Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]1[CH2:17][O:16][C:8]([CH3:15])([CH2:9][CH2:10][CH2:11][C:12](=O)[CH3:13])[O:7]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:6]1[CH2:17][O:16][C:8]([CH3:15])([CH2:9][CH2:10][CH2:11][C:12]([CH3:1])=[CH2:13])[O:7]1
Reactant: [Li]CCCC
Reactant: CC(=O)CCCC1(C)OCCO1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C)CCCC1(C)OCCO1
Reaction time: 1 h
Yield: 38 %

Procedure:
To a slurry of methyl triphenylphosphonium bromide (218 g) in anhydrous tetrahydrofuran (1.8 l) cooled to 0° C. is added 1.6 M n-butyllithium (270 ml) and2.6 M n-butyl lithium (37.5 ml). After stirring for 1 hour, 6,6-ethylenedioxy-heptane-2-one (91.3 g) in anhydrous tetrahydrofuran (200 ml) is added dropwise and the mixture stirred for 1.5 hours at room temperature. The reaction mixtures is then filtered and the filter cake washed with ether. The solent is removed via distillation at atmospheric pressure. The crude residue is purified via vacuum distillation to give 6,6-ethylenedioxy-2-methyl-hept-1-ene (33.95 g, 38%) bp 75°@15 mm; nmr (CDCl3,δ), 1.32 (s, 3H, ##STR53## 1.7 (s, 3H, CH3 --C=), 3.92 (s, 4H, OCH2CH2O), 4.67 (bs, 2H, ##STR54##
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@H:19]2[C@H:11]([C:12](=O)[C:13]3[C:18]2=[CH:17][C:16]([Br:21])=[CH:15][C:14]=3[CH3:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)CO>[CH2:1]([N:8]1[CH2:20][C:19]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[C:16]([Br:21])[CH:17]=3)[CH2:12][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)cc2c1C(=O)[C@@H]1CCN(Cc3ccccc3)C[C@H]21
Agent: NN
Solvent: OCCO
Solvent: O
Product: Cc1cc(Br)cc2c1CC1=C2CN(Cc2ccccc2)CC1
Temperature: 180 °C
Yield: 6.7 %

Procedure:
To a solution of cis-3-benzyl-6-bromo-8-methyl-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one (680 mg, 1.8 mmol) in ethylene glycol (9.0 mL) was added hydrazine hydrate (1.8 mL). The reaction mixture was heated at 120° C. for 2 h and at 180° C. for additional 15 h. The reaction was cooled to 20° C., quenched by addition of brine and extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed in silica gel column (hexane/EtOAc 9/1) to give the title compound (42 mg, 0.12 mmol): MS (ES) 354.1 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[CH:45]=[CH:44][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:20]=3)[C:15]([C:30](=[O:43])[C:31]([NH:33][C:34]3[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=3)[C:37](O)=[O:38])=[O:32])=[CH:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.CCN=C=NCCCN(C)C.[CH3:62][C:63]1[CH:64]=[CH:65][C:66]([S:69]([NH2:72])(=[O:71])=[O:70])=[CH:67][CH:68]=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:20]=3)[C:15]([C:30](=[O:43])[C:31]([NH:33][C:34]3[CH:42]=[CH:41][CH:40]=[C:36]([C:37]([NH:72][S:69]([C:66]4[CH:65]=[CH:64][C:63]([CH3:62])=[CH:68][CH:67]=4)(=[O:71])=[O:70])=[O:38])[CH:35]=3)=[O:32])=[CH:14]2)=[CH:44][CH:45]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc(C(=O)O)c1)C(=O)c1cn(Cc2ccc(Cc3ccccc3)cc2)c2ccc(OCc3ccccc3)cc12
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)c2cccc(NC(=O)C(=O)c3cn(Cc4ccc(Cc5ccccc5)cc4)c4ccc(OCc5ccccc5)cc34)c2)cc1
Reaction time: 8 h
Yield: 35.8 %

