Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[CH3:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.CN1CCCC1=O>O>[CH3:12][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][C:6](=[O:13])[NH:7]2)=[C:2]([N:18]2[CH:19]=[C:15]([CH3:14])[N:16]=[CH:17]2)[N:11]=1
Reactant: Cc1c[nH]cn1
Reactant: Cc1cc2[nH]c(=O)ccc2c(Br)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cn(-c2nc(C)cc3[nH]c(=O)ccc23)cn1
Temperature: 140 °C
Reaction time: 20 h
Yield: 62.5 %

Procedure:
A mixture containing 9.56 g of 5-bromo-7-methyl-1,6-naphthyridin-2(1H)-one, 8.2 g of 4-methyl-1H-imidazole and 22 ml of N-methylpyrrolidin-one was heated with stirring in an oil bath at 140° C. for 20 hours. The reaction mixture containing some separated solid was diluted with about 150 ml of water and the solid was collected, triturated with water, washed with ethanol and dried to give 6.0 g of 7-methyl-5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 307°-308° C.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:18])=[O:27])[N:12]=3)=[CH:9][N:8]=[CH:7][N:6]=2)[CH2:2][CH2:3]1
Reactant: CSc1nccc(-c2cncnc2CC2CC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2cncnc2CC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4′-(cyclopropylmethyl)-2-(methylsulfanyl)-4,5′-bipyrimidine (4a) (62.5 mg, 0.242 mmol) in DCM (968 μl), mCPBA (65.1 mg, 0.290 mmol) was added and the reaction mixture was stirred at rt for 1 hour. The crude reaction mixture was partitioned between saturated sodium bicarbonate solution and DCM. The aqueous layer was separated and back-extracted twice with DCM. The combined organic extracts were washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was carried on to the next step without further purification. MS (ES+): m/z=275.2 (100) [MH+]. HPLC: tR=0.72 minute over 3 minutes. Purity: 100% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][C:22](O)=[O:23].B.O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][OH:23]
Reactant: CSc1ccc(/C=C2/C(C)=C(CC(=O)O)c3cc(F)ccc32)cc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(/C=C2/C(C)=C(CCO)c3cc(F)ccc32)cc1
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a solution of (Z)-5-fluoro-2-methyl-1-(4-methylthiobenzylidene)inden-3-ylacetic acid (1.70 g, 5 mmol) in THF (25 mL) at 0° C. and under nitrogen atmosphere, there was added a solution of borane (1M) in THF (5.5 mL, 5.5 mmol) and the mixture stirred in the cold for 30 minutes, then at room temperature for 2 hours. More borane was added (2.5 mL) and stirring was continued for 1 hour. Water was added slowly (20 mL), the THF was evaporated and the residue partitioned between water and ethyl acetate. The crude product from the organic phase was purified by chromatography on silica gel using a 1:2 mixture of ethyl acetate-hexane as eluent to afford the desired product (1.25 g) as a yellow oil which solidified on standing. This was triturated with hexane and filtered to yield the title compound as a yellow solid, mp 101-103° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:18])([CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9].[C:19](Cl)(=[O:21])[CH3:20]>>[C:19]([O:1][CH2:2][C:3]([CH3:18])([CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9])(=[O:21])[CH3:20]
Reactant: CC(C)(CO)COc1cccc([N+](=O)[O-])c1C#N
Reactant: CC(=O)Cl
Product: CC(=O)OCC(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 66 %

Procedure:
Prepared as in Example 231c from 2-(3-hydroxy-2,2-dimethylpropoxy)-6-nitrobenzonitrile (Example 233d) and acetyl chloride in 66% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.04 (s, 6H), 2.00 (s, 3H), 3.95 (s, 2H), 4.02 (s, 2H), 7.70-7.72 (m, 1H), 7.85-7.92 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[Br:9]Br.C(OCC)(=O)C>C(Cl)(Cl)Cl>[Br:9][C:5]1[S:4][C:3]([CH:7]=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1ccsc1C=O
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)sc1C=O
Temperature: 0 °C

