Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([OH:13])[CH:11]=[CH2:12].[Li]CCCC.[B:19](OC(C)C)(OC(C)C)[O:20]C(C)C>C1COCC1>[CH:11]([CH:10]1[O:13][B:19]([OH:20])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)=[CH2:12]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C=CC(O)c1ccccc1Br
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC1OB(O)c2ccccc21
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a suspension of NaH (1.23 g, 28.2 mmol, 1.2 equiv., 60% content) in THF (10 mL) was added a solution of 1-(2-bromophenyl)prop-2-en-1-ol (5.0 g, 23.5 mmol, 1.0 eq) in THF (10 mL) dropwise at 0° C. The mixture was stirred for 1 h, then, cooled to −70° C. n-BuLi (11.3 mL, 28.2 mmol, 1.2 eq., 2.5M in THF) was added. The mixture was stirred for 1 h, then, triisopropyl borate (5.3 g, 28.2 mmol, 1.2 equiv.) was added. The mixture was stirred for 5 h, then, quenched with 2N H2SO4. The mixture was partitioned between brine and ethylacetate. The organic layer was washed over brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to yield 3-vinylbenzo[c][1,2]oxaborol-1(3H)-ol (2.2 g, 57%). LC-MS (m/z)=158.9, 160.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18]C(=O)C3C=CC=CC=3)=[N:9]2)[CH:7]=1.N12CCCN=C1CCCCC2>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:16])([F:17])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1
Reactant: O=C(NC1=N[C@](CF)(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: NC1=N[C@](CF)(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 65 °C
Yield: 80.9 %

Procedure:
To a solution of N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1i, 8.58 g, 17.98 mmol) in MeOH (50 mL) was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (3.22 ml, 21.57 mmol) and the resulting mixture was heated at 65° C. for 5 h. The reaction went to completion. The mixture was concentrated, diluted with EtOAc, washed with water, saturated NH4Cl solution, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using a gradient of 0-20% EtOAc/hexanes to afford a white solid as (4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (5.43 g, 14.55 mmol, 81% yield). MS m/z=374.9 [M+H]+. Calculated for C12H10BrF5N2O: 373.1
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Temperature: 130 °C
Yield: 95.1 %

Procedure:
To a solution of 2-chloro-6-(trifluoromethyl)pyridine (1.5 g, 8.26 mmol) and 4-hydroxybenzaldehyde (1.009 g, 8.26 mmol) in DMF (18 mL), was added K2CO3 (1.713 g, 12.39 mmol). The mixture was heated at 130° C. for 5 h, and then transferred to a sealed tube and heated with a microwave condition at 135° C. for 3 h. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (2.10 g) as a brown oil. LCMS: rt=3.25 min, [M+H+]=268
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH3:18])=[N:16][N:17]=2)=[CH:9][CH:8]=1.CO.C1COCC1>O>[CH3:18][C:15]1[O:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:19])=[O:5])=[CH:8][CH:9]=2)=[N:17][N:16]=1
Reactant: COC(=O)c1ccc(-c2nnc(C)o2)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc(C(=O)O)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
Oxalyl chloride (1.05 g, 8.3 mmol) was added to a stirred solution of terephthalic acid monomethyl ester (1 g, 5.55 mmol) in DCM (12 mL) and stirring was continued at ambient temperature for 4 hr. The reaction mixture was concentrated under reduced pressure to afford the residue. The residue was dissolved in DCM (4 mL) and to the resulting solution was added, acetic acid hydrazide (490 mg, 6.66 mmol), Et3N (670 mg, 6.66 mmol) and stirring was continued at temperature overnight. The reaction mixture was diluted with water and extracted with ethylacetate, dried over sodium sulfate and concentrated under reduced pressure to afford 1 g (76.39% Yield) of 4-(N′-acetyl-hydrazinocarbonyl)-benzoic acid methyl ester. A stirred solution of 4-(N′-acetyl-hydrazinocarbonyl)-benzoic acid methyl ester (500 mg, 5.55 mmol) in POCl3 (12 mL) was heated at 100° C. for 3 hr. The reaction mixture was concentrated under reduced pressure to afford the residue. The residue was diluted with cold water, extracted with ethyl acetate, washed the organic layer with sodium bicarbonate solution, saturated brine solution and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to 350 mg (75.92% Yield) of afford 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid methyl ester. LiOH.H2O (330 mg, 8 mmol) was added to a solution of 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid methyl ester (350 mg, 1.6 mmol) in the mixture of methanol (4 mL), THF (10 mL) and H2O (4 mL). The resulting reaction mixture was stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated The residue was diluted with water, acidified with aqueous citric acid solution, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford 280 mg (87.46% Yield) of 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid.
Reaction SMILES: [I:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]2[C:8](=[C:9]([O:12][CH3:13])[C:10]=1[I:11])[C:7](=[NH:14])[NH:6][C:5]2=N.[ClH:18].[CH2:19]([N:21]([CH2:28][CH3:29])[C:22]1[S:23][CH2:24][C:25](=[NH:27])[N:26]=1)[CH3:20].Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:18].[NH2:14][CH:7]1[C:8]2[C:4](=[C:3]([O:16][CH3:17])[C:2]([I:1])=[C:10]([I:11])[C:9]=2[O:12][CH3:13])[C:5](=[C:24]2[S:23][C:22]([N:21]([CH2:28][CH3:29])[CH2:19][CH3:20])=[N:26][C:25]2=[NH:27])[NH:6]1
Reactant: COc1c(I)c(I)c(OC)c2c1C(=N)NC2=N
Reactant: CCN(CC)C1=NC(=N)CS1
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Product: CCN(CC)C1=NC(=N)C(=C2NC(N)c3c(OC)c(I)c(I)c(OC)c32)S1

Procedure:
Following the procedure described in Example 9, part B above but using equivalent amounts of 5,6-diiodo-4,7-dimethoxy-1,3-diiminoisoindoline and 2-diethylamino-4-imino-2-thiazoline hydrochloride in place of 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, there is obtained as the product 1-amino-5,6-diiodo-4,7-dimethoxy-3-(2-diethylamino-4-imino-2-thiazolin-5-ylidene)isoindoline hydrochloride.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][S:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)=O)(C)(C)C.[ClH:22].O1CCOCC1.CCOCC>ClCCl>[ClH:22].[NH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(SCCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1ccc(SCCN)cc1

Procedure:
A solution of methyl 4-(2-tert-butoxycarbonylaminoethylsulfanyl)benzoate (1.00 g, 3.21 mmol) in dichloromethane (8 ml) was treated with a solution of HCl in dioxane (4M, 8 ml, 10 eq.) at room temperature for 3 h. Ether (100 ml) was added and the mixture was filtered, washed with ether and pumped dry to give methyl 4-(2-aminoethylsulfanyl)benzoate hydrochloride.
Reaction SMILES: [ClH:1].[C:2]1([O:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:11]1[CH2:16][CH2:15][C:14](O)(O)[CH2:13][CH2:12]1.Cl>CC(O)C>[ClH:1].[CH2:12]1[C:13]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:8][C:14]=2[CH2:15][CH2:16][NH:11]1
Reactant: NOc1ccccc1
Reactant: OC1(O)CCNCC1
Agent: Cl
Solvent: CC(C)O
Product: c1ccc2c3c(oc2c1)CCNC3
Temperature: 20 °C
Yield: 64.1 %

Procedure:
A mixture of O-phenylhydroxylamine hydrochloride (1:1) (0.625 mol) and 4,4-piperidinediol hydrochloride (1:1) (0.682 mol) in 2-propanol (615 ml) was stirred at 20° C. HCl (353 ml) was added dropwise at 20° C. The reaction mixture was gently heated to reflux temperature. The reaction mixture was stirred and refluxed for 3 hours, then cooled to room temperature. The precipitate was filtered off, washed with DIPE, and dried. This fraction was crystallized from water (1600 ml). The desired compound was allowed to crystallize out while stirring. The precipitate was filtered off, washed with 2-propanol and DIPE, then dried, yielding 84 g (64%) of 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine hydrochloride (1:1) (interm. 1).
Reaction SMILES: [ClH:1].Cl.Br[C:4]1[CH:5]=[C:6]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:28](=[O:29])[C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4S3(=O)=O)[CH2:16][CH2:15]2)[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1.BrCCCCN1C(=O)C2C(=CC=CC=2)[C:42]1=[O:51]>>[ClH:1].[Cl:1][C:4]1[CH:5]=[C:6]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:42](=[O:51])[C:26]4[C:27](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:29])[CH2:16][CH2:15]2)[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCN1CCN(c2cc(Br)cc3c2OCCO3)CC1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: Cl
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2cc(Cl)cc3c2OCCO3)CC1

Procedure:
This compound was prepared analogous to the method described for 2-(4-(4-(7-bromo-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl)-butyl)-1H-isoindole-1,3(2H)-dione, dihydrochloride (Example 3) using intermediate 2a (1.30 g, 4.5 mmol) and 2-(4-bromobutyl)-1H-isoindole-1,3(2H)-dione (1.40 g, 4.9 mmol). Yield 2.20 g, m.p. 222°-4° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[CH2:13][C@@H:12]1[F:18].[NH3:19]>>[NH2:19][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[CH2:13][C@@H:12]1[F:18]
Reactant: N
Reactant: OC[C@@H]1C[C@H](F)[C@H](n2cnc3c(Cl)ncnc32)O1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)C[C@@H]1F

Procedure:
A solution of 6-chloro-9-(2,3-dideoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purine (16 mg, 0.059 mmol) in saturated methanolic ammonia (5 ml) was sealed in a glass tube under an atmosphere of ammonia.
Reaction SMILES: [C:1]([C:4](C(OCC)=O)([CH2:15][CH2:16][CH2:17][CH:18]([O:28]C(=O)C)[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])(=[O:3])[CH3:2].[OH-].[Na+]>O.CO>[C:1]([CH:4]([CH2:15][CH2:16][CH2:17][CH:18]([OH:28])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(CC#CCCCC(=O)OC)(CCCC(COc1ccc(F)cc1)OC(C)=O)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)C(CC#CCCCC(=O)O)CCCC(O)COc1ccc(F)cc1

Procedure:
Methyl 8-acetyl-8-ethoxycarbonyl-12-acetoxy-13-(4-fluorophenoxy)-5-tridecynoate (40.00 g., 0.079 mole) is added to a solution of sodium hydroxide (18.96 g.; 0.474 mole) in water (132.7 ml.) and methanol (462.9 ml.). The resulting solution is allowed to stand for 191/2 hours at 55°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[N:9]=2)=[CH:5][C:4]([C:16]([F:19])([F:18])[F:17])=[N:3]1.[H][H]>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH2:15])[N:9]=2)=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cccc(C#N)n1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cn1nc(C(F)(F)F)cc1Oc1cccc(CN)n1
Reaction time: 2 h

Procedure:
7.00 g (26.1 mmol) of 2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-6-cyanopyridine were dissolved in 150 ml of glacial acetic acid, admixed with 1.40 g of Pd(OH)2, 20% on charcoal, and hydrogenated under a hydrogen overpressure of 17 bar. After 2 h, the catalyst was removed by filtration and the filtrate was concentrated by evaporation. The residue was taken up in water, admixed with 20 ml of 2 N HCl and subjected to multiple extraction with ethyl acetate. The aqueous phase was subsequently adjusted to a pH of 10 using 2 N NaOH and then subjected to multiple extraction with ethyl acetate. The combined organic extracts were then dried using MgSO4, filtered and concentrated.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=4)=[C:20]([Cl:31])[CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:32][CH3:33].[N:34]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:31][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[S:24][C:25]1[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=1)[NH:17][C:9]1[C:8]2[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:42]3[CH2:43][CH2:44][CH:39]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:40][CH2:41]3)=[C:6]([O:32][CH3:33])[CH:7]=2)[N:12]=[CH:11][C:10]=1[C:15]#[N:16]
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1OCCCl
Reactant: C1CCN(C2CCNCC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1OCCN1CCC(N2CCCC2)CC1
Yield: 82.1 %

Procedure:
A mixture of 200 mg (0.40 mmol) of 7-(2-chloroethoxy)-4-{3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]anilino]-6-methoxy-3-quinolinecarbonitrile and 1.5 g (10 mmol) of 4-pyrrolidin-1-yl-piperidine are heated in N,N-dimethylformamide at 85° C. for 5 hours and at 40° C. for 60 hours. The reaction mixture is poured slowly into saturated aqueous sodium bicarbonate to yield a solid which is subsequently filtered off. The crude solid is washed with water, then recrystallized from anhydrous ethyl ether to give 203 mg of 4-{3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]anilino}-6-methoxy-7-{2-[4-(1-pyrrolidinyl)-1-piperidinyl]ethoxy}-3-quinolinecarbonitrile as an off-white solid, mp 127-130° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[C:15]([N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:18]1[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)=[O:16].NN>CCO>[NH2:3][CH2:12][CH2:13][N:14]([C:37]1[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=1)[C:15]([N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:18]1[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=1)=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1CCN(C(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Agent: NN
Solvent: CCO
Product: NCCN(C(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 50 mL round-bottomed flask was added (R)—N-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-N-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (16 mg, 27 μmol, from step 4), EtOH (1 mL), hydrazine, anhydrous (3.5 μL, 109 μmol, Aldrich). The solution was stirred at RT for 18 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 10% MeOH/CH2Cl2+1% ammonia (37% in water) to give (R)—N-(2-aminoethyl)-N-(4-fluorophenyl)-1-(4-(trifluoromethyl)-phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide. MS (ESI pos. ion) m/z: 458 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:21][C:20]3[C:11](=[CH:12][C:13]4[CH2:14][C@@H:15]([C:31](O)=[O:32])[N:16]([C@@H:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][CH3:24])[CH2:17][C:18]=4[CH:19]=3)[N:10]([CH3:34])[C:9]2=[O:35])=[CH:4][CH:3]=1.Cl.[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH2:56])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>>[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH:56][C:31]([C@@H:15]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:20]([O:21][C@@H:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9](=[O:35])[N:10]3[CH3:34])=[CH:19][C:18]=2[CH2:17][N:16]1[C@@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:32])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Product: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (130 mg) was prepared from (3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (153 mg) and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride following general procedure A. LC-MS (m/z) 736.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][C:31](=[O:34])[CH2:32][OH:33])[NH:26][C:25](=[O:35])[CH2:24]2>>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13](/[CH:16]=[C:24]3\[C:25](=[O:35])[NH:26][C:27]4[C:23]\3=[CH:22][C:21]([F:20])=[C:29]([NH:30][C:31](=[O:34])[CH2:32][OH:33])[CH:28]=4)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Reactant: O=C(CO)Nc1cc2c(cc1F)CC(=O)N2
Product: Cc1c(/C=C2\C(=O)Nc3cc(NC(=O)CO)c(F)cc32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Yield: 83.4 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide 27b as starting materials to obtain (Z)—N-{3-[5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide 27 (80 mg, yield 83.4%) as an orange solid.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][OH:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.N>C(Cl)Cl.O>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:13][CH2:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-adamantaneethanol (3.06 g, 16.9 mmol) and triethylamine (2.8 mL, 20.1 mmol) in methylen chloride (30 mL) was added at 0° C. a suspension of 4-methylbenzene-1-sulfonyl chloride (3.88 g, 20.3 mmol) in methylen chloride (40 mL). The reaction mixture was stirred at room temperature overnight. Then, ice and a solution of ammonia 50% in water were added into the reaction mixture. The mixture was extracted with pentane and the organic layer was washed with water and brine. The solvent was removed under reduced pressure and the title compound was obtained as an oil (5.4 g, 90%). MS (M+): 335.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>C(O)C.O>[NH2:18][C:16]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:17]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1N1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(N)cc1N1CCOCC1
Temperature: 80 °C
Yield: 47.6 %

Procedure:
A mixture of 1.16 g of ethyl 2-morpholin-4-yl-4-nitrobenzoate, 1.1 g of ammonium chloride, 1.0 g of reduced iron and 14 ml of ethanol-water (5:2) mixed solvent was stirred at 80° C. for 4Hours. The reaction solution was filtered while hot, and the white crystals precipitated after spontaneous cooling were collected by filtration to obtain 493 mg of ethyl 4-amino-2-morpholin-4-ylbenzoate. EP: 251.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([CH3:18])=[N:12]2>S(=O)(=O)(O)O.ClCCl>[Br:6][C:7]1[C:16]([F:17])=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([CH3:18])=[N:12]2
Reactant: Cc1ccc2c(Br)c(F)ccc2n1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc2c(Br)c(F)cc([N+](=O)[O-])c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
A solution of 11.5 g of potassium nitrate in 30 ml of concentrated sulfuric acid was added to 21.0 g of 5-bromo-6-fluoroquinaldine in 117 ml of concentrated sulfuric acid dropwise at -5° C. After stirring at room temperature for 5 hours, the reaction mixture was poured into 2 l of ice water to precipitate solids which were then collected by filtration. The filtrate was rendered alkaline to form a small amount of solids, which together with the former solids were dissolved in dichloromethane. After the solution was dried over sodium sulfate the solvent was distilled off. Recrystallization of the residue from isopropanol gave 22.9 g of 5-bromo-6-fluoro-8-nitroquinaldine. m.p. 135°-137° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[SH:12].C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)[CH2:21][C:22]1[CH:31]=C2C(C=CC=C2)=C[CH:23]=1.ClCC(C)=C>CC(C)=O>[CH:21]([S:12][C:3]1[C:4]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])=[C:22]([CH3:31])[CH3:23]
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CC(C)(C)c1cccc(Br)c1S
Agent: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=CSc1c(Br)cccc1C(C)(C)C
Temperature: 24 °C

Procedure:
A mixture of 2-bromo-6-tert-butylthiophenol (6.04 g, 22.7 mmol), K2CO3 (3.76 g, 27.2 mmol), Nal (0.34 g, 2.27 mmol), and 3-chloro-2-methylpropene (2.3 mL, 22.7 mmol) in acetone (125 mL) is heated at reflux for 3 h. The reaction is allowed to cool to 24° C. The solids are filtered and discarded, and the filtrate is evaporated to a biphasic oil. The upper light colored layer is separated, taken up in hexane (50 mL), and treated with SiO2 (5 g). Filtration and evaporation provides 2-bromo-6-tert-butylphenyl isobutenyl thioether as a yellow oil.
Reaction SMILES: [CH:1]([OH:3])=O.[F:4][C:5]1([F:22])[O:10][C:9]2[CH:11]=[C:12]([F:17])[C:13]([NH:15][NH2:16])=[CH:14][C:8]=2[N:7]([CH2:18][C:19]#[CH:20])[C:6]1=[O:21]>ClCCl>[F:22][C:5]1([F:4])[C:6](=[O:21])[N:7]([CH2:18][C:19]#[CH:20])[C:8]2[CH:14]=[C:13]([NH:15][NH:16][CH:1]=[O:3])[C:12]([F:17])=[CH:11][C:9]=2[O:10]1
Reactant: O=CO
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(NN)cc21
Solvent: ClCCl
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(NNC=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Formic acid (0.157 ml, 4.09 mmol) was added to 2,2,7-trifluoro-6-hydrazinyl-4-(prop-2-ynyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (the product of Step 1.7 above, 1.0 g, 3.69 mmol) in dichloromethane at room temperature under stirring. The mixture was then stirred overnight at room temperature. The resulting precipitate was isolated over a glass filter and washed with diisopropyl either to yield 858 mg of product (>95% purity), which was used without further purification.