Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[CH2:11][CH2:10][CH2:9]1)=[O:7].[C:20]([C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[C:26]([C:36]([F:39])([F:38])[F:37])[N:25]=1)([CH3:23])([CH3:22])[CH3:21].[Na+].[Br-].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[C:20]([C:24]1[N:29]=[C:28]([N:30]2[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[C:12](=[O:19])[CH2:11][CH2:10][CH2:9]3)=[O:7])[CH2:34][CH2:35]2)[CH:27]=[C:26]([C:36]([F:37])([F:38])[F:39])[N:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C(F)(F)F)n1
Reactant: O=C1CCCN(C(=O)CCCCCl)c2ccccc21
Agent: [Br-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1nc(N2CCN(CCCCC(=O)N3CCCC(=O)c4ccccc43)CC2)cc(C(F)(F)F)n1
Yield: 40.8 %

Procedure:
1-(5-Chloropentanoyl)-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one from Example 12a (1.43 mmol, 0.50 g), 2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (1.43 mmol, 0.41 g, preparation according to DE 19735410), NaBr (7.14 mmol, 0.74 g), DIPEA (diisopropylethylamine) (14.01 mmol, 1.81 g) and N-methylpyrrolidinone (0.6 ml) were heated to 120° C. for 5 h. Subsequently, the reaction mixture was filtered and the resulting filtrate was concentrated to dryness. Afterward, ethyl acetate was added to the resulting residue and it was washed with saturated, aqueous sodium chloride solution. The organic phase was dried and then concentrated to dryness. The residue was purified by chromatography on silica gel, eluent: methyl tert-butyl ether/methanol (0-100%); to obtain 0.31 g of the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(N(CC)CC)C.[F:16][C:17]([F:34])([F:33])[C:18]1[CH:22]=[C:21]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[O:20][N:19]=1>C(Cl)(Cl)Cl>[Br:1][C:22]1[C:18]([C:17]([F:16])([F:33])[F:34])=[N:19][O:20][C:21]=1[NH:23][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Nc1cc(C(F)(F)F)no1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1onc(C(F)(F)F)c1Br)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
N-Bromosuccinimide (64 mg, 0.35 mmol) and triethylamine (0.072 ml, 0.51 mmol) were added to a solution of N-(3-trifluoromethyl-5isoxazolyl)benzenesulfonamide(100 mg, 0.34 mmol)in chloroform (20 ml) at room temperature. The reaction was stirred at room temperature for 2 h. Chloroform (30 ml) was added and the solution was washed with 1N hydrochloric acid (40 ml), dried over magnesium sulfate and concentrated. The crude product was purified by HPLC to afford 114 mg (90%) N-(4-bromo-3-trifiuoromethyl-5-isoxazolyl)benzenesulfonamide as an off-white solid, m.p. 104°-105° C.
Reaction SMILES: [C:1]([C:5]([C:8]([O:11][C:12]([C:15]([C:18]([O:21]C(C(OC(C(C(F)(F)F)(F)F)(F)F)(C(F)(F)F)F)=O)(F)[F:19])([F:17])[F:16])([F:14])[F:13])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[F-].[Na+]>>[C:1]([C:5]([C:8]([O:11][C:12]([C:15]([C:18]([F:19])=[O:21])([F:17])[F:16])([F:14])[F:13])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: O=C(OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [F-]
Agent: [Na+]
Product: O=C(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)F
Temperature: 120 °C
Yield: 57 %

Procedure:
CF3CF2CF2OCF2CF2CF2OCOCF(CF3)OCF2CF2CF3 (0.8 g) obtained in Example 42 was charged into a flask together with a NaF powder (0.01 g) and heated at 120° C. for 10 hours in an oil bath with vigorous stirring. At an upper portion of the flask, a reflux condenser adjusted to a temperature of 20° C. was installed. After cooling, a liquid sample (0.7 g) was recovered. By GC-MS, it was confirmed that CF3CF(OCF2CF2CF3)COF and the above-identified compound were the main products. The yield was 57.0%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH2:20]([NH:24][C:25]([C:27]1[C:31]2[CH:32]=[CH:33][C:34]([OH:36])=[CH:35][C:30]=2[O:29][C:28]=1[CH3:37])=[O:26])[CH:21]([CH3:23])[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:20]([NH:24][C:25]([C:27]1[C:31]2[CH:32]=[CH:33][C:34]([O:36][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:35][C:30]=2[O:29][C:28]=1[CH3:37])=[O:26])[CH:21]([CH3:23])[CH3:22]