Procedure:
26 g of 3-methyl-2-thiophenecarboxaldehyde was dissolved in 100 ml of chloroform and the solution was stirred by cooling with ice 11 ml of bromine was added dropwise thereto. The temperature was elevated to room temperature and the mixture was stirred overnight. About 1 l of ethyl acetate was added thereto and the mixture was washed with water, then with a saturated aqueous sodium hydrogencarbonate solution and finally with a saturated aqueous common salt solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 46.8 g of 5-bromo-3-methyl-2-thiophenecarboxaldehyde in the form of a dark brown solid, which was subjected to the subsequent reaction without purification.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[CH2:16])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)C)C=CC=CC=1.C(Cl)(=[O:33])C>>[C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:33])[CH3:16])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: C=Cc1ccccc1C(C)c1ccccc1
Agent: CC(c1ccccc1)c1ccccc1
Product: CC(=O)c1ccccc1C(C)c1ccccc1

Procedure:
These compounds can be prepared through various chemical synthesis methods. For example, phenyl(vinylphenyl)ethane is prepared by reacting diphenylethane with acetyl chloride in the presence of Friedel-Crafts catalyst to obtain phenyl(acetylphenyl)ethane, then it is reduced with sodium borohydride and dehydrated. Phenyl(isopropenylphenyl)ethane is prepared by reacting phenyl(formylpheny)ethane with a Grignard reagent such as methylmagnesium iodide, which is followed by dehydration.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>O1CCCC1>[C:21]([O:20][C:18](=[O:19])[CH2:17][O:3][C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (704 mg, 60% in mineral oil, 17.6 mmol) was added to an ice-cooled solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (J. Med. Chem. 1998, 41(25), 4983) (5 g, 26.7 mmol) in tetrahydrofuran (100 ml), and the mixture was allowed to warm to room temperature and stirred for 20 minutes. tert-Butyl bromoacetate (5.2 g, 26.7 mmol) was added and the mixture was heated under reflux for 18 hours, then cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the phases separated. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 20:80) to afford the title compound, 1.95 g. 1H-NMR (CDCl3, 400 MHz) δ: 1.42 (s, 9H), 1.44 (s, 9H), 1.85-2.05 (m, 2H), 3.40 (m, 4H), 3.94 (m, 2H), 4.10 (m, 1H). LRMS: m/z (ES+) 324 [MNa+]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18]
Reactant: C=Cc1cc(C(=O)OC)c(NC(=O)OC(C)C)cc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C(=O)OC)c(NC(=O)OC(C)C)cc1C(F)(F)F
Reaction time: 2 h
Yield: 95.9 %

Procedure:
Add 10% palladium on carbon (4.06 g, 12.22 mmol) to a solution of 2-isopropoxycarbonylamino-4-trifluoromethyl-5-vinyl-benzoic acid methyl ester (40.48 g, 122.19 mmol) in methanol (350 mL) in a Parr bottle. Subject the mixture to a hydrogen atmosphere at a pressure of 30 psi at room temperature with shaking on a Parr shaker apparatus for 2 h. Filter the mixture through Celite and remove the solvent under reduced pressure to provide the title compound as a white solid (39.07 g, 96%): TLC Rf 0.62 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 1.13-1.42 (m, 9H), 2.71-2.80 (m, 2H), 3.89 (s, 3H), 5.21-5.27 (m, 1H), 7.98 (s, 1H), 8.81 (s, 1H), 10.23 (bs, 1H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[C:18]1(CCN)[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1.C(OCC)(=O)C>CN(C)C=O>[C:18]1([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: NCCC1=CCCCC1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCC1=CCCCC1)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(1-cyclohexenyl)ethylamine (0.64 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.82 g (55%) of the titled product as yellow needles:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:12]N1C(=O)CCC1=O.O>O1CCCC1>[Br:12][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc[nH]c1C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)[nH]c1C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (1.53 g) in tetrahydrofuran (20 mL) was added N-bromosuccinimide (1.78 g) at −78° C., and the mixture was stirred at the same temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure at not more than 5° C. The residue washed with hexane to give the title compound as a colorless solid (yield 2.26 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)([OH:48])[CH2:9][NH:10][C:11]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][C@@H:22]([NH:25]C(OC(C)(C)C)=O)[CH2:21]3)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:33]2[CH2:37][C@H:36]([NH:38][C:39]([CH2:41][O:42]C(=O)C)=[O:40])[C@@H:35]([OH:46])[C@H:34]2[OH:47])=[CH:4][CH:3]=1.Cl>CO.O1CCOCC1>[NH2:25][C@@H:22]1[CH2:23][CH2:24][N:20]([C:18]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][N:15]3[C@@H:33]3[CH2:37][C@H:36]([NH:38][C:39](=[O:40])[CH2:41][OH:42])[C@@H:35]([OH:46])[C@H:34]3[OH:47])=[C:11]([NH:10][CH2:9][C:8]([C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=3)([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[OH:48])[N:19]=2)[CH2:21]1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H]1CCN(c2nc(NCC(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of acetic acid {(1S,2R,3S,4R)-4-[6-[2,2-bis-(4-chloro-phenyl)-2-hydroxy-ethylamino]-2-((R)-3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate Z01) in MeOH (˜0.5M) is treated with an equal volume of 4M HCl in dioxane and stirred at room temperature for 2 hours. The solvent is removed in vacuo and purification is carried out by column chromatography/crystallisation to afford the title compound.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([NH2:21])=[O:20])[CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([NH2:21])=[O:20])[CH2:14]1
Reactant: BrCC1COc2ccccc2O1
Reactant: NC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)C1CCCN(CC2COc3ccccc3O2)C1

