3:47])=[CH:27]/[CH:28]=[CH:29]/[CH:30]([CH3:46])[CH2:31][CH:32]2[O:45][CH:33]2[CH:34]([CH3:44])[CH:35]([O:38][CH:39]([O:41][CH2:42][CH3:43])[CH3:40])[CH2:36][CH3:37])[CH:22]([CH3:25])[CH:23]=[CH:24]1)=[O:19])=[O:10].C(OCC)(=O)C.O>CN(C)C=O>[CH2:52]([O:51][CH:49]([O:48][CH:16]1[CH2:15][CH2:14][C:13]([O:55][CH:56]([O:58][CH2:59][CH3:60])[CH3:57])([CH3:54])[CH:12]([O:11][C:9](=[O:10])[CH2:8][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:24]=[CH:23][CH:22]([CH3:25])[CH:21](/[C:26](/[CH3:47])=[CH:27]/[CH:28]=[CH:29]/[CH:30]([CH3:46])[CH2:31][CH:32]2[O:45][CH:33]2[CH:34]([CH3:44])[CH:35]([O:38][CH:39]([O:41][CH2:42][CH3:43])[CH3:40])[CH2:36][CH3:37])[O:20][C:18](=[O:19])[CH2:17]1)[CH3:50])[CH3:53]
Reactant: C1COCCN1
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)CCl)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)CCl)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)CN2CCOCC2)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)CN2CCOCC2)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Morpholine (9 mg, 0.103 mmol) was added to a solution of (8E,12E,14E)-7-chloroacetoxy-3,6,21-tri(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (8.1 mg, 10.3 μmol) in N,N-dimethylformamide (1 mL) at room temperature, followed by stirring at 60° C. for one hour. Ethyl Acetate and water were added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic layer was washed with water. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and then evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane=1:2 and 1:1, successively) to obtain the title compound (7.3 mg, 85%) as a colorless oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45](C4C(C#N)=CSC=4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[O:55]1[CH2:60][CH2:59][N:58]([CH2:61][CH2:62][O:63]C2C=CC(O)=CC=2)[CH2:57][CH2:56]1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45]([O:63][CH2:62][CH2:61][N:58]4[CH2:59][CH2:60][O:55][CH2:56][CH2:57]4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: Oc1ccc(OCCN2CCOCC2)cc1
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCOc3ccc(OCCN4CCOCC4)cc3)s1)CC2

Procedure:
The title compound 88 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 88B: 1H NMR (DMSO-d6): δ 12.86 (s, 1H), 9.96 (s, 1H), 8.03 (d, J=7.98 Hz, 1H), 7.79 (d, J=7.98 Hz, 2H), 7.67 (d, J=7.36 Hz, 1H), 6.86-6.94 (m, 4H), 4.83 (s, 2H), 4.25-4.27 (m, 2H), 3.91-4.02 (m, 4H), 3.73 (t, J=5.98 Hz, 2H), 3.14-3.22 (m, 4H), 3.03 (t, J=5.98 Hz, 2H), 1.94-2.01 (m, 2H). ESI (+)/MS: 700 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:39]=[C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=4)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=3)[CH:3]=2)[CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1F
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidine (example E.101) (0.415 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as white foam (0.43 g), which was subsequently deprotected.