Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[OH:26][CH2:27][CH2:28][N:29]([CH2:33][CH2:34][OH:35])[CH2:30][CH2:31][NH2:32]>C(O)C>[OH:26][CH2:27][CH2:28][N:29]([CH2:33][CH2:34][OH:35])[CH2:30][CH2:31][NH:32][C:21](=[O:22])[CH2:20][N:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[N:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[N:9]1
Reactant: NCCN(CCO)CCO
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Solvent: CCO
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)NCCN(CCO)CCO

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 1.0 g of N,N-bis(2-hydroxyethyl)ethylenediamine are boiled under reflux for 24 h in 8 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on silica gel. After concentration and drying, N-{2-[bis(2-hydroxyethyl)amino]ethyl}-2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetamide remains as a colorless foam. Rf value: 0.35 (silica gel 60, methylene chloride/methanol=9/1). 1H-NMR (DMSO-d6): 2.5 (m, 6H), 3.1 (m, 2H), 3.4 (m, 4H), 4.2 (bs, 2H), 4.9 (s, 2H), 7.0 (m, 4H), 7.4 (m, 3H), 7.95 (d, 1H), 8.1 (t,1H), 11.0 ppm (s, 1H).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[C:9]2[N:10]([CH3:14])[C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([N:15]2[CH2:19][C@H:18]([C:20]([O:22]C)=O)[O:17][C:16]2=[O:24])[CH:5]=1>CO>[F:3][C:4]1[C:9]2[N:10]([CH3:14])[C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([N:15]2[CH2:19][C@H:18]([C:20]([NH:2][CH3:1])=[O:22])[O:17][C:16]2=[O:24])[CH:5]=1
Reactant: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)oc(=O)n3C)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2cc(F)c3c(c2)oc(=O)n3C)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
A solution of methylamine in methanol (2M, 5 ml) is added to solid methyl (5R)-3-(4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 86, Step 9, 0.250 g, 0.806 mmol) and the suspension stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the residue purified by PTLC (10% methanol/dichloromethane) to give product as a white solid (0.049 g, 19%); MS for C13H12FN3O5 m/z 310 (M+H)+; 1H NMR (DMSO-d6, 300 Mhz) δ 8.40 (m, 1H), 7.49 (d, 1H), 7.42 (dd, 1H), 5.07 (dd, 1H), 4.26 (t, 1H), 4.02 (dd, 1H), 3.42 (s, 3H), 2.65 (d, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:13]1([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)CCl>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:23]2[CH:24]=[CH:25][C:20]([O:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:21][CH:22]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
By following the manipulative procedure described above in Example 4(a), 32.0 g of 1-acetylisonipecotoyl chloride, [Example 1(b)] are added to a stirring solution of 30.6 g of diphenylether and 45.3 g of aluminum chloride in 100 ml of ethylene dichloride to produce a yellow oil of 1-acetyl- 4-(4-phenoxybenzoyl)piperidine.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:29][CH2:30][CH:31]([N:34]6[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]6)[CH2:32][CH2:33]5)=[CH:24][CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CN1CCN(C2CCN(c3ccc(Br)cc3)CC2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(C2CCN(c3ccc(Nc4nc5c(-c6ccc(S(C)(=O)=O)cc6)cccn5n4)cc3)CC2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (55.0 mg, 0.191 mmol) and 1-[1-(4-bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine (70.0 mg, 0.207 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (22.0 mg, 0.0402 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as yellow solid (0.014 g, 13%). MP=237-240° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.6 Hz, 1H), 8.23 (d, J=7.7 Hz, 2H), 8.08 (d, J=8.0 Hz, 2H), 7.63 (d, J=7.2 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.01-6.95 (m, 3H), 6.66 (s, 1H), 3.70-3.62 (m, 2H), 3.10 (s, 3H), 2.73-2.32 (m, 11H), 2.30 (s, 3H), 1.98-1.90 (m, 2H), 1.77-165 (m, 2H). MS=546 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH:11]=[C:12](C(O)=O)[N:13]=[CH:14][C:8]=3[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1>CN1CCCC1.CN1C(=O)CCC1>[Cl:1][C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][N:13]=[CH:14][C:8]=3[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2c(cn1)[nH]c1nccc(Cl)c12
Agent: CN1CCCC1
Solvent: CN1CCCC1=O
Product: Clc1ccnc2[nH]c3cnccc3c12
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid (390 mg, 1.57 mmol) in N-methylpyrrolidine (8 mL) was heated under reflux for 8 hours. The mixture was allowed to cool to ambient temperature. The compound was used as a solution in NMP for subsequent reactions. LCMS (Method B): RT=2.15 min, M+H+=204.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[S:7][C:8]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)=[CH:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([OH:26])=[O:25]>>[CH:19]([N:18]1[C:14]([C:8]2[S:7][C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:31]5[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=5)[C:24]([OH:26])=[O:25])=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][C:10]=3[CH:9]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(-c3cccc(C(=O)O)c3)cc1OCC2

