Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][CH:21]([CH2:24][C:25]1[N:26]=[CH:27][N:28]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=1)[CH2:22][OH:23])([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.[H-].[Na+].Cl[C:52]1[C:56]2[CH:57]=[C:58]([Cl:61])[CH:59]=[CH:60][C:55]=2[O:54][N:53]=1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:61][C:58]1[CH:59]=[CH:60][C:55]2[O:54][N:53]=[C:52]([O:23][CH2:22][CH:21]([NH:20][C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:24][C:25]3[N:26]=[CH:27][N:28]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:29]=3)[C:56]=2[CH:57]=1
Reactant: OCC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1ccc2onc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2onc(OCC(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)NC(c3ccccc3)(c3ccccc3)c3ccccc3)c2c1

Procedure:
A solution of 2.0 g of 2-tritylamino-3-(1-trityl-4-imidazolyl)-1-propanol in 10 ml of N,N-dimethylformamide is dropwise added to a suspension of 0.14 g of 60% (w/w) sodium hydride in 15 ml of N,N-dimethylformamide at room temperature over 15 minutes, and the temperature is then elevated gradually to 80° C., after which this is added to a solution of 0.6 g of 3,5-dichloro-1,2-benzoisoxazole in 10 ml of N,N-dimethylformamide. They are subjected to reaction at the same temperature for six hours. After cooling, water and ethyl acetate are added and shaken, and the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluant:n-hexane:ethyl acetate=3:1], to obtain 1.12 g of colorless, crystalline 5-chloro-3-[2-tritylamino-3-(1-trityl-4-imidazolyl)propoxy]-1,2-benzoisoxazole having a melting point of 113.4°-114.7° C.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O>[CH2:15]([O:10][C:9](=[O:11])[CH2:8][C:3]([C:5]([O:7][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[O:6])([OH:4])[CH2:2][C:1]([O:13][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[O:12])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCCCCCCI
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOC(=O)CC(O)(CC(=O)OCCCCCCCCCCCCCCCC)C(=O)OCCCCCCCCCCCCCCCC
Temperature: 50 °C
Reaction time: 21 h
Yield: 83 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene(1,5-5)(4.567 g, 30 mmol) was added at room temperature to a solution of citric acid (1.924 g, 10 mmol) in N,N-dimethylformamide (50 ml). 1-Iodohexadecane (10.570 g, 30 mmol) was added and the resulting mixture was stirred at 50° C. for 21 hours. The precipitated product was filtered off and washed with N,N-dimethylformamide and the crude product was purified by flash chromatography on silica gel using chlorform/hexane for elution. Yield: 83%. 1H-NMR (300 MHz, CDCl3): δ 088(t,9H), 1.26(m,78H), 1.60(m,6H), 2.84(q,4H), 4.07(t,4H), 4.13(s,1H), 4.20(t,2H). FAB-MS: 887.6(M+Na).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][CH3:6].[Cl:7][C:8]1[C:16]([NH2:17])=[C:12]2[CH2:13][CH2:14][O:15][C:11]2=[C:10]([C:18]2[O:22][N:21]=[C:20]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:19]=2)[CH:9]=1.C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[ClH:1].[Cl:7][C:8]1[C:16]([NH2:17])=[C:12]2[CH2:13][CH2:14][O:15][C:11]2=[C:10]([C:18]2[O:22][N:21]=[C:20]([CH:23]3[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][O:5][CH3:6])[CH2:25][CH2:24]3)[N:19]=2)[CH:9]=1
Reactant: Nc1c(Cl)cc(-c2nc(C3CCNCC3)no2)c2c1CCO2
Reactant: COCCCCl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCN1CCC(c2noc(-c3cc(Cl)c(N)c4c3OCC4)n2)CC1
Product: Cl
Temperature: 60 °C
Reaction time: 48 h
Yield: 21.8 %