Reactant: Cc1oc2cc(O)ccc2c1C(=O)NCC(C)C
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCC(C)C)c(C)oc5c4)c3s2)C1

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4b with 6-hydroxy-2-methyl-benzofuran-3-carboxylic acid isobutyl amide 83b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (CD3CN) δ8.53 (1H, d, J=5.5 Hz), 7.88 (1H, d, J=3.0 Hz), 7.82 (1H, d, J=8.5 Hz), 7.41 (1H, d, J=2.3 Hz), 7.20 (1H, dd, J=8.5, 2.3 Hz), 6.70 (2H, d, J=5.5 Hz), 4.10-3.83 (3H, m), 3.73-3.58 (2H, m), 3.33, 3.29 (3H, 2s), 3.23 (2H, t, J=6.8 Hz), 2.65 (3H, s), 2.10-1.95 (2H, m), 0.98 (6H, d, J=6.6 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=O)([O-])=O.[CH3:13][NH:14][CH3:15].Cl[Sn]Cl.C1COCC1>CCOC(C)=O>[CH3:13][N:14]([CH2:7][C:6]1[CH:5]=[C:4]([CH:12]=[CH:11][CH:10]=1)[NH2:1])[CH3:15]
Reactant: CNC
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(N)c1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with 3-[(dimethylamino)methyl]aniline to generate the title compound. The 3-[(dimethylamino)methyl]aniline was prepared by treatment of commercial 3-nitrobenzoyl chloride with dimethylamine followed by sequential reduction with SnCl2 in EtOAc at 20° C. for 18 hours and then BH3 /THF.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.ClCl.[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21])=[N+:14]=[N-:15]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])=[O:21])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=NCCCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: ClCl
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)CCCCN=[N+]=[N-])C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (4.45 g, 30.9 mmol) and 4-dimethylaminopyridine (7.55 g, 61.8 mmol) in 100 ml of CH2 Cl2 was added the solution of crude 5-azidovaleric chloride in 10 ml of CH2Cl2 at 0° C. The mixture was stirred at 0° C. for 1 hr and at room temperature for 1 hr. The solution was washed with 1N aqueous HCl (100 ml), brine (250 ml) and dried over Na2SO4. After evaporation of solvent, 5-(5-azidopentanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was obtained as a light pink oil (8.17 g, 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:20])[CH:14]=2)[NH:9]1.[NH2:21][C:22]1([C:25]([OH:27])=[O:26])[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[Cl:20][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:21][C:22]([CH3:24])([CH3:23])[C:25]([OH:27])=[O:26])[CH2:17][C:16]2([CH3:19])[CH3:18]
Reactant: CC1(C)CC(c2ccccc2Br)Nc2ccc(Cl)cc21
Reactant: NC1(C(=O)O)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1ccccc1C1CC(C)(C)c2cc(Cl)ccc2N1)C(=O)O
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A solution of 2-(2-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (200 mg, 0.57 mmol), copper(I) iodide (33 mg, 0.17 mmol), 1-amino-cyclopropanecarboxylic acid (235 mg, 2.29 mmol) and potassium carbonate (240 mg, 1.7 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (127 mg, 60.0%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 371.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:13])#[N:2].Br[CH2:15][C:16](=[O:32])[CH2:17][C@H:18]1[C@H:23]([O:24][CH3:25])[CH2:22][CH2:21][CH2:20][N:19]1[C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27]>>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]([CH2:15][C:16](=[O:32])[CH2:17][C@H:18]1[C@H:23]([O:24][CH3:25])[CH2:22][CH2:21][CH2:20][N:19]1[C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[C:6]2=[O:13])#[N:2]
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: N#Cc1ccc2nc[nH]c(=O)c2c1
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2ccc(C#N)cc2c1=O
Yield: 49 %

Procedure:
By the method of Example 4, 6-cyanoquinazolin-4(3H)-one and allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxypiperidine-1-carboxylate were converted to title compound in 49% yield; 1H-NMR(CDCl3) 1.2-1.9 (m, 4H), 2.9 (d, 2H), 2.9-3.5 (m, 4H), 4.6-6.2 (m, 5H), 5.2 (s, 2H), 7.8-8.6 (m, 4H).