Procedure:
Following the procedure for 114, 5 5-(8-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazole was reacted with 3-carboxyphenylboronic acid to give 147. MS(ESI+) 432.1
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[SH:21][CH:22]([CH3:30])[C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24]>>[S:17]([C:14]1[CH:15]=[CH:16][C:11]([NH:3][C:2]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][S:21][CH:22]([CH3:30])[C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])=[O:1])=[CH:12][CH:13]=1)(=[O:19])(=[O:18])[NH2:20]
Reactant: NS(=O)(=O)c1ccc(-n2sc3ccccc3c2=O)cc1
Reactant: CC(S)C(=O)NCC(=O)O
Product: CC(SSc1ccccc1C(=O)Nc1ccc(S(N)(=O)=O)cc1)C(=O)NCC(=O)O
Yield: 92.3 %

Procedure:
This compound was prepared according to the method of Example 132 using 0.46 g (1.5 mmol) of 4-(3-oxo-3H-benzo[d]isothiazol-2-yl)benzenesulfonamide and 0.25 g (1.5 mmol) of 2-mercapto-propionylglycine. The product was washed with ether and dried in vacuo to give 0.65 g of the title compound, mp 254°-256° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:12]=[C:11](C(Cl)(Cl)Cl)[O:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:17]>CCOCC>[NH2:17][C:11]1[O:10][N:9]=[C:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: ClC(Cl)(Cl)c1nc(Cc2ccccc2)no1
Reactant: N
Solvent: CCOCC
Product: Nc1nc(Cc2ccccc2)no1

Procedure:
A mixture of 60 g. (0.22 moles) of 3-(phenylmethyl)-5-trichloromethyl-1,2,4-oxadiazole and 50 ml. of ether are added dropwise with stirring into 100 ml. of liquid ammonia and stirred for an additional hour. The ammonia and ether are evaporated, the residue is treated with a little water and filtered under suction. 33.3 g. of 5-amino-3-(phenylmethyl)-1,2,4-oxadiazole are obtained, m.p. 142°-145°. After recrystallization from ethanol the compound melts at 145°-146°.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:7][NH:8][C:9]2=O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=2)[C:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(-c2ccc(F)cc2)c2ccc(F)cc12
Product: Fc1ccc(-c2nnc(Cl)c3cc(F)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-fluoro-4-(4-fluorophenyl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19]([Cl:23])=[N:18][N:17]=[C:16]3Cl)=[O:12])[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+].[O:29]1CCOCC1.Cl>O>[F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19]([Cl:23])=[N:18][NH:17][C:16]3=[O:29])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: C1COCCO1
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1)c1ccc2c(Cl)nnc(Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1cccc(OC(F)(F)F)c1)c1ccc2c(Cl)n[nH]c(=O)c2c1
Temperature: 50 °C

Procedure:
A mixture of 1,4-dichloro-phthalazine-6-carboxylic acid (3-trifluoromethoxy-phenyl)-amide (350 mg, 0.87 mmol), 2N NaOH (4.4 mL, 8.70 mmol) and dioxane (4 mL) was heated to 50° C. for 3 h. The reaction was diluted with water, acidified with conc. HCl to ˜pH 6. The reaction mixture was concentrated to low volume and filtered through celite. Chromatography (Hex/EtOAc) afforded 1-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (3-trifluoromethoxy-phenyl)-amide (14 mg) as a white solid, 1H NMR (400 MHz, d6-DMSO) δ: 7.14 (m, 1H), 7.52 (t, 1H), 7.82 (d, 1H), 7.95 (s, 1H), 8.14 (d, 1H), 8.53 (dd, 1H), 8.89 (s, 1H), 10.88 (s, 1H), 13.04 (s, 1H) ppm; m/z (M+1) 384.05; and 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid (3-trifluoromethoxy-phenyl)-amide (20 mg) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ: 7.06 (d, 1H), 7.44 (t, 1H), 7.70 (d, 1H), 7.85 (s, 1H), 8.34 (m, 2H), 8.39 (s, 1H), 10.87 (s, 1H), 12.92 (s, 1H) ppm; m/z (M+1) 384.05.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34]N)=[CH:30][CH:29]=1.CCN(CC)CC>C(O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:30][CH:29]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nccc2-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 4-methoxyphenylhydrazine hydrochloride (262 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (154 mg, 37%).
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][OH:21])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31]>>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][O:21][CH2:29][C:30](=[O:31])[N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C(CCl)N1CCOCC1
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Agent: [Na]
Product: CCOC(=O)c1c2ccc(CC(=O)NOCC(=O)N3CCOCC3)ccc-2c(C(=O)OCC)c1N
Yield: 33 %