Procedure:
A mixture of methyl (3-chloropropyl) ether (1.6 g), intermediate 4 (3.9 g), triethylamine (5 ml) and potassium iodide (a catalytic amount) in dimethylformamide (60 ml) was stirred for 48 hours at 60° C. The reaction mixture was cooled and the solvent evaporated. The residue was partitioned between CH2Cl2 and a saturated aqueous NaCl solution. The organic layer was separated, dried over MgSO4, filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 /CH3OH 90/10). The desired fractions were collected and the solvent was evaporated. The residue was solidified in DIPE, filtered off, dissolved in 2-propanol and converted into the hydrochloric acid salt (1:1) with HCl/2-propanol. The precipitate was filtered off and dried, yielding 1.14 g (22.1%) of 5-chloro-2,3-dihydro-7-[3-[1-(3-methoxypropyl)-4-piperidinyl]-1,2,4-oxadiazol-5-yl]-4-benzofuranamine monohydrochloride.hemihydrate (compound 1; mp. 244.3° C.).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C([Cl:28])=O>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([Cl:28])=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
4-[4-Octyloxyphenyl]benzoic acid (OPBA) was converted into its acid chloride, OPBC, by heating it at reflux with oxalyl chloride after which excess oxalyl chloride was allowed to distil out and the residue taken up in ethanol free chloroform.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]([N+:17]#[C-:18])([CH3:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13].[CH:19]1[C:32]2[C:23](=[CH:24][C:25]3[C:30]([C:31]=2[CH:33]=O)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=[CH:21][CH:20]=1>Cl(O)(=O)(=O)=O>[CH:29]1[C:30]2[C:25](=[CH:24][C:23]3[C:32]([C:31]=2[C:33]2[N:1]=[C:2]4[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]4[C:18]=2[NH:17][C:10]([CH3:16])([CH3:9])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccnc(N)n1
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Reactant: O=Cc1c2ccccc2cc2ccccc12
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1ccn2c(NC(C)(C)CC(C)(C)C)c(-c3c4ccccc4cc4ccccc34)nc2n1

Procedure:
Compound (37) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-4-methylpyrimidine solution (0.1 M, DCM), 0.575 ml of 1,1,3,3-tetramethylbutyl isocyanide solution (0.2 M, DCM), 0.500 ml of anthracene-9-carbaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11](Cl)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH:26]=[C:25]([C:11]2[N:10]=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]([CH3:14])[C:12]=2[CH3:15])[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1c(Cl)nnc(Cc2ccccc2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccccc2)nnc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 100 °C
Yield: 76.6 %

Procedure:
To a solution of 3-benzyl-6-chloro-4,5-dimethylpyridazine (800 mg, 3.44 mmol) in 20 mL DMF is added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.3 g, 4.1 mmol), followed with potassium carbonate (1.43 g, 10.3 mmol) and Pd(PPh3)4 (397 mg, 0.344 mmol) in a round bottom flask. The vial is evacuated and flushed with nitrogen. The reaction mixture is heated to 100° C. for 16 h. The mixture is filtered through Celite and the filtrate is concentrated to afford the crude material. The mixture is purified by flash chromatography on silica gel, eluting with 3%-15% MeOH:DCM. Fractions containing the desired product are combined and concentrated to afford a brown solid (1.0 g, 77%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=1[O:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].C([O:35]CC)C.CCCCCC>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:35])=[O:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=1[O:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C=O)ccc1C(C)(C)C)c1cccc(OC)c1OC
Reactant: CCOCC
Solvent: CCCCCC
Product: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1cccc(OC)c1OC

Procedure:
Following a procedure similar to that described in Preparation 21, but using N-(2-t-butyl-5-formylphenyl)-3-(2,3-dimethoxyphenyl)octanamide (prepared as described in Preparation 24) as a starting material, the title compound was obtained as crystals, melting at 146°-147° C. (from diethyl ether-hexane).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[S:10])[NH:8][CH:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH3:14]I.Cl>>[C:1]([C:4]1[C:5](=[O:11])[NH:6][C:7]([S:10][CH3:14])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)c1c[nH]c(=S)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CSc1ncc(C(C)=O)c(=O)[nH]1
Temperature: 40 °C
Yield: 69.1 %

Procedure:
5-Acetyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (Ryan Scientific) (2.3 g, 13.51 mmol) was dissolved in NaOH (20.27 mL, 20.27 mmol), then MeI (0.894 mL, 14.30 mmol) was added to the reaction mixture while stirring. The reaction mixture was heated at 40° C. for 1.5 hours. Additional MeI (0.894 mL, 14.30 mmol) was added and the reaction was allowed to stir at rt for 18 hours. The reaction mixture was cooled with an ice-water bath, acidified to pH 6 with concentrated HCl solution, then the resulting precipitate was filtered to obtain 1.72 g of the desired product (69% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.49 (br. s., 6H) 8.35 (s, 1H) 13.40 (br. s., 1H). MS (ES+): m/z=185.1 (100) [MH+]. HPLC: tR=1.0 minute over 3 minutes. Purity: >90% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: C1(C)C=CC=CC=1.CS(O)(=O)=O.[C:13]1(=[O:19])[O:18][C:16](=O)[CH:15]=[CH:14]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](N)[CH:23]=1.C([N:31](CC)CC)C>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:15]2[C:16]([NH:31][C:13](=[O:19])[CH:14]=2)=[O:18])[CH:25]=[CH:26][CH:27]=1
Reactant: COc1cccc(N)c1
Reactant: CCN(CC)CC
Reactant: O=C1C=CC(=O)O1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: COc1cccc(C2=CC(=O)NC2=O)c1
Temperature: 25 °C

Procedure:
Toluene (100 mL), triethylamine (10 g), methanesulfonic acid (15 g) were placed into a 500 ml, single-neck flask. Maleic anhydride (21.0 g, 214 millimoles) was dissolved into this mixture. This mixture was stirred magnetically at room temperature and m-anisidine (24.67 g, 200 millimoles) was then added drop-wise over a twenty minute period. A Dean-Stark trap and condenser were attached and the mixture was refluxed for three hours. A total of 3.7 ml of water was collected in the trap. The mixture was cooled to room temperature and the upper (toluene) phase was decanted off. The lower phase was extracted with 6×70 ml portions of fresh toluene. The collected toluene phase was passed over 27 grams of silica gel. The toluene was removed on a rotary evaporator to yield 27.3 g (67% of theory) of a clear yellow liquid. The product crystallized to a solid upon standing at room temperature. The solid melted at 75-76.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:10]([C:12]1([CH2:16][CH:17]=O)[CH2:15][O:14][CH2:13]1)[CH3:11]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:11]/[CH2:10][C:12]1([CH2:16][CH3:17])[CH2:15][O:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCC1(CC=O)COC1
Solvent: ClCCl
Product: CCC1(C/C=N/CC(=O)OC(C)(C)C)COC1
Yield: 100.9 %

