Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1B(O)O>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Reactant: Cc1ccncc1B(O)O
Product: Cc1ccncc1-c1cc([N+](=O)[O-])ccc1Cl

Procedure:
The title compound was prepared by a Suzuki coupling of 3-bromo-4-chloronitrobenzene and 4-methyl-3-pyridylboronic acid. This gave (D61) (0.2 g, 33%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[N:11]O)=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[H][H]>C(O)C.[C].[Pd]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH2:11])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: [H][H]
Reactant: ON=C1CCc2cc(N3CCOCC3)c(F)cc21
Agent: [Pd]
Solvent: CCO
Product: NC1CCc2cc(N3CCOCC3)c(F)cc21
Yield: 27.2 %

Procedure:
A solution of 6-fluoro-5-morpholin-4-ylindan-1-one (200 mg), hydroxylammonium chloride (102 mg) and sodium acetate (241 mg) in ethanol (5.0 mL) was heated to reflux for 1 hour. After confirming that the raw materials disappeared, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 218 mg of 6-fluoro-5-morpholin-4-ylindan-1-one oxime. Next, 10% palladium-carbon (water content: 48%, 200 mg) was added to a solution of the resulting 6-fluoro-5-morpholin-4-ylindan-1-one oxime (218 mg) in ethanol (5.0 mL), and the reaction solution was stirred in a hydrogen atmosphere (0.4 MPa) at room temperature for 9 hours. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 56.0 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: C(O)(C(F)(F)F)=[O:2].N[C@@H](C(N[C@@H](C(N[C@@H](C(N[C@@H](C(N[C@@H](C(N[C@@H](C(N[C@@H](C(N[C@@H]([C:76]([NH:78][CH2:79][C:80]([NH:82][C@@H:83]([C:92]([NH2:94])=[O:93])[CH2:84][C:85]1[CH:90]=[CH:89][C:88]([OH:91])=[CH:87][CH:86]=1)=[O:81])=[O:77])CCCC)=O)CCCC)=O)CCCC)=O)CCCNC(=N)N)=O)CCCC)=O)CCCC)=O)CCCC)=O)CCCNC(=N)N.C(O)(C(F)(F)F)=O.C1(O)C=CC=CC=1.[C:109]1([CH3:115])[CH:114]=CC=C[CH:110]=1>C1COCC1>[NH:78]([C:76]([O:77][C:109]([CH3:115])([CH3:114])[CH3:110])=[O:2])[CH2:79][C:80]([NH:82][C@@H:83]([C:92]([NH2:94])=[O:93])[CH2:84][C:85]1[CH:86]=[CH:87][C:88]([OH:91])=[CH:89][CH:90]=1)=[O:81]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCC[C@@H](NC(=O)[C@H](N)CCCNC(=N)N)C(=O)N[C@H](CCCC)C(=O)N[C@H](CCCC)C(=O)N[C@H](CCCNC(=N)N)C(=O)N[C@H](CCCC)C(=O)N[C@H](CCCC)C(=O)N[C@H](CCCC)C(=O)NCC(=O)N[C@H](Cc1ccc(O)cc1)C(N)=O
Reactant: Cc1ccccc1
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC(=O)N[C@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C

