Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+:2].[Cl:3][C:4]1[CH:27]=[CH:26][C:7]([C:8]([N:10](CCC#N)[CH:11]([C:17]([O:19]CC)=[O:18])[C:12]([O:14]CC)=[O:13])=[O:9])=[CH:6][CH:5]=1>CO>[OH2:9].[OH2:1].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]([CH2:6][CH2:7][C:8]#[N:10])([C:17]([O-:19])=[O:18])[C:12]([O-:14])=[O:13])=[O:9])=[CH:26][CH:27]=1.[Na+:2].[Na+:2]
Reactant: [OH-]
Reactant: CCOC(=O)C(C(=O)OCC)N(CCC#N)C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CO
Product: N#CCCC(NC(=O)c1ccc(Cl)cc1)(C(=O)[O-])C(=O)[O-]
Product: O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 1N solution of sodium hydroxide (80 ml) was added dropwise to a solution of 7.3 g of diethyl N-(p-chlorobenzoyl)-2-(2-cyanoethyl)aminomalonate in methanol (60 ml) at 0°-5° C., and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure to a volume of 80 ml, and 60 ml of ethanol were added to the concentrate. The precipitate was filtered off, washed with 50 ml of ethanol and dried for 16 hours in vacuo, to afford 6.0 g of the desired disodium salt (a) as a colourless powder melting at 254°-255° C. (with decomposition).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[S:5][CH:6]=[C:7]([CH:9]=O)[N:8]=1)[CH3:2].[S:13]1[CH2:19][C:17](=[O:18])[N:16]([CH2:20][C:21]([OH:23])=[O:22])[C:14]1=[S:15].[Cl-].[NH4+]>C(O)C>[NH3:3].[CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[S:5][CH:6]=[C:7]([CH:9]=[C:19]2[S:13][C:14](=[S:15])[N:16]([CH2:20][C:21]([OH:23])=[O:22])[C:17]2=[O:18])[N:8]=1)[CH3:2]
Reactant: CCN(CC)c1nc(C=O)cs1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCN(CC)c1nc(C=C2SC(=S)N(CC(=O)O)C2=O)cs1
Product: N

Procedure:
The reaction described in Example 1 was repeated, but using 1.2 g of 2-diethylaminothiazole-4-carbaldehyde, 1 g of rhodanine-3-acetic acid. 0.8 g of ammonium chloride. 0.8 ml of 28% v/v aqueous ammonia, and 25 ml of ethanol, giving the title compound as yellowish-brown needles.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:17])[F:18])=[CH:10][CH:9]=2)[CH2:12][CH2:13]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)COc1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(OCC(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
1-[4-(2,2,2-trifluoroethoxy)phenyl]piperazine (13.48 g, 50 mmol) was dissolved in DCM (500 mL) and cooled to 0° C. Triethylamine (29 mL, 0.2 mol) was added, followed by the dropwise addition of methanesulfonyl chloride (4.2 mL, 55 mmol). The reaction was then allowed to warm to room temperature and stir overnight, before being quenched by the addition of water. The layers were separated, and the organic phase dried (MgSO4), filtered and concentrated. The residue was recrystallised from hot ethanol to give pure 1-(methylsulfonyl)-4-[4-(2,2,2-trifluoroethoxy)phenyl]piperazine (3.3 g, 18%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:4]=2.[NH3:28]>>[ClH:1].[NH2:28][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:4]=2
Reactant: CCCCCCCCCCCCc1ccc2nc3c(c(Cl)c2c1)CCCC3
Reactant: N
Product: CCCCCCCCCCCCc1ccc2nc3c(c(N)c2c1)CCCC3
Product: Cl
Reaction time: 2 h