Procedure:
Step B In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1 g, 7.8 mmol) was reacted with (3-ethyl-oxetan-3-yl)-acetaldehyde (1 g, 7.8 mmol) in CH2Cl2 at room temperature for 18 h to give [2-(3-ethyl-oxetan-3-yl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (1.9 g, 100%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[N+](C1C=CC([O:19][C:20]([N:22]2[CH2:25][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][N:28]=3)[CH2:23]2)=O)=CC=1)([O-])=O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([NH:3][C:20]([N:22]2[CH2:23][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][N:28]=3)[CH2:25]2)=[O:19])[N:5]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(I)cn2)C1
Reactant: Nc1cccnn1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccnn1)N1CC(Oc2ccc(I)cn2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To an ice-bath cooled solution of sodium hydride (60 wt % in mineral oil, (2.1 g, 52.4 mmol) in DMF (50 mL) under nitrogen atmosphere was added (dropwise) a solution of 3-aminopyridazine (2.74 g, 28.79 mmol) in DMF (50 mL). After several minute a solution of 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid 4-nitro-phenyl ester (Example 5, step 3); 11.54 g, 26.18 mmol) in DMF (40 mL) was added. After 5 min the cooling bath was removed and reaction allowed to warm to ambient temperature and stir for 1.5 hr. Saturated sodium bicarbonate solution (500 mL) was added and the mixture was extracted with EtOAc (4×400 mL). Combined organic phases were washed with sat sodium chloride solution (500 mL), dried over sodium sulphate and filtered. The filtrate solvents were removed in vacuo to afford a crude product that was triturated with diethyl ether to afford the title compound (7.52 g, 72%) as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])(=[O:30])=[O:31])=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl) amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 4-methoxy-2-nitrobenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 348 mg of benzo[b]thiophene-2-sulfonic acid [2-(4-methoxy-2-nitro-benzenesulfonylamino)phenyl]-amide. LC: Tr 1.09 min; MS: 520.7 (M+1)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH3:26])[N:20]=3)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH:27]1([C@H:33]([NH2:35])[CH3:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1>[CH:27]1([C@H:33]([NH:35][C:5](=[O:6])[C:4]2[CH:8]=[C:9]([O:12][C:13]3[C:18]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH3:26])[N:20]=4)=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:10]=[CH:11][C:3]=2[F:2])[CH3:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C[C@@H](N)C1CCCCC1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(F)c(C(=O)Cl)c2)n1
Agent: Cl
Solvent: C1CCOC1
Product: CNc1nccc(-c2cccnc2Oc2ccc(F)c(C(=O)N[C@H](C)C3CCCCC3)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoro-5-[3-(2-methylamino-pyrimidin-4-yl)-pyridin-2-yloxy]-benzoyl chloride hydrochloride (86 mg, 0.22 mmol) in THF (2.0 mL) was added (R)-1-cyclohexyl-ethylamine (0.029 mL, 0.20 mmol). The mixture was stirred overnight at RT, quenched with excess NEt3, concentrated and purified by preparative TLC (100% EtOAc) to yield N-((1R)-1-cyclohexylethyl)-2-fluoro-5-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)benzamide. MS m/z=450 [M+1]+. Calc'd for C25H28FN5O2: 449.53.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.CN1CCOCC1.Cl.[CH3:21][O:22][C:23](=[O:28])[C@H:24]([CH2:26][OH:27])[NH2:25].C(Cl)(Cl)Cl>ClCCl>[CH3:21][O:22][C:23](=[O:28])[C@H:24]([CH2:26][OH:27])[NH:25][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CO)NC(=O)Cc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
To an ice cooled solution of 3,5-difluorophenylacetic acid (2.16 g) in anhydrous dichloromethane (100 mL) under nitrogen was added HOBt-hydrate (4.23 g), EDAC-HC1 (3.6 g), and NMM (2.2 mL). The reaction mixture was stirred at 0° C. under nitrogen for 15 min and L-serine methyl ester-HCl (1.96 g) was added followed by NMM (1.38 mL). The reaction was stirred at 0° C. for 1 H and RT for 2 H. The reaction mixture was concentrated in vacuo and partitioned between water (100 mL) and ethyl acetate (125 mL). The organic phase was collected and consecutively washed with water, dilute aqueous sodium bicarbonate, brine, dried, filtered and the solvent removed in vacuo to yield a white solid. Trituration with CHCl3 afforded pure title compound (1.8 g). The impure filtrate was subjected to flash chromatography (20% acetone/CHCl3) to afford additional title compound (800 mg, total yield 76%). 1H NMR (300 MHz, d6-DMSO) δ3.57 (d, 2H), 3.62(s, 3H), 3.7 (m, 1H), 4.35, (m, 1H), 5.1 (bs, 1H), 7.00 (d, 2H), 7.09 (t, 1H), 8.53, (d, 1H). MS APCI, m/z=274 (M+1). LC/MS: 1.34 min.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)[CH:20]=1.[C:34]1([NH:40][CH2:41][CH2:42][NH2:43])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[NH:40]([CH2:41][CH2:42][NH:43][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:33][CH:32]=1)=[O:18])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCCNc1ccccc1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Product: CON=C1C[C@@H](C(=O)NCCNc2ccccc2)N(C(=O)c2ccc(-c3cccnc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and N1-phenyl-1,2-ethanediamine, the title compound was obtained in 85% purity by HPLC. MS(ESI+): m/Z=458.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Br:13][C:14]1[C:15]([O:24][CH3:25])=[C:16]([O:22][CH3:23])[CH:17]=[C:18]([CH:21]=1)[CH:19]=O.[C:26](#[N:30])[CH2:27][C:28]#[N:29].C1N2CCN(CC2)C1>C(O)C.O>[NH2:30][C:26]1[O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[N:10]=3)[CH:5]=[CH:4][C:3]=2[CH:19]([C:18]2[CH:17]=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[C:14]([Br:13])[CH:21]=2)[C:27]=1[C:28]#[N:29]
Reactant: N#CCC#N
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: COc1cc(C=O)cc(Br)c1OC
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccc(C)nc32)cc(Br)c1OC
Temperature: 80 °C
Reaction time: 72 h
Yield: 24 %

Procedure:
8-Hydroxyquinaldine (382 mg, 2.4 mmol), 5-bromo-3,4-dimethoxybenzaldehyde (490 mg, 2 mmol) and malononitrile (132 mg, 2 mmol) were taken in 25 ml ethanol at room temperature, charged with DABCO (22 μl, 0.3 mmol) and then stirred at 80° C. under LC-MS control for 3 days. The reaction mixture was cooled down to room temperature, diluted with water to about 100 ml and then extracted with ethyl acetate (2×50 ml). The organic solution was washed with 5% sodium bicarbonate solution (2×50 ml) and then dried over magnesium sulfate, solvent was evaporated under vacuum at 40° C. and the residue was dried under high vacuum giving 217 mg of the title compound (0.48 mmol, 20%).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][C:5](=[O:8])[NH:4][CH2:3][CH2:2]1.[C:9]([O:13][C:14](=O)[O:15]C(C)(C)C)([CH3:12])([CH3:11])[CH3:10].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>ClCCl.O>[O:8]=[C:5]1[CH2:6][CH2:7][O:1][CH2:2][CH2:3][N:4]1[C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C1CCOCCN1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 465 %

Procedure:
To a solution of 1,4-oxazepan-5-one (6.9 g, 60.0 mmol) in dichloromethane (120.0 mL) were added di-tert-butylcarbonate (1.75 g, 8.00 mmol) and dimethylaminopyridine (7.90 g, 65.0 mmol), and triethylamine (12.5 mL, 90.0 mmol) was added dropwise. After stirring for 16 hours at room temperature, to the mixture was added water, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated aqueous solution of ammonium chloride and brine, and then dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified with silica gel column (hexane/ethyl acetate=90/10 to 0/100) to give the title compound (7.30 g, 37.2 mmol, 62%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26].C(O)(=O)C.N1CCCCC1>C(O)(C)C>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:28])[C:24](=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:25](=[O:27])[CH3:26]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)CCCCCCCCCCBr
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)CCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 108 h
Yield: 77 %

Procedure:
4.7 g of 3-nitrobenzaldehyde and 9.5 g of 14-bromotetradecane-2-4-dione are dissolved in 100 ml isopropanol, 0.18 ml of acetic acid and 0.15 ml of piperidine are added and the mixture is stirred at RT for 4.5 days. It is cooled in an ice bath, and the crystallized product is filtered off with suction, washed with ice-cold isopropanol and dried. 10.5 g of the compound of m.p. 64-67° C. are obtained.