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[C:3]#[N:4].C1C[O:12]CC1.S(=O)(=O)(O)O.N>C(Cl)Cl>[NH2:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[C:3]([NH2:4])=[O:12]
Reactant: CC(C)C(C)(N)C#N
Reactant: C1CCOC1
Agent: N
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)C(C)(N)C(N)=O
Temperature: 0 °C

Procedure:
A solution of 3.0 g of (-)-2-amino-2,3-dimethylbutyronitrile, [α]D =-6.71° (c=0.03307 g/ml THF) in 10 ml methylene chloride is added with stirring at 80° C. to 13.95 g of concentrated sulfuric acid. The solution is heated for one hour, allowed to cool and 14 g of ice is added. Next, 27 ml of concentrated ammonia is added while cooling. The resulting solution is extracted with methylene chloride (5×25 ml). The combined extracts are dried and evaporated to dryness to afford 3.23 g of title product, mp 81°-83° C., [α]D =+53.04° (c =0.0313 g/ml THF).
Reaction SMILES: C1(C)C=CC(S([C:10]([CH3:23])([CH3:22])[CH:11]([CH:17]([O:20]C)[O:18]C)[CH2:12][C:13]([O:15]C)=O)(=O)=O)=CC=1.CCOCC.[Cl-:30].[Li+].Cl>O>[Cl:30][C:10]([C@H:11]1[C@H:17]([OH:18])[O:20][C:13](=[O:15])[CH2:12]1)([CH3:22])[CH3:23]
Reactant: COC(=O)CC(C(OC)OC)C(C)(C)S(=O)(=O)c1ccc(C)cc1
Reactant: [Cl-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(Cl)[C@@H]1CC(=O)O[C@H]1O
Temperature: 25 °C
Reaction time: 54 h
Yield: 109.4 %

Procedure:
A mixture of 1 g of the product of Example 2, 25 ml of ether and 1 g of dry lithium chloride was stirred under a current of gaseous hydrogen chloride at -30° C. for 2 hours and then at 0° C. for 2 hours after which the current of gaseous hydrogen chloride was stopped. The mixture was stirred at room temperature for 48 hours and after 54 hours of contact, the mixture was poured into iced water. The mixture was extracted with benzene and the organic phase was dried and evaporated to dryness under reduced pressure. The 1.1 g of residue was chromatographed over silica gel and was eluted with a 1-1 benzene-ethyl acetate mixture to obtain 545 mg of dl trans 4-(2-chloro-prop-2-yl)-5-hydroxy-tetrahydrofuran-2-one in the form of crystals melting at 80° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[N:15]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:16]([CH3:23])=[C:17]([S:19](=[O:22])(=[O:21])[NH2:20])[CH:18]=2)[CH:13]=1)[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:64][CH:65]([CH3:68])[CH2:66][NH2:67]>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[N:15]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:16]([CH3:23])=[C:17]([S:19](=[O:22])(=[O:21])[NH2:20])[CH:18]=2)[CH:13]=1)[C:8]([NH:67][CH2:66][CH:65]([CH3:68])[CH3:64])=[O:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(=O)O)cc(C(C)(C)C)c2)n1CC1CCCCC1
Reactant: CC(C)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(C(=O)NCC(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
A mixture of compound 13b (90 mg, 0.21 mmol), DIPEA (134 mg, 1.04 mmol) and HATU (157 mg, 0.41 mmol) in DMF was stirred at rt for 1 h, then 2-methylpropan-1-amine (18 mg, 0.25 mmol) was added. The mixture was stirred at rt overnight and concentrated. The product was isolated by CC to get compound 13 (45 mg, 45%). 1H-NMR (400 MHz, DMSO-d6) δ: 8.57 (m, 1H), 7.85 (s, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 6.94 (s, 2H), 6.39 (s, 1H), 3.82 (d, J=5.6 Hz, 2H), 3.09 (s, 2H), 2.45 (s, 3H), 1.85-1.84 (m, 1H), 1.46 (s, 3H), 1.33-1.25 (m, 12H), 0.94-0.88 (m, 9H), 0.66-0.63 (m, 2H). MS Found: 488 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[CH2:8][NH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS([Cl:45])(=O)=O>CN(C=O)C>[Cl:45][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[N:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C2=CC=C(CO)CN2)C(OCc2ccc3ccccc3c2)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCl)cn2)C(OCc2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