Procedure:
A 4.0 g sample of 9-Chloro-7-dodecyl-1,2,3,4-tetrahydroacridine was heated at 150° C. as NH3 was bubbled into the solution. After 2 hours the reaction mixture was distributed between 10% NaOH and 2-butanone and then the organic phase was dried and concentrated. The residue was dissolved in Et2O and treated with 5% HCl. The insoluble hydrochloride was filtered off and recrystallized from MeOH/Et2O to give 2.32 g of analytically pure product, m.p. 257° d.
Reaction SMILES: NC1SC=C(C(=NOCC2C=CC(Cl)=CC=2)C(N[C@@H:11]2[C:26](=[O:27])[N:13]3[C:14](C(O)=O)=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=O)N=1.CN([Si](C)(C)C)C(C(F)(F)F)=O.[Si]([I:54])(C)(C)C.C1COCC1>C(Cl)Cl>[I:54][CH2:18][C:15]1[CH2:16][S:17][C@@H:12]2[CH2:11][C:26](=[O:27])[N:13]2[CH:14]=1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOCc3ccc(Cl)cc3)c3csc(N)n3)[C@H]2SC1
Reactant: C[Si](C)(C)I
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1C[C@H]2SCC(CI)=CN12
Temperature: 40 °C

Procedure:
To a suspension of 200 mg (0.35 mmole) of 7β-[2-(2-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid in 5 ml of methylene chloride was added 0.5 ml of MSTFA and the suspension was stirred at 40° C. until solution occurred. The solution was cooled to room temperature and 0.13 ml (0.87 mmole) of TMSI was added. The reaction stirred at room temperature for 30 minutes and evaporated to an oil. The oil was dissolved in 3 ml of acetonitrile and 0.12 ml (1.5 mmole) of THF was added. The mixture was then stirred at room temperature for 5 minutes to destroy excess TMSI and provide in solution the corresponding 3-iodomethyl-3-cephem derivative.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10](O)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:16](Cl)(=[O:20])[C:17](Cl)=O.CN(C)C=O.[N+:27](=C)=[N-:28]>ClCCl.CCOCC>[N+:27](=[CH:17][C:16]([CH2:10][C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][CH:14]=[CH2:15])=[O:20])=[N-:28]
Reactant: C=CC[C@H](C(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC[C@@H](CC(=O)C=[N+]=[N-])c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 2-(S)-(3,4-dichlorophenyl)-pent-4-enoic acid (5.04 g, 20.6 mmol) in 60 mL of dichloromethane was added oxalyl chloride 2.15 mL (24.6mmol) and dimethylformamide (0.1 mL) upon cooling in an ice-water bath. The cooling bath was then removed and the reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure. The resulting material was diluted in ethyl acetate and concentrated in vacuo in order to remove residual HCl. The residual crude acid chloride was dissolved in 70 mL of ether and was slowly added to a 100 mL ether solution of diazomethane (77 mmol). After stirring for 2 hr at rt, the solvent was removed under vacuum. The resulting yellow oil was chromatographed on silica gel column eluting with a gradient of hexane:ethyl acetate=20:1 to 3:1 to give 4.66g (84%) of diazomethyl-(2-(S)-(3,4-dichlorophenyl)-pent-4-en-yl)-ketone.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[C:30]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42](O)=[O:43])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C=O.C(OCC)(=O)C>[C:33]([O:32][C:30]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42](=[O:43])[NH:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)C(N)Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1)NC(=O)C1CCCN1C(=O)OC(C)(C)C
Reaction time: 10 h
Yield: 32.1 %

Procedure:
A solution of 5[4-(4-(2-amino-2-methoxycarbonylethyl)phenoxy)benzylidene]thiazolidin-2,4-dione hydrochloride (2.5 g, 5.76 mmol) and N-Boc-pyrolidin-2-carboxylic acid (1.238 g, 5.76 mmol) in dimethyl formamide (25 ml) was stirred for 60 minutes at 0° C. N,N′-Dicyclohexylcarbodiimide (1.423 g, 6.91 mmol) was added to it and stirring was continued for 10 h at ambient temperature. Water (200 ml) was added to the reaction mixture and stirred for 15 minutes. Ethyl acetate (200 ml) was added to the reaction mixture and stirring continued for another 15 minutes. The organic layer was separated, washed with water (75 ml), dried over anhydrous sodium sulphate and concentrated to afford the crude product, which was purified by column chromatography to furnish the required product (1.1 g, yield 32.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23](OC)=[O:24])=[CH:13][C:12]=2[N:11]=1.[F:27][C:28]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:29]=1[NH2:30].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([NH:30][C:29]3[CH:31]=[C:32]([C:35]([F:36])([F:37])[F:38])[CH:33]=[CH:34][C:28]=3[F:27])=[O:24])=[CH:13][C:12]=2[N:11]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2nc(C)oc12
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1nc2c(o1)c(C(=O)Nc1cc(C(F)(F)F)ccc1F)cc1nc(Nc3c(F)cccc3Cl)[nH]c12
Yield: 23 %