Procedure:
To the acid obtained in Example 71 (0.1 g) in CH2C2 (10 mL) is added THF (5 mL) to help dissolve the compound. EDCI (0.045 g) and DMAP (0.02 g) was added and the mixture was stirred a room temperature of 1 h. p-Toluenesulfonamide (0.04 g) was added and the reaction was stirred overnight. The reaction mixture was take up in ethyl acetate and washed with water, dried (MgSO4), filtered and concentrated. Chromatography (7% MeOH/CH2Cl2) afforded the title compound (0.045 g, 40%) as a yellow solid. MS: m/z (M-1) 746
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(OC(C)C)OC(C)C>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[F:20])[NH:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: Fc1ccc(Nc2ncnc3ccc(Br)cc23)cc1Cl
Reactant: CC(C)OB(OC(C)C)c1cccs1
Agent: Cl
Product: Fc1ccc(Nc2ncnc3ccc(-c4cccs4)cc23)cc1Cl
Yield: 36 %

Procedure:
Using an analogous procedure to that described in Example 5 except that the reaction mixture was heated to reflux for 3 hours, 6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt was reacted with di-isopropyl 2-thienylboronate to give 4-(3-chloro-4-fluoroanilino)-6-(2-thienyl)quinazoline in 36% yield, m.p. 205°-208° C.;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][N:10]([CH3:14])[CH2:11][C:12]#[CH:13]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][N:10]([CH3:14])[CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: C#CCN(C)C
Reactant: Oc1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1ccccc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a deoxygenated solution of o-bromophenol (10.0 g) in triethylamine (120 ml) may be added 1-dimethylamino-2-propyne (2.82 g), bis(triphenylphosphine)palladium(II) chloride (400 mg), and cuprous iodide (54 mg). The mixture may be stirred at room temperature under an atmosphere of argon for approximately 6 hours, heated briefly (ca. 10 minutes) to 60° C. The reaction mixture is then cooled, filtered through diatomaceous earth, and the solvent may be removed by evaporation in vacuo. The residue can then be dissolved in ethyl acetate, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent may be removed by evaporation in vacuo, and the residue may be purified by chromatography over silica gel (50% ethyl acetate in hexanes may be used as the eluant) to give the purified product.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2.C(N(CC)CC)C>ClCCl>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:1]([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)[CH2:25]2
Reactant: Brc1ccc2c(c1)CNC2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Brc1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Yield: 85.5 %

Procedure:
Trityl chloride (2.30 g, 8.23 mmol) was added to a solution of 5-bromo-2,3-dihydro-1H-isoindole (1.64 g, 8.23 mmol) and triethylamine (1.4 mL, 9.9 mmol) in dichloromethane (20 mL). After 18 hours the solvent was removed in vacuo, the residue taken up in ethyl acetate and washed with water (×2) and brine, dried (MgSO4) and concentrated. The crude material was purified by flash chromatography on silica eluting with 1% triethylamine/10% ethyl acetate/petrol to give 5-bromo-2-trityl-2,3-dihydro-1H-isoindole as a reddish-brown solid (3.10 g, 85%). 1H NMR (CDCl3) 7.91-7.84 (1H, m), 7.57 (6H, d), 7.45-7.41 (1H, m), 7.33-7.14 (9H, m), 6.95 (1H, d), 3.90 (2H, s), 3.86 (2H, s). MS: Ph3C+ 243.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:18])[CH:14]=2)[CH:9]1[C:19](=[O:29])[NH:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[F:28])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=1[NH:20][C:19]([CH:9]1[C:10]2[C:15](=[CH:14][C:13]([Cl:18])=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)ccc2C1C(=O)Nc1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1c(F)cccc1F)C1NCCc2cc(Cl)ccc21
Reaction time: 1 h
Yield: 85.9 %

Procedure:
In a 50 mL pear-shaped flask, 6-chloro-1-(2,6-difluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.6 g, 1.42 mmol, Eq: 1.00) was combined with DCM (25 mL) to give a light brown solution. TFA (4.85 g, 3.28 mL, 42.6 mmol, Eq: 30) was added. After 1 h, the reaction was concentrated, the residue dissolved in EtOAc and the mixture washed with 1 N NaOH and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford 0.3937 g 6-chloro-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2,6-difluoro-phenyl)-amide as a brown oil which was used without purification. 86.0% MS m/z 323.0 (M+H)
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[N:36]1([CH2:41][CH2:42][NH2:43])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:43][CH2:42][CH2:41][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:3])=[N:13][C:14]([NH:19][C:20]2[CH:21]=[CH:22][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:33]=3[CH:34]=2)=[N:15][CH:16]=1
Reactant: NCCN1CCCC1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCN4CCCC4)n3)cc2CC1

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and 2-pyrrolidin-1-yl-ethylamine in an analogous manner to Example 1396. Product isolated as a tan solid (25 mg, 54%). m.p.=172-174° C.; LCMS (m/e) 564 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.19 (s, 1H), 8.68 (d, 1H, J=8.6 Hz), 8.10 (s, 1H), 7.57-7.52 (m, 1H), 7.48-7.41 (m, 1H), 7.38-7.34 (m, 1H), 7.30-7.23 (m, 1H), 7.14-7.08 (m, 1H), 7.07-6.95 (m, 2H), 6.90-6.85 (m, 1H), 3.62-3.53 (m, 4H), 3.39 (s, 3H), 2.97-2.87 (m, 4H), 2.81-2.69 (m, 8H), 2.65-2.53 (m, 4H), 1.88-1.78 (m, 4H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])[C:19]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])C.[NH4+:30]>CO>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])[C:19]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[NH2:30]
Reactant: [NH4+]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1ccco1
Solvent: CO
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1

Procedure:
The process was repeated with ammonium (6R,7R)-3-acetoxymethyl-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate (syn isomer) (40 mg) as substrate and with the addition of pig liver acetylesterase (1 unit). Analysis of the product by TLC (silicachloroform/methanol/90% formic acid - 90:16:4) showed the presence of a new u.v. absorbing spot with an identical Rf to the standard sample of title compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([N:17](C)[C:18](=O)OC(C)(C)C)[CH2:13]2)[C:9]2[CH2:8][CH2:7][C:6]3[O:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]4[C:5]=3[C:4]=2[N:3]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:18][NH:17][C@@H:14]1[CH2:15][CH2:16][N:12]([C:10]2[C:9]3[CH2:8][CH2:7][C:6]4[O:26][CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]5[C:5]=4[C:4]=3[N:3]=[C:2]([NH2:1])[N:11]=2)[CH2:13]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2nc(N)nc3c2CCC2=C3C3CCCCC3O2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H]1CCN(c2nc(N)nc3c2CCC2=C3C3CCCCC3O2)C1
Reaction time: 16 h

Procedure:
A solution of the product from Example 2C (51 mg, 0.115 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (0.18 mL) at ambient temperature and stirred for 16 hours. The mixture was diluted with dichloromethane (20 mL) and basified with sodium hydroxide (1 N). The organic layer was separated, dried with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a silica gel column eluting with ammonium hydroxide/methanol/dichloromethane (0.8/8/92) to provide the title product: 1H NMR (CD3OD) δ 1.10-1.22 (m, 1H), 1.25-1.36 (m, 1H), 1.42-1.55 (m, 1H), 1.56-1.68 (m, 2H), 1.78-1.90 (m, 1H), 1.95-2.07 (m, 2H), 2.11-2.31 (m, 2H), 2.48 (t, 2H), 2.55-2.60 (m, 3H), 2.98-3.09 (m, 3H), 3.49-3.56 (m, 1H), 3.65-3.77 (m, 2H), 3.80-3.91 (m, 2H), 4.68-4.75 (m, 1H); MS (DCl/NH3) m/z 342 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=1.[Li]CCCC.[Si:21]([O:28][C:29]1[CH:30]=[C:31]([CH:38]=[CH:39][C:40]=1[F:41])[C:32](N(OC)C)=[O:33])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].Cl>CCOCC>[Si:21]([O:28][C:29]1[CH:30]=[C:31]([C:32]([C:2]2[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=2)=[O:33])[CH:38]=[CH:39][C:40]=1[F:41])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Reactant: CON(C)C(=O)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reaction time: 1 h
Yield: 71 %