Procedure:
The deprotected peptide SF1257-13 (TFA-(D)Arg-(D)Nle-(D)Nle-(D)Nle-(D)Arg-(D)Nle-(D)Nle-(D)Nle-Gly-(D)Tyr-NH2 (SEQ ID NO:1) is made by slowly adding TFA (A×3 l) to a mixture of SF1257-12 (A kg) and phenol (A×0.1 kg) in toluene and THF while maintaining the temperature at ≦18° C. The reaction mixture is allowed to warm up to room temperature. Following completion of cleavage, the solvent is diluted with THF and then concentrated in vacuo. Residual TFA is removed by azeotropic distillation with toluene. The residue is poured into a mixture of petroleum ether and diisopropyl ether. The solid is filtered, washed with diisopropyl ether and dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Li]CCCC.CCCCCC.[CH3:18][C:19]1([CH3:31])[CH2:28][C:27](=O)[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:30])[CH:25]=2)[O:20]1>C1COCC1.C(OCC)(=O)C>[CH3:18][C:19]1([CH3:31])[CH:28]=[C:27]([C:4]2[S:3][C:2]([CH3:1])=[CH:6][CH:5]=2)[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:30])[CH:25]=2)[O:20]1
Reactant: CC1(C)CC(=O)c2cc(Br)ccc2O1
Reactant: Cc1cccs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Oc3ccc(Br)cc32)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of 2-methylthiophene (820 mg, 8.3 mmol) in THF (16 mL) was added n-BuLi in hexane (1.6M, 4.4 mL, 8.5 mmol). The mixture was warmed to ambient temperature and stirred for 15 minutes. This solution was added to a flask containing cold (−78° C.) solution of 2,2-dimethyl-6-bromo-chroman-4-one (1.08 g, 4.2 mmol) in THF (4 mL). The mixture was stirred and allowed to gradually warm to ambient temperature over 8 hours, and then stirred for an additional 4 hours at ambient temperature. The mixture was diluted with ethyl acetate (200 mL), washed with 10% HCl, brine (20 mL), dried and the solvent was removed by evaporation. The product was purified by chromatography on a silica gel column to afford the title compound as a colorless oil.
Reaction SMILES: NC(OCC)=O.C(OC([N:12]([CH2:15][CH2:16][CH:17]1[N:25]2[C:26]3[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=3[CH2:28][CH2:29][C:23]3=[C:24]2[C:19](=[CH:20][CH:21]=[CH:22]3)[CH:18]1[CH3:34])[CH2:13][CH3:14])=O)C.[Cl:35]C(OCC)=O.[OH-].[K+]>O.C(O)C>[CH2:13]([NH:12][CH2:15][CH2:16][C@@H:17]1[N:25]2[C:26]3[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=3[CH2:28][CH2:29][C:23]3=[C:24]2[C:19](=[CH:20][CH:21]=[CH:22]3)[C@H:18]1[CH3:34])[CH3:14].[ClH:35]
Reactant: CCOC(=O)N(CC)CCC1C(C)c2cccc3c2N1c1ccccc1CC3
Reactant: CCOC(=O)Cl
Agent: CCOC(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCNCC[C@H]1[C@H](C)c2cccc3c2N1c1ccccc1CC3
Product: Cl

Procedure:
11.3 g (0.0298 mol) of the urethane, 1-[2-(N-ethoxycarbonyl-N-ethylamino)-ethyl]-1,2,6,7-tetrahydro-2-methylindolo[1,7-ab][1]benzazepine obtained after three successive treatments with ethyl chloroformate, were autoclaved for 8 hours at 140° C with a solution of 5.9 g [3 equivalents] of potassium hydroxide in 5.9 ml of water and 53 ml of ethanol. The resulting mixture was worked up as described in part B of Example 2 to yield the basic product, together with some unhydrolysed urethane which was given a second treatment with alkali. The combined basic products were distilled to give 5.9 g (64.7% yield) of pale-yellow, syrupy trans-1-(2-ethylaminoethyl)-1,2,6,7-tetrahydro-2-methylindolo[1,7-ab][1]benzazepine (boiling point 140° C [air-bath temperature]/2 × 10-5 mm Hg) whose hydrochloride melted at 169°-171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:34])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=O)[NH:12][CH:11]3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:44]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:34])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[S:44])[NH:12][CH:11]3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2ccccc2C(F)(F)F)N1
Solvent: Cc1ccccc1
Product: O=C1Nc2cc(Cl)ccc2C12C(c1cccc(Cl)c1)CC(=S)NC2c1ccccc1C(F)(F)F
Yield: 36.4 %

Procedure:
In a manner similar to the method described in example 30, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(trifluoromethyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.4 g, 0.79 mmol) prepared in example 32b was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (0.4 g, 0.99 mmol) in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-6′-thioxo-2′-[2-(trifluoromethyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2(1H)-one (Yield 0.15 g, 36%).
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:20][N+:21]([O-:23])=[O:22])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].[OH2:24]>CO>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:20][N+:21]([O-:23])=[O:22])(=[O:2])=[O:24])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC(C)(C)c1ccc(SC[N+](=O)[O-])cc1
Reactant: O
Agent: [K+]
Solvent: CO
Product: CC(C)(C)c1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
A solution of potassium peroxymonosulphate [`Oxone` (trade mark); 38.7 g, 63 mmol]in water (100 ml) was added in one portion to a vigorously stirred solution of (4-t-butylphenylthio)nitromethane (A) (4.76 g, 21.9 mmol) in methanol (90 ml). A cream coloured precipitate was formed. The mixture was stirred overnight. Water (200 ml) was then added and the mixture was extracted with ethyl acetate. The extracts were combined, dried (MgSO4) and the solvent was removed by evaporation. The residual yellow solid was recrystallised from cyclohexane to give (4 t-butylphenylsulphonyl)nitromethane, as a colourless solid (3.34 g), m.p. 90°-91° C., microanalysis found: C, 51.4; H, 5.9; N, 5.4%; C11H15NO4S: requires: C, 51.4; H, 5.9; N, 5.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:13][C:8]3([NH:12][CH2:11][CH2:10][NH:9]3)[C:6]=2[CH:7]=1.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[ClH:1].[CH2:14]([S:13][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[CH:8]1[NH:12][CH2:11][CH2:10][NH:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: Clc1ccc2c(c1)C1(NCCN1)S2
Solvent: CO
Product: Cl
Product: Clc1ccc(SCc2ccccc2)c(C2NCCN2)c1

Procedure:
32 parts of 4-chlorobenzothietane-2spiro-2'-imidazolidine is reacted with 19 parts of benzyl chloride in 300 parts of methanol as described in Example 11. The yield is 43 parts (84% of theory) and the melting point is 260° C. with decomposition.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1.[S:9]([O-:12])([O-:11])=[O:10].[Na+:13].[Na+]>O>[CH3:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][S:9]([O-:12])(=[O:11])=[O:10])[N:4]=1.[Na+:13]
Reactant: Cc1nc(CCl)cs1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(CS(=O)(=O)[O-])cs1
Yield: 101.2 %

Procedure:
4-Chloromethyl-2-methylthiazole (250 mg, 1.69 mmol) is dissolved in H2O (2 mL) and treated with sodium sulfite (224 mg, 1.78 mmol). The reaction mixture is subjected to microwave irradiation for 20 minutes at 200° C. The reaction mixture is diluted with H2O (30 mL) and washed with EtOAc (2×25 mL). The aqueous layer is concentrated to afford 0.368 g of the desired product as a yellow solid. LC/MS ESI+194 (M+1, free acid).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1.C(N(CC)CC)C>C1C=CC=CC=1.O>[CH2:5]([O:4][C:2]([O:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: O=C(OCc1ccccc1)On1nnc2ccccc21
Reaction time: 3 h
Yield: 90.2 %