Procedure:
The title compound was prepared following the procedure as described for Example-185 using methyl 7-[(2-chloro-6-fluorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylate (Step-3 of Intermediate-56, 0.100 g, 0.266 mmol), 2-fluoro-5-trifluoromethylaniline (0.071 g, 0.125 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 2.72 (s, 3H), 7.41-7.47 (m, 3H), 7.63 (s, 2H), 7.76 (s, 1H), 8.54 (d, J=6.9 Hz, 1H), 9.45 (s, 1H), 9.92 (s, 1H), 11.71 (s, 1H); MS [M+H]+: 522.12.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:10](=O)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].O>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH:1]([C:4]1[CH:5]=[C:6](/[C:10](=[N:19]/[S@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])/[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)c1cccc(C(C)C)c1
Reactant: CC(C)(C)[S@@](N)=O
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Solvent: O
Product: C/C(=N\[S@@](=O)C(C)(C)C)c1cccc(C(C)C)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
The mixture of 1-(3-isopropylphenyl)ethanone (5.8 g, 0.036 mol), (S)-2-methylpropane-2-sulfinamide (5.2 g, 0.043 mol) and Ti(OiPr)4 in THF was stirred at 90° C. for 16 hours. Then the mixture was poured to water and the solid was filtered, the filtrate was partitioned between EtOAc and water. The layers were separated and the organic layer was washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give the titled compound.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.O=S(Cl)Cl.[CH3:19]O>>[CH3:19][O:9][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:12]([I:14])=[CH:13][C:5]=1[NH2:4]
Reactant: CC(=O)Nc1cc(I)ccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(I)cc1N
Temperature: 65 °C

Procedure:
To 2-acetylamino-4-iodo-benzoic acid (13.8 g, 45.3 mmol) in 200 mL of dry methanol was added SOCl2 (32.7 mL, 453 mmol) dropwise at 0° C. The reaction mixture was then heated at 65° C. for 2 h. The reaction was then cooled to 0° C., an additional portion of SOCl2 (10 mL, 137 mmol) was added, and the reaction was heated at 65° C. for 2 h. The reaction was then cooled to 0° C., a final portion of SOCl2 (10 mL, 137 mmol) was added, and the reaction was heated at 65° C. for 48 h. The reaction was then cooled to 22° C. and concentrated in vacuo. The resulting residue was diluted with H2O and extracted with 3×150 mL CH2Cl2. The combined organic fractions were washed with brine and dried over Na2SO4 to give i-b (11.7 g, 93%): MS m/z=278 (M+H).
Reaction SMILES: [Li].[F:2][CH:3]([F:22])[O:4][C:5]1[CH:6]=[C:7]([C:12]([O-])=[CH:13][C:14](=O)[C:15]([O:17]CC)=[O:16])[CH:8]=[C:9]([F:11])[CH:10]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:46][C:47]1[CH:52]=[C:51]([NH:53][NH2:54])[CH:50]=[CH:49][N:48]=1>>[F:11][C:9]1[CH:8]=[C:7]([C:12]2[N:53]([C:51]3[CH:50]=[CH:49][N:48]=[C:47]([Cl:46])[CH:52]=3)[N:54]=[C:14]([C:15]([OH:17])=[O:16])[CH:13]=2)[CH:6]=[C:5]([O:4][CH:3]([F:2])[F:22])[CH:10]=1
Reactant: NNc1ccnc(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(F)cc(OC(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(F)cc(OC(F)F)c2)n(-c2ccnc(Cl)c2)n1

Procedure:
590 mg (1.01 mmol) of the compound of Example 7A is reacted analogously to the synthesis of the compound of Example 20A with 200 mg (1.11 mmol) of 2-chloropyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 160 mg (41% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10](CC3C=CC(OC)=CC=3)[C:6]=2[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][N:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)c2ccn(Cc3ccc(OC)cc3)c12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnc(Cl)c2cc[nH]c12
Yield: 37.6 %