Procedure:
At −78° C. under argon, to a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (2.04 g, 7.01 mmol) in anhydrous ether (20 mL) was added nBuLi (3.5 mL, 2.0 M in cyclohexane, 7.0 mmol) dropwise and the reaction mixture was stirred for 1 h. 3-(Tert-butyldimethylsilyloxy)-4-fluoro-N-methoxy-N-methylbenzamide (2.00 g, 6.38 mmol) was added in one portion and the reaction mixture was stirred at −78° C. for 1.5 h. The pale yellow solution was poured into 1 N HCl aqueous solution (30 mL) and ether (30 mL) was used to rinse the reaction flask. The aqueous phase was separated and extracted with ether (20 mL). The combined ether portions were dried over Na2SO4, filtered and concentrated. The resulting oil was purified by ISCO chromatography (120 g column) using hexanes/EtOAc (0-100% over 30 min) to give (3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone at a retention time of 7 min (2.11 g, 71% yield). LCMS: RT=2.41 min [M+H] 465.19 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDC3) 7.33 ppm, 3H, m; 7.28 ppm, 1H, m; 7.11 ppm, 2H, m; 5.86 ppm, 1H, t, J=53.39 Hz; 0.95 ppm, 9H, s; 0.15 ppm, 6H, s.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[CH:8]=2)[N:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[CH:8]=2)[N:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(-c2ccc3nc(N)nc(O)c3c2)cc1OC
Product: COc1ccc(-c2ccc3nc(NC(C)=O)nc(O)c3c2)cc1OC
Yield: 90 %

Procedure:
A suspension of crude 2-amino-6-(3,4-dimethoxyphenyl)-4-hydroxy-quinazoline (3.0 g, 10 mmol) in acetic anhydride (20 ml) was refluxed for 40 minutes. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1:40), yielding the title compound as a white solid (3.05 g, yield: 90%) which was characterized by its mass spectrum as follows: MS (m/z): 340 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=1)#[CH:21].C(N(CC)CC)C>O1CCCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(NCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(NCc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 13.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-benzylamino-phenyl)-acetohydroximoyl chloride (150 mg, 0.546 mmol) described in Manufacturing Example 68-1-4 and 3-ethynyl-pyridin-2,6-diamine (46.4 mg, 0.348 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (190 μL, 1.37 mmol). The mixture was stirred for 6.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (17 mg, 8.4%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][NH2:16])[O:14][CH2:13][CH2:12][O:11]2)=[CH:6][CH:5]=1.[N:17]([CH2:20][CH:21]([CH3:23])[CH3:22])=[C:18]=[S:19].C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH2:15][NH:16][C:18]([NH:17][CH2:20][CH:21]([CH3:23])[CH3:22])=[S:19])[O:11][CH2:12][CH2:13][O:14]2)=[CH:8][CH:9]=1
Reactant: CC(C)CN=C=S
Reactant: COc1ccc(C2(CN)OCCO2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccc(C2(CNC(=S)NCC(C)C)OCCO2)cc1
Yield: 89.65 %