Procedure:
To a mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (0.2 g, 0.87 mmol) and piperidine-3-carboxylic acid amide (0.13 g, 1.05 mmol) in acetonitrile (20 ml) was added K2CO3 (0.60 g, 4.36 mmol) and KI (0.72 g, 4.36 mmol). The reaction mixture was refluxed for 2 h. Water (100 ml) was then added. The reaction mixture was extracted with EtOAc (3×5 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (EtOAc/heptane, 50:50).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[NH4+].N(N(C1C=CC=CC=1)O)=O>N1C=CC=CC=1>[C:1]([O:6][CH2:7][CH:8]([OH:10])[CH2:9][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: O=Cc1ccc(O)cc1
Agent: O=NN(O)c1ccccc1
Agent: [NH4+]
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCC(O)COc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a reaction vessel were placed 56 g of glycidyl methacrylate, 48 g of p-hydroxybenzaldehyde, 2 g of pyridine and 1 g of N-nitroso-phenylhydroxylamine ammonium salt and reacted with stirring in a water bath at 80° C. for 8 hrs to obtain p-(3-methacryloxy-2-hydroxypropyloxy)benzaldehyde.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl
Reactant: c1c[nH]cn1
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,5-dichloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH2:8]([CH:10]1[C:16]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][NH:12][C:11]1=[O:23])[CH3:9].I[CH2:25][CH3:26]>O>[CH2:8]([CH:10]1[C:16]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][N:12]([CH2:25][CH3:26])[C:11]1=[O:23])[CH3:9]
Reactant: CCI
Reactant: CCC1C(=O)NCCc2ccc(OC)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1C(=O)N(CC)CCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Charge NaH (60% dispersion in mineral oil) to 100 ml RBF and wash with hexanes. Charge 10 ml anhydrous DMF and 1-Ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (0.500 g, 2.28 mmol). Stir 10 minutes at room temperature and then charge iodoethane (900 uL, 10 mmol) dropwise with syringe. Allow to stir overnight. Pour reaction into 75 ml water and extract with 3×30 ml EtOAc. Dry combined organic over MgSO4, filter and evaporated to yield 1,3-Diethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one. The crude product was used in the next step.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[C:14]([C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30]([CH:32]3[CH2:33][CH2:34]3)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15]
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: CC(=O)c1cccc(OCCCCCCl)c1
Product: CC(=O)c1cccc(OCCCCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{3-[(5-chloropentyl)oxy]phenyl}ethanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 449.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[H-].[Na+].[Cl:13][CH:14]1[N:19](Cl)[CH:18]=[CH:17][CH:16]=[N:15]1>CN(C=O)C>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C:2]2[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CC(C)(C)c1cc(N)no1
Reactant: ClC1N=CC=CN1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Nc2ccnc(Cl)n2)no1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 3-amino-5-t-butylisoxazole (922 mg 6.58 mmol) in 15 mL of DMF at 0° C. was added 268 mg (6.71 mmol) of NaH (60% dispersion in mineral oil) in 4 portions over 1 min. The resulting mixture was stirred at 0° C. for 30 min when 1.0 g (6.71 mmol) of 2,3-dichloropyrimidine was added in 1 portion. The resulting mixture was warmed to RT (ice melt in dewar) and was stirred at RT for 22 h. The reaction mixture was quenched with saturated aqueous NH4Cl and diluted with H2O and EtOAc. The organic layer was washed 1× with brine. The combined aqueous layer and brine wash were extracted 1× with EtOAc. The combined organics were dried over Na2SO4, concentrated and purified by flash chromatography (elution with 2/1 hexanes/EtOAc) to give (2-chloro-pyrimidin-4-yl)-(5-tert-butyl-isoxazol-3-yl)-amine as a yellowish white solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C(#N)C.Br[CH2:21][CH2:22][CH2:23][CH3:24]>O>[CH2:21]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH2:22][CH2:23][CH3:24]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCN1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 556.3 %