Procedure:
In an analogous manner to that described in Example 1, from diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and N-chloroacetyl-morpholine the title compound of m.p. 196-198° C. is obtained in 33% yield.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1([CH3:12])[CH2:10][C:9](=[O:11])[O:8][C:6]1=[O:7]>O1CCCC1>[CH3:1][N:2]([CH3:3])[C:9](=[O:11])[CH2:10][C:5]([CH3:12])([CH3:4])[C:6]([OH:8])=[O:7]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)CC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of dimethylamine (6.8 g, 150 mmol) in tetrahydrofuran (150 ml) at 0° C. was added dropwise a solution of 2,2-dimethylsuccinic anhydride (4.8 g, 37.5 mmol) in tetrahydrofuran (50 ml) and reaction mixture stirred for about 16 hours at ambient temperature. The solvent was removed in vacuo and the residue was washed with 6N hydrochloric acid (5 ml) and methylene chloride was added to dissolve the precipitate. The solution was washed with saturated aqueous sodium chloride (2×25 ml), dried over magnesium sulfate and concentrated to a pale yellow solid. The solid was dissolved in methylene chloride (20 ml) and the desired product precipitated upon the addition of hexane to yield a colorless solid. mp 119°-121° C.
Reaction SMILES: [Mg].Br[CH:3]([CH2:5][CH3:6])[CH3:4].[CH3:7][C:8](=[CH:11][CH2:12][CH3:13])[CH:9]=[O:10]>CCOCC>[CH3:7][C:8]([CH:9]([OH:10])[CH:3]([CH3:4])[CH2:5][CH3:6])=[CH:11][CH2:12][CH3:13]
Reactant: CCC(C)Br
Reactant: CCC=C(C)C=O
Agent: [Mg]
Solvent: CCOCC
Product: CCC=C(C)C(O)C(C)CC

Procedure:
A Grignard reagent, prepared by reacting 18.7 g (0.77 g atom) of magnesium in 100 ml of ether and 105.4 g (0.77 mol) of 2-bromobutane in 300 ml of ether, is reacted with 62.72 g (0.64 mol) of 2-methyl-2-pentenal in 200 ml of ether in a manner analogous to Example 5. Fractional distillation of the crude product (98.8 g) over a 20 cm Widmer column gives 68.4 g (68.5%) of olfactorily good 4,6-dimethyl-3-octen-5-ol of boiling point 83° C./12 mm Hg.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH2:59][CH2:60][CH2:61][N:62]1[CH2:66][CH2:65][CH2:64][C:63]1=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][CH:59]5[CH2:60][CH2:61][N:62]([CH2:66][CH3:65])[CH2:63][CH2:64]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: NCCCN1CCCC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC(F)(F)C(=O)N4C)c(OC)c2)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-(3-aminopropyl)pyrrolidin-2-one. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (t, J=7.07 Hz, 3 H) 1.17 (m, 2 H) 1.35-1.80 (m, 12 H) 2.32 (q, J=7.07 Hz, 2 H) 2.87 (br. d., 2 H) 3.33 (s, 3 H) 3.76 (m, 1 H) 3.94 (s, 3 H) 4.06 (t, J=13.64 Hz, 2 H) 4.46 (m, 1 H) 7.47 (d, J=8.59 Hz, 1 H) 7.50 (s, 1 H) 8.14 (d, 1 H) 8.21 (s, 1 H) 8.26 (d, J=8.34 Hz, 1 H). [M+H] calculated for C29H39F2N7O3, 572; found 572.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(Cl)c1
Yield: 62.1 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 278 mg of 3-chloro-4-fluoroaniline in place of the 2,4-difluoroaniline. 218 mg of N-(3-chloro-4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([CH:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1)=[O:15].O>CN(C)C=O>[CH3:3][C:2](=[CH2:4])[C:1]([O:6][CH2:10][CH2:11][CH2:12][O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([CH:22]2[CH2:23][CH2:24][CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27]2)[CH2:18][CH2:17]1)=[O:15])=[O:5]
Reactant: CCCCCC1CCC(C2CCC(C(=O)OCCCBr)CC2)CC1
Reactant: C=C(C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCCOC(=O)C1CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methacrylic acid (3.5 g, 40.7 mmol) in dimethylformamide (100 ml) is added dropwise to an ice cooled slurry of sodium hydride (60% suspension in paraffin oil) (1.6 g, 40.0 mmol) in dimethylformamide (100 ml). Once addition is complete, the mixture is allowed to warm to room temperature and is stirred for 1 h, the intermediate 4′-pentyl-bicyclohexyl-4-carboxylic acid 3-bromo-propyl ester (15.0 g, 37.4 mmol) in dimethylformamide (100 ml) is added dropwise. The mixture is stirred at 50° C. overnight. The mixture is cooled to room temperature, poured into icy water, and this is extracted three times with DCM. The DCM solution is washed with brine, water and then dried over sodium sulphate. The solution is evaporated to dryness and recrystallised from industrial methylated spirits to afford a white crystalline solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[C:10]1[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:13]([Cl:21])=[CH:12][C:11]=1[O:22][CH3:23])[CH2:4]C)C.C(N(CC)CC)C.[CH3:32][N:33]([CH3:38])[S:34](Cl)(=[O:36])=[O:35].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[C:10]1[CH:15]=[C:14]([N:16]([S:34]([N:33]([CH3:38])[CH3:32])(=[O:36])=[O:35])[S:17]([CH3:20])(=[O:19])=[O:18])[C:13]([Cl:21])=[CH:12][C:11]=1[O:22][CH3:23])[CH3:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCN(CC)CCNC(=O)c1cc(NS(C)(=O)=O)c(Cl)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Cl)c(N(S(C)(=O)=O)S(=O)(=O)N(C)C)cc1C(=O)NCCN(C)C