Procedure:
A solution of ethyl 4-chloro-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (2.00 g) in TFA (30 ml), anisole (1.84 ml), and sulphuric acid (15 ml) was stirred at room temperature for 30 minutes. The solution was added to an aqueous saturated sodium bicarbonate solution at 0° C. and extracted with ethyl acetate. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a brown solid (0.49 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCCl>[CH3:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:25][CH2:26][N:27]([CH:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]4)[CH2:28][CH2:29]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1ccc2c(c1)[nH]c(=O)n2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)[nH]c(=O)n2C1CCN(C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.4 %

Procedure:
A mixture of 4.5 g N-t-butyloxycarbonyl-4-piperidone, 4.7 g of 4-(5-methyl-2-oxo-1-benzimidazolinyl)piperidine, 65 mL of 1,2-dichloroethane, 1.3 mL of glacial acetic acid and 6.4 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 500 mL chloroform and 500 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×250 mL of chloroform and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Recrystallization of the crude product from50 mL of ethyl acetate gave in two crops 6.18 g of pure 5-methyl-1,3-dihydro-1-{1-[1-(t-butyloxycarbonyl)piperidin-4-yl]piperidin-4-yl}-2H-benzimidazol-2-one as a white solid: mp 210°-211° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][NH2:28])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1>>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][NH:28][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=4)[C:5]([F:16])=[CH:4][N:3]=3)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: NCc1ccc2c(c1)OCCO2
Product: Oc1cccc(Nc2nc(NCc3ccc4c(c3)OCCO4)ncc2F)c1

Procedure:
In a manner analogous to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 2,3-dihydro-1,4-benzodioxin-6-ylmethylamine gave N2-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3) δ 4.24 (s, 4 H), 4.45 (d, J=6.0 Hz, 2 H), 6.55 (ddd, J=0.9, 2.4 and 8.4 Hz, 1 H), 6.66 (d, 1 H), 6.84 (m, 4 H), 6.90 (m, 1 H), 7.14 (t, J=8.1 Hz, 1 H), 7.30 (m, 1 H), 7.86 (d, J=3.3 Hz, 1 H); 19F NMR (282 MHz, CDCl3) δ −170.44; LCMS: ret. time: 18.33 min.; purity: 96.75%; MS (m/e): 369.03 (MH+).
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:31]1([C:37]2[NH:41][N:40]=[C:39]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.[F:50][C:51]1[CH:52]=[C:53]([CH:59]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:61]=1)[O:54][CH:55]1CNC1>CN(C=O)C>[F:50][C:51]1[CH:52]=[C:53]([CH:59]=[C:60]([C:62]([F:63])([F:64])[F:65])[CH:61]=1)[O:54][CH:55]1[CH2:6][CH2:4][N:3]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:39]2[CH:38]=[C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:41][N:40]=2)=[O:43])[CH2:7][CH2:9]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Fc1cc(OC2CNC2)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)cc(C(F)(F)F)c2)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 45 %

Procedure:
DIPEA (97 mg, 0.75 mmol) followed by HOBt (35 mg, 0.26 mmol) and EDCI (50 mg, 0.26 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (62 mg, 0.25 mmol) in DMF (2 mL). After 2 minutes of stirring, 3-(3-fluoro-5-trifluoromethyl-phenoxy)-azetidine hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (75 mg, 0.25 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between cold water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (using silica gel 60-120 and 40% EtOAc in hexane as eluent) afforded 54 mg (45% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(3-fluoro-5-trifluoromethyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 491, 94%. 1H NMR (300 MHz, DMSO-d6): δ 13.8 (s, 1H), 8.5 (b, 1H), 7.8 (d, 2H), 7.4 (m, 2H), 7.3 (m, 2H), 7.2 (m, 2H), 7.1 (m, 1H), 4.8 (m, 1H), 4.2 (m, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.3 (m, 1H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]([NH:17][C@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][C:20](O)=[O:21])=[O:16])[CH:12]=[CH:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:5][C:4]=1[O:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39].[CH3:41][S:42]([NH2:45])(=[O:44])=[O:43].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]([NH:17][C@@H:18]([CH2:19][C:20]([NH:45][S:42]([CH3:41])(=[O:44])=[O:43])=[O:21])[C:23]([CH3:25])([CH3:24])[CH3:26])=[O:16])[CH:12]=[CH:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:5][C:4]=1[O:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccccc1-c1ccc(C(=O)N[C@@H](CC(=O)O)C(C)(C)C)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(C(=O)N[C@@H](CC(=O)NS(C)(=O)=O)C(C)(C)C)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 250 mg (0.42 mmol) of (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoic acid hydrochloride and 49 mg (0.51 mmol) of methanesulfonamide in 2 mL of DCM are successively added 52 mg (0.42 mmol) of DMAP and 89 mg (0.47 mmol) of EDC.HCl. The reaction medium is stirred for 16 hours at room temperature. A further 0.42 mmol of EDC.HCl and 0.42 mmol of methanesulfonamide are added and the reaction mixture is stirred for a further 3 days and then concentrated under reduced pressure. The residue is taken up in 100 mL of EtOAc and the organic phase is washed with 30 mL of water and then with 30 mL of aqueous 4M NaHCO3 solution. After drying over Na2SO4 and concentrating under reduced pressure, the residue is purified by chromatography on a column of silica gel, eluting with a DCM/methanol gradient of from 0 to 10% methanol. After concentrating under reduced pressure, the residue is taken up in 2 mL of methanol and 0.5 mL of aqueous 1N HCl solution and then purified by reverse-phase HPLC (RP18), eluting with a 10−2N HCl/acetonitrile gradient of from 5% to 100% acetonitrile over 90 minutes. After concentrating under reduced pressure and freeze-drying, 130 mg of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-N-[(1S)-2,2-dimethyl-1-{2[(methylsulfonyl)amino]-2-oxoethyl}propyl]-5-(2-methylphenyl)pyridine-2-carboxamide hydrochloride are obtained in the form of a white powder.
Reaction SMILES: [N:1]1[C:11]2[C:10](=O)[CH2:9][CH2:8][C:7](=[O:13])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:20](=[CH:21][CH:22]=1)[NH:23][C:10]1[C:11]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[NH:6][C:7](=[O:13])[CH2:8][C:9]2=1
Reactant: O=C1CCC(=O)c2ncccc2N1
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2[nH]c3c(c2c1)CC(=O)Nc1cccnc1-3
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
5H-Pyrido[3,2-b]azepine-6,9(7H,8H)-dione (484 mg; 2.74 mmol), (4-methoxyphenyl)hydrazine hydrochloride (527 mg, 3.02 mmol), and sodium acetate (242 mg; 3.02 mmol) were suspended in glacial acetic acid (30 mL) and stirred for 30 min. at 70° C. After cooling to room temperature, the mixture was poured into a 5% aqueous sodium acetate solution. The precipitate, consisting of the corresponding phenyl hydrazone, was filtered off with suction, washed successively with 5% aqueous sodium acetate solution and water and was then refluxed 4 h in 70 mL ethanol. After cooling, 206 mg (27%) of a brown powder precipitated, m.p. >330° C.; IR (KBr): 3269 cm−1 (NH), 1669 cm−1 (C═O); 1H-NMR (d6-DMSO, 400 MHz): δ (ppm)=3.66 (s, 2H, azepine-CH2), 3.81 (s, 3H, OCH3), 6.84 (dd, 1H, 8.8/2.4 Hz, arom. H), 7.21 (d, 1H, 2.3 Hz, arom. H), 7.35-7.40 (m, 2H, arom. H), 7.60 (dd, 1H, 8.2/1.4 Hz, arom. H), 8.46 (dd, 1H, 4.5/1.4 Hz, arom. H), 10.20 (s, 1H, NH), 11.54 (s, 1H, NH); 13C-NMR (DMSO-d6, 100.6 MHz): δ (ppm)=55.4 (OCH3), 31.8 (azepine-CH2), 99.6, 112.7, 113.6, 122.3, 129.3, 144.2 (tert. arom. C-atoms), 108.7, 126.6, 131.9, 132.7, 133.0, 140.6, 153.5 (quat. arom. C-atoms), 171.2 (C═O). purity: 99.8% (HPLC, ts=3.57 min, acetonitrile/water: 25/75); EI/HRMS for C16H13N3O2 (279.30) calculated: 279.10077. found: 279.10010.