Procedure:
A mixture of 22 parts of 2-(4-methoxyphenyl)-1,3-dioxolane-2-methanamine hydrochloride, 11.5 parts of 1-isothiocyanato-2-methylpropane, 20.7 parts of potassium carbonate and 200 parts of 2-propanol is stirred and refluxed for 3 hours. The reaction mixture is filtered while hot and the filtrate is evaporated. The solid residue is crystallized from a mixture of benzene and petroleumether. The product is filtered off and dried, yielding 26 parts (89.65%) of N-[2-(4-methoxyphenyl)-1,3-dioxolan-2-ylmethyl]-N'-(2-methylpropyl)thiourea; mp. 96° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[O:12]1[CH:14]([CH2:15][CH3:16])[CH2:13]1.[OH-].[K+]>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:13][CH:14]([OH:12])[CH2:15][CH3:16]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC(O)COc1cccc(C(F)(F)F)c1
Temperature: 65 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
A mixture of 3-trifluoromethylphenol (75 ml, 0.617 moles), 1,2-epoxybutane (58 ml, 0.617 moles), potassium hydroxide pellets (86%, 0.062 moles), and water (10 ml) were heated with stirring at 65° C. for four hours. At this point more 1,2-epoxybutane (58 ml, 0.617 moles) was added and stirring at 65° C. continued overnight. The reaction was allowed to cool to room temperature and the lower phase taken off and the upper phase extracted with methylene chloride (2×100 ml). The organic phases were combined and washed with 5% sodium hydroxide solution (150 ml) and water (3×150 ml). This reaction solution was dried over anhydrous magnesium sulfate and stripped under vacuo to yield 138 g of the desired alcohol, as determined by infra-red spectroscopy, mass spectrometry and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:24]1[CH2:25][CH2:26][N:21]([C:18]2[C:17]([CH3:27])=[CH:16][C:15]([CH:12]3[CH2:13][CH2:14]3)=[CH:20][N:19]=2)[CH2:22][CH2:23]1)=[O:6]
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(Cl)cc1Br
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)cc2Br)CC1
Yield: 95.1 %

Procedure:
Using 2-bromo-4-chlorobenzoic acid (1 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (0.92 g) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (1.75 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:13][CH:12]([C:14]([N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:25]1([CH2:24][N:19]2[CH2:20][CH2:21][CH2:22][N:16]([C:14]([CH:12]3[CH2:13][N:10]([C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[O:9])[CH2:11]3)=[O:15])[CH2:17][CH2:18]2)[CH2:27][CH2:26]1
Reactant: BrCC1CC1
Reactant: Cc1ccc(C(=O)N2CC(C(=O)N3CCCNCC3)C2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C(=O)N2CC(C(=O)N3CCCN(CC4CC4)CC3)C2)cn1
Temperature: 70 °C
Yield: 38.3 %

Procedure:
To a stirred solution of 1-({1-[(6-methylpyridin-3-yl)carbonyl]azetidin-3-yl}carbonyl)-1,4-diazepane (100 mg, 0.33 mmol) and 1-(bromomethyl)cyclopropane (53 mg, 0.39 mmol) in ACN (5 mL) was added potassium carbonate (91 mg, 0.66 mmol). The mixture was heated to 70° C. in a sealed tube for 20 hours and then concentrated at reduced pressure. The crude residue was purified by silica FCC (eluting with 97:3:1 DCM/MeOH/NH3) and then preparative HPLC (Method 2) to give the title compound (45 mg, 38% yield) as pale yellow oil
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[CH3:30][C:31]1[CH:35]=[CH:34][NH:33][N:32]=1>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:33]2[CH:34]=[CH:35][C:31]([CH3:30])=[N:32]2)=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: Cc1cc[nH]n1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Product: Cc1ccn(-c2ccc(S(C)(=O)=O)cc2C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)n1
Yield: 15 %

Procedure:
The title compound was prepared according to the procedure described for example 294 from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK) and 3-Methyl-1H-pyrazole (15% yield, white solid, MS (m/e): 493.5 (M+H, 100%)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]=1[OH:15].Cl(O)(=O)(=O)=O>C(OCC)(=O)C.C(OC(=O)C)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:10](=[O:14])[CH3:11])[C:9]=1[O:15][C:9](=[O:15])[CH3:8]
Reactant: Oc1cccc(CCCCCCBr)c1O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cccc(CCCCCCBr)c1OC(C)=O
Reaction time: 1.5 h
Yield: 191.5 %

Procedure:
To 1.0 g (3.8 mmol) of 1-(6-bromohexyl)-2,3-dihydroxybenzene in 150 mL of ethyl acetate and 15 mL of acetic anhydride was added 0.03 mL of 70% perchloric acid. The solution was left at room temperature for 1.5 hours and then was washed with sodium bicarbonate solution. After drying, the organic layer was concentrated to give 1.3 g of 1-(6-bromohexyl)-2,3-bis(acetyloxy)benzene as an oil.