Procedure:
A solution of N-(diethylaminoethyl)-4-chloro-5-methanesulfonamido-2-methoxybenzamide (570 mg), triethylamine (914 mg) and N,N-dimethylsulfamoyl chloride (1.3 g) in methylene chloride (30 ml) is refluxed for 40 hours. The reaction mixture is mixed with aqueous sodium hydrogen-carbonate. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate and concentrated. The intermediary N-(dimethylaminoethyl)-4-chloro-5-[N-(dimethylaminosulfonyl)-methanesulfonamido]-2-methoxybenzamide obtained as a residue is mixed with 10% aqueous sodium hydroxide (10 ml) and methanol (10 ml) and refluxed for 10 minutes. The reaction mixture is concentrated to remove methanol and the residue is once acidified with 6N hydrochloric acid, neutralized with aqueous sodium hydrogen-carbonate, salted out with brine, and shaken with methylene chloride. The organic layer is dried over anhydrous sodium sulfate and the methylene chloride is evaporated. The residue is chromatographed on a column of alumina, which is eluted with methylene chloride to 1% methanol/methylene chloride. The eluate is concentrated and the residue is washed with ethyl acetate-isopropyl ether to give N-(diethylaminoethyl) -4-chloro-5-(N-dimethylaminosulfonyl)amino-2-methoxybenzamide (410 mg) as crystals melting at 110° to 110.5° C.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[SH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42]>C1(C)C=CC=CC=1>[C:1]([S:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCCCCCCCCCS
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCCCCCCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of trityl chloride (4.6 g, 17 mmol) and diisopropylethylamine (DIEA, 4.2 g, 33 mmol) in toluene (50 mL) was added 11-mercaptoundecanoic acid, 1 (6.0 g, 14 mmol), and the solution was stirred at room temperature for 3 h. The solution was evaporated, and the product separated between dichloromethane and water. The organic phase was washed with water (2×100 mL), dried (MgSO4), filtered, and concentrated to yield crude 2 (6.3 g, 13.6 mmol, 97%). 1H NMR (CDCl3, 500 MHz): δ1.14-1.42 (br m, 14H), 1.59-1.68 (br t, 2H), 2.06-2.09 (br m, 2H), 2.36-2.40 (t, 2H), 7.19-7.23 (m, 6H), 7.26-7.29 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:17]1[C:20]2([CH2:23][NH:22][CH2:21]2)[CH2:19][O:18]1>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([N:22]2[CH2:23][C:20]3([CH2:17][O:18][CH2:19]3)[CH2:21]2)=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)c2c(C)cccc12
Reactant: C1NCC12COC2
Product: COc1ccc(C(=O)N2CC3(COC3)C2)c2c(C)cccc12

Procedure:
4-Methoxy-8-methyl-1-naphthoic acid (Step-5 of Intermediate-22) was reacted with 2-oxa-6-azaspiro[3.3]heptane by following the similar procedure as described in Step-6 of Intermediate-22.