Procedure:
To a mixture of 15 g (0.015 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 15.93 g (0.115 mol) of K2CO3, and 100 ml of acetonitrile is added drowpwise 11.25 ml (0.105 mol) of 1-bromobutane. The mixture is stirred overnight at room temperature and then at 65° C. for 2 hours. After cooling, the mixture is diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to yield 16.63 g (80%) of the title compound as a yellow liquid: IR (neat) 2959 and 1092 cm-1 ; NMR (CDCl3)δ3.97 (s, 4H), 2.56 (s, 4H), 2.38 (m, 2H), 1.77 (t, 4H), 1.49 (m, 2H), 1.34 (m, 2H), 0.92 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[Cl:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.C(=O)(O)[O-].[Na+]>O>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 10 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g), m-chlorophenol (26 g), sodium bicarbonate (34 g), and water (200 ml) was stirred at 85° C for 10 hours. After cooling, excess m-chlorophenol was removed by extraction with diethyl ether, and 4-(m-chlorophenoxy)-3-nitro-5-sulphamyl-benzoic acid was precipitated from the aqueous layer by the addition of 4N hydrochloric acid. After recrystallization from aqueous methanol, the melting point was 230°-232° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[CH2:18][CH2:19]2)=[CH:11][CH:10]=1)(=[O:7])=[O:8])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[N:30]=[CH:31][CH:32]=[N:33]2)=[CH:27][CH:28]=1
Reactant: ClCc1ccc(-n2nccn2)cc1
Reactant: COC(=O)CNS(=O)(=O)c1ccc(OCC2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN(Cc1ccc(-n2nccn2)cc1)S(=O)(=O)c1ccc(OCC2CC2)cc1
Reaction time: 18 h

Procedure:
To a solution of 1 g (3.3 mmol) of the compound of Stage 3.7 in 10 ml of DMF, 0.8086 g (4.175 mmol) of 2-(4chloromethyl-phenyl)-2H-[1,2,3]triazole, 0.05559 (0.33 mmol) of KI and 0.646 g (4.68 mmol) of K2CO3 are added successively at r.t. After stirring for 18 h, the reaction is quenched with ice water and the mixture is extracted with AcOEt. The combined extracts are washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure to give a solid which is washed with diethylether and MeOH to give the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:20](C1C=C2C(=CC=1)NC=C2)#[N:21]>>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Reactant: N#Cc1ccc2[nH]ccc2c1
Product: N#Cc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Yield: 50 %

Procedure:
This compound was prepared in the manner described above for intermediate 1a by replacing indole with 5-cyanoindole (29.98 g, 0.21 mol) to afford 29.32 g (50%) of the title compound as a white solid: mp 158-160° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:18]([OH:22])[C:19](O)=[O:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([O:33][NH2:34])([CH3:32])[CH3:31]>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH:18]([OH:22])[C:19]([NH:34][O:33][CH:30]([CH3:32])[CH3:31])=[O:20])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Reactant: CC(C)ON
Product: CC(C)ONC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1

Procedure:
The reaction can be carried out in analogy to reaction step 20.3 by reacting 3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoic acid with O-isopropylhydroxylamine.