Procedure:
Benzyl chloroformate (8.5 g.) was dropwise added under ice-cooling to a solution of 1-hydroxy-1H-benzotriazole (6.8 g.) and triethylamine (7.0 ml.) in a mixture of benzene (100 ml.) and water (50 ml.), and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was filtered and the precipitated crystals were washed with water and dried. The benzene layer was washed with water, dried and concentrated. The residue and the crystals above obtained were put together and recrystallized from a mixed solvent of benzene and petroleum ether to give 1-benzyloxycarbonyloxy-1H-benzotriazole (12.1 g.), mp 130° to 131° C.
Reaction SMILES: [CH3:1][C:2]([S:23]([CH3:26])(=[O:25])=[O:24])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[C:3]([O:5]CC)=[O:4].O.[OH-].[Li+].O>O1CCCC1.CO.Cl>[CH3:1][C:2]([S:23]([CH3:26])(=[O:24])=[O:25])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(CCc1ccc(Sc2ccccc2)cc1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(CCc1ccc(Sc2ccccc2)cc1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]butanoate (348.6 mg, 0.887 mmol) in tetrahydrofuran/methanol (4:1, 10 mL) was added a solution of lithium hydroxide monohydrate in water (1.78 M, 3.55 mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with aqueous HCl (1N in water) and extracted with diethyl ether 2×. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to afford 2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]butanoic acid as a solid. 323 mg. LCMS: (M−1) 363.3.
Reaction SMILES: S(Cl)([Cl:3])=O.N1C2C=CC=CC=2N=N1.[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:16]=1[CH:17]=[CH:18][CH2:19]O>ClCCl>[Cl:3][CH2:19]/[CH:18]=[CH:17]/[C:16]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:15]=1[F:14]
Reactant: OCC=Cc1cc(F)ccc1F
Reactant: O=S(Cl)Cl
Agent: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Product: Fc1ccc(F)c(/C=C/CCl)c1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A solution of 0.34 cm3 (4.66 mmol) of thionyl chloride and 0.555 g (4.66 mmol) of benzotriazole in 40 cm3 of dichloromethane is added at a temperature in the region of 20° C. under an argon atmosphere to 0.646 g (3.8 mmol) of 2,5-difluorocinnamyl alcohol in solution in 40 cm3 of dichloromethane. After stirring for 10 minutes, the reaction mixture is filtered on No. 3 sintered glass and the solid residue rinsed with twice 10 cm3 of dichloromethane. The filtrate is washed 3 times with 30 cm3 of water. The organic phase is dried over magnesium sulfate and filtered to give a solution of 2-[(1E)-3-chloro-1-propenyl]-1,4-difluorobenzene (3.8 mmol) which is then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 20° C., before dissolution in acetonitrile.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.C([O:56][C:57]([CH2:59]CCCCOS(C1C=CC(C)=CC=1)(=O)=O)=[O:58])(C)(C)C.COC(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCOCC)C>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:59][C:57]([OH:58])=[O:56])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCC(=O)OC(C)(C)C)cc1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCOCC
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-glucopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 15.22 g (100 mmol) of DBU in 300 ml of diethoxymethane is cooled to 0° C. At 0° C., 78 g (150 mmol) of 5-tosyloxy-pentanecarboxylic acid-tert-butyl ester, dissolved in 40 ml of tetrahydrofaran, is added in drops over 30 minutes while being stirred vigorously. It is stirred for 3 hours at 0° C. 300 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of methanol. 50 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for one hour. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 500 ml of ethyl acetate, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of dichloromethane. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate, and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]2[N:18]=[CH:19][CH:20]=[CH:21][C:6]1=2>C(O)C.C(O)(=O)C.[Pd]>[Br:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]2[N:18]=[CH:19][CH:20]=[CH:21][C:6]1=2
Reactant: COc1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)C(CCCBr)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.8 %

Procedure:
To a solution of the product of step 2 (160 mg) in ethanol (3 ml) and acetic acid (1 ml) were added 10% Pd—C (79 mg) was stirred under hydrogen (under a balloon) at room temperature for 24 hour. The mixture was filtered through the celite and distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography eluting with ethyl acetate-hexane (1:2) to give 5-(3-bromopropyl)-5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepine (48 mg).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:47][C:18]2[N:19]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=4)=[CH:35][CH:34]=3)[C:20](=[O:31])[N:21]([CH2:24][CH:25]([OH:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>O.C(OCC)(=O)C>[CH2:13]([C:15]1[S:47][C:18]2[N:19]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[C:45]4[NH:3][C:4](=[O:7])[O:5][N:46]=4)=[CH:37][CH:38]=3)[C:20](=[O:31])[N:21]([CH2:24][CH:25]([OH:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC(O)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(O)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.69 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C. for 30 min, 4′-{[6-ethyl-3-(2-hydroxy-3,3-dimethylbutyl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.62 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.42 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([CH3:12])[CH3:11].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([CH:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: NCc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(CNCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 105.9 %

Procedure:
To a solution of 4-chlorobenzylamine (2.83 g, 20.0 mmol) and 4-isopropylbenzaldehyde (2.96 g, 20.0 mmol) in methanol (100 mL) were added acetic acid (4.6 mL, 80 mmol) and sodium cyanoborohydride (1.51 g, 24.0 mmol) and the solution was stirred at room temperature for three days. Water (5 mL) was added and the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (100 mL) and aqueous 1 M KOH (100 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×100 mL) and the combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 5.80 g of crude product as a white semicrystalline oil. The product was used in the subsequent reaction step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:34]=[CH:33][C:29]2[N:30]=[CH:31][S:32][C:28]=2[CH:27]=1>>[S:32]1[C:28]2[CH:27]=[C:26]([NH:25][C:21]([C:20]3[CH:24]=[C:16]([N:14]4[CH2:15][C@@H:10]5[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][C@@H:11]5[CH2:13]4)[CH:17]=[N:18][CH:19]=3)=[O:22])[CH:34]=[CH:33][C:29]=2[N:30]=[CH:31]1
Reactant: Nc1ccc2ncsc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)Nc4ccc5ncsc5c4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 6-aminobenzothiazole were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 466 (M+H)+.