A solution of 70 mg (0.156 mmol) of tert-butyl (3'RS,4'RS)-5-hydroxymethyl-3'-(naphthalen-2-ylmethoxy)-3',4',5',6-tetrahydro-2'H-[2,4']bipyridine-1'-carboxylate in 2 ml of absolute DMF was cooled to -10° C. and treated with 26 μl (19 mg, 0.187 mmol) of triethylamine. 13 μl (20 mg, 0.172 mmol) of methanesulphonyl chloride and 2 mg of N,N-dimethylaminopyridine (DMAP) were added at -10 to -15° C. and subsequently the mixture was stirred at 0° C. for 1 hour. For the working-up, the mixture was partitioned between 25 ml of ethyl acetate and 25 ml of aqueous 5% ammonium chloride solution and the organic phase was separated. The aqueous phase was extracted three times with 10 ml of ethyl acetate each time. The combined ethyl acetate phases were dried over magnesium sulphate and finally evaporated under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:1 mixture of ethyl acetate and hexane as the eluent. There were obtained 22 mg (35% of theory) of tert-butyl (3'RS,4'RS)-5-chloromethyl-3'-(naphthalen-2-ylmethoxy)-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridine-1'-carboxylate as a light yellow oil; MS: 467, 469 (M+H)+.
Reaction SMILES: CCN(CC)CC.Cl.[CH3:9][O:10][C:11](=[O:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:27](=[O:28])[NH:26][C:21]1[CH:22]=[C:23]([Cl:25])[CH:24]=[C:19]([Cl:18])[CH:20]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
Et3N (1.7 mL) was added to an ice-cold solution of (S)-proline methyl ester hydrochloride (1.31 g) and 3,5-dichlorophenylisocyanate (1.97 g) in CH2Cl2 (40 mL). The mixture was stirred for 3 hours. It was washed with water, brine, dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/3) afforded (S)—N—[N-(3,5-dichlorophenyl)carbamoyl]proline methyl ester (2.27 g). mp. 110-112° C.; MS (m/z) 339 (M++Na). (2) A solution of the compound obtained above (14.3 g) in toluene (100 mL) containing p-toluenesulfonic acid (0.5 g) was refluxed for 2 hours. The solution was diluted with EtOAc and was washed with satd. NaHCO3, water, brine, dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: CHCL3/MeOH: 10/1) and recrystallization from EtOH afforded 8.87 g of (S)-3-(3,5-dichlorophenyl)-1,3-diazabicyclo[3.3.0]octane-2,4-dione. mp. 169° C.; MS (m/z) 307 (M++Na). (3) A solution of n-BuLi (2.2 mL) in hexane (1.6 N) was added to a solution of diisopropylamine (0.381 g) in THF (5 mL) at −78° C. After 15 minutes, a solution of the compound obtained above (0.894 g) in THF (8 mL) was added to the mixture. HMPA (8 mL) and additional THF (8 mL) were added to the mixture. After 35 minutes, a solution of 4-(bromomethyl)benzonitrile (0.697 g) in THF (8 mL) was added and the mixture stirred for 30 minutes at that temperature. The mixture was slowly warmed to room temperature, stirred for 30 minutes and finally quenched with 0.5 N HCl (10 mL). The mixture was diluted with water and extracted with EtOAc. The extract was washed with water, brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/2, Chromatotron) afforded the titled compound (0.833 g). MS (m/z) 422 (M++Na).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1F.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(F)c(N2CCOCC2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 117 %

Procedure:
A mixture of 1,2,4-trifluoro-5-nitrobenzene (4.0 mL, 35 mmol), morpholine (3.1 mL, 35 mmol), and K2CO3 (4.8 g, 35 mmol) in DMSO (35 mL) was stirred at room temperature overnight. The mixture was diluted with AcOEt and washed with water and brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (10 g, 63% yield) as a pale yellow solid: NMR (300 MHz, DMSO-d6): δ ppm 3.15-3.49 (4H, m), 3.50-3.90 (4H, m), 7.13 (1H, dd, J=14.3, 7.5 Hz), 8.01 (1H, dd, J=13.6, 7.5 Hz). LC-MS (ESI) m/z 245 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[CH2:10][C:9]1=[O:15])[C:4]([O:6][CH3:7])=[O:5].[CH3:17][C:18]([CH3:20])=[O:19].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]([CH3:16])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[C@@H:10]([C:18]([OH:19])([CH3:20])[CH3:17])[C:9]1=[O:15])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)=O
Reactant: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@@H]1[C@@H](C(C)(C)O)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
1.55M Butyl lithium-hexane solution (2.82 ml) was added to a solution of N-isopropylcyclohexylamino (0.72 ml) in tetrahydrofuran (6 ml) at -70° C., and the mixture was stirred for 20 minutes at -70° C. This mixture was added to a solution of methyl 3-methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (247 mg) in tetrahydrofuran (6 ml) at -70° C. and the mixture was stirred for 1 hour at -70° C., and for 30 minutes at -30° C. Acetone (0.12 ml) was added to the reaction mixture at -70° C., and the mixture was stirred for 1 hour at -70° C. and for 30 minutes at -30° C.--15° C. 3N Hydrochloric acid was added to the reaction mixture at -70° C. and the mixture was diluted with ethyl acetate (200 ml). The solution was washed with water, brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. Triethylamine (0.15 ml) was added to a solution of the residue in dichloromethane (3 ml) at 0° C. and the mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate (20 ml) and the solution was washed with 0.1N hydrochloric acid (15 ml) brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) eluting with a mixture of benzene and acetone (10:1-2:1) to give methyl 3-methyl-2-[(3S,4R)-3-(1hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (100 mg);
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.O[CH:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: CN1CCC(O)CC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OC1CCN(C)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
Diethyl azodicarboxylate (218 mg, 1.25 mmol) was added dropwise to a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (159 mg, 0.5 mmol), (prepared as described for the starting material in Example 2), 4-hydroxy-1-methylpiperidine (115 mg, 1 mmol) and triphenylphosphine (328 mg, 1.25mmol) in methylene chloride (5 ml) cooled at 5° C. under nitrogen. The mixture was stirred for 1 hour at ambient temperature, the solvent was removed by evaporation and the residue was partitioned between 2M hydrochloric acid and ether. The aqueous layer was separated, adjusted to pH9 with aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The methylene chloride layer was washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified on neutral alumina eluting with methylene chloride/methanol (97/3). The purified product was triturated with ether, collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidine-4-yloxy)quinazoline (180 mg, 79%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16].[O:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:23]=2[O:22][CH2:21][CH2:20]1>>[O:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([N:29]3[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]4([CH2:17][CH3:18])[C:14]5[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=5)[NH:8][C:7]4=[O:16])[CH2:31][CH2:30]3)[C:23]=2[O:22][CH2:21][CH2:20]1
Reactant: CCC1(CCCCCl)C(=O)Nc2cc(F)ccc21
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Product: CCC1(CCCCN2CCN(c3cccc4c3OCCO4)CC2)C(=O)Nc2cc(F)ccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine.