Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[CH:11]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:10]2[CH2:21][CH2:22][CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1.C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[C:15]1([S:12]([C:11]2[CH:10]3[CH2:21][CH2:22][CH:3]([CH:2]=2)[C:4]2[C:9]3=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:14])=[O:13])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(c1ccccc1)C1C2CCC(c3ccccc32)C1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=S(=O)(C1=CC2CCC1c1ccccc12)c1ccccc1
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
A solution of 0.3 g (0.91 mmol) of the obtained 2-chloro-1,2,3,4-tetrahydro-3-phenylsulfonyl-1,4-ethanonaphthalene and 15 ml of anhydrous THF was cooled to 0° C., added with 2.5 ml of 1,8-diazabicyclo[5.4.0]-7-undecene and stirred for 30 minutes. The solution is then added with a dilute hydrochloric acid solution, extracted with chloroform, washed with distilled water, an aqueous saturated sodium bicarbonate solution and saturated saline and dried with anhydrous sodium sulfate. The product was purified with silica gel column chromatography (chloroform) to obtain 1,4-dihydro-2-phenylsulfony-1,4-ethanonaphthalene (0.264 g, 0.89 mmol, yield: 98%).
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21]>C(O)C>[CH2:24]([O:23][C:19]([CH2:20][CH2:21][NH:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:22])[CH3:25]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C(C)C(N)Cc1ccccc1OC
Solvent: CCO
Product: CCOC(=O)CCNC(Cc1ccccc1OC)C(C)C(=O)OCC
Yield: 99.6 %

Procedure:
148 g (0.6 mol) of ethyl 3-amino-4-(2-methoxyphenyl)-2-methylbutanoate 13 and 119 g (1.2 mol) of ethyl acrylate are dissolved in 250 mL of abs. ethanol and refluxed for 6 h. Then the mixture is concentrated by evaporation in vacuo. The residue is again taken up in 300 mL of toluene and once more concentrated by evaporation in vacuo. 210 g (100%) of the desired product are isolated as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]#[N:7])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(#N)C>[CH2:19]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:1][CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1cc(C#N)cc(C)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
3-Ethyl-4-hydroxy-5-methyl-benzonitrile (6.0 g, 37 mmol) is dissolved in acetonitrile (80 mL) and K2CO3 (10.1 g, 73 mmol) and benzyl bromide (6.56 g, 38 mmol) are added. The resulting suspension is stirred at 60° C. for 18 h, then water is added (100 mL) and the org. phase is collected. The aq. phase is extracted with EtOAc (100 mL) and the combined org. extracts are washed with water followed by brine, dried over MgSO4, filtered, evaporated and purified by CC (eluting with Heptane/EtOAc 9:1) to give 4-benzyloxy-3-ethyl-5-methyl-benzonitrile as a yellow oil (7.02 g); LC-MS: tR=1.11 min, [M+H]+=293.16.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:3]([C:4]([OH:6])=[O:5])=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Reactant: OB(O)c1ccccc1F
Product: CS(=O)(=O)c1ccc(-c2ccccc2F)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example B25 from 2-Iodo-5-methanesulfonyl-benzoic acid (example B19(b)) and 2-fluorobenzeneboronic acid. Light brown solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[C@H:30]([OH:43])[CH2:29]1.C(OC([N:51]1[CH2:55][CH2:54][C:53]([C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)([C:56](O)=[O:57])[CH2:52]1)=O)(C)(C)C>C(Cl)Cl>[Cl:65][C:62]1[CH:63]=[CH:64][C:59]([C:53]2([C:56]([N:40]3[CH2:39][CH2:38][N:37]([C:35]4[C:36]5[C@H:28]([CH3:27])[CH2:29][C@@H:30]([OH:43])[C:31]=5[N:32]=[CH:33][N:34]=4)[CH2:42][CH2:41]3)=[O:57])[CH2:54][CH2:55][NH:51][CH2:52]2)=[CH:60][CH:61]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)C4(c5ccc(Cl)cc5)CCNC4)CC3)c21
Temperature: 25 °C
Reaction time: 10 h
Yield: 80.8 %

Procedure:
HBTU (37 mg, 0.098 mmol) was added to a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (30 mg, 0.098 mmol) and 1-(tert-butoxycarbonyl)-3-(4-chlorophenyl)pyrrolidine-3-carboxylic acid (32 mg, 0.098 mmol) in DCM (5 mL) and TEA (1 mL). The mixture was stirred at room temperature for 10 hours. The solvent was removed, and the residue was subjected to column chromatography, eluted by ethyl acetate-DCM/MeOH (20:1). The product was treated with HCl (4M, 2 mL) in DCM (5 mL) to afford (3-(4-chlorophenyl)pyrrolidin-3-yl)(4-((5R,7R) -7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone as the HCl salt (35 mg, 81%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].FC(F)(F)S(O[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.O>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C=O)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To 400 mg (2.67 mmol) of 4-formyl-phenylboronic acid diluted in a dimethoxyethane/water mixture (40 ml/4 ml) are respectively added 1.33 g (5.78 mmol) of tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate, 154 mg (0.133 mmol) of palladium tetrakistriphenylphosphine and 1.74 g (5.34 mmol) of cesium carbonate. The solution is purged under argon then stirred at 80° C. for 18 h and filtered on Celite with ethyl acetate. The filtrate is washed with water, then with sodium chloride saturated solution, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 85:15 to 70:30) to yield 677 mg of tert-butyl 4-(4-formylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:13])[S-:12].C([NH+](CC)CC)C.[C:21]([O:24][CH2:25][C:26]([CH2:28]Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:12])[S:13][CH2:28][C:26](=[O:27])[CH2:25][O:24][C:21](=[O:23])[CH3:22]
Reactant: CC(=O)OCC(=O)CCl
Reactant: Fc1ccc(NC(=S)[S-])c(F)c1F
Agent: CC[NH+](CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)CSC(=S)Nc1ccc(F)c(F)c1F
Reaction time: 0.17 h
Yield: 64 %

Procedure:
Triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (2.15 g) prepared in the same manner as in Reference Example 1 was added to methylene chloride (30 ml) and thereto 1-acetoxy-3-chloroacetone (1.0 g) was added dropwise at 2° to 7° C. with stirring over a period of 10 minutes. The mixture was stirred for 20 minutes and washed with 3N hydrochloric acid and then with water. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane-ethyl acetate to give the title compound (1.43 g) as colorless crystals.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([S:15][C:16]([S:18][C@H:19]([CH3:35])[CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])=[S:17])[NH:13][C:12]1=[O:36])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[C:38]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=1)(=[O:41])[CH:39]=[O:40].CC(C)=O>C1C=CC=CC=1.CCCCCC>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([S:15][C:16]([S:18][C@H:19]([CH3:35])[CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=2)=[O:23])=[S:17])[N:13]([CH:39]([OH:40])[C:38]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([N+:50]([O-:52])=[O:51])=[CH:48][CH:49]=2)=[O:41])[C:12]1=[O:36])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H](CNC(=O)OCc1ccc([N+](=O)[O-])cc1)SC(=S)S[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: O=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C[C@H](CNC(=O)OCc1ccc([N+](=O)[O-])cc1)SC(=S)S[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 85.6 %

Procedure:
(3S, 4R)-3-[(R)-1-t-Butyldimethylsilyloxyethyl]-4-[(R)-1-methyl-2-(p-nitrobenzyloxycarbonylamino)ethylthio(thiocarbonyl)]thioazetidin-2-one (10.8 g, 18.8 mmole) and p-nitrobenzyl glyoxylate hydrate (8.53 g, 37.6 mmole) were refluxed in benzene (100 ml) for 20 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was purified by column chromatography (150 g of silica gel), eluted first with a 15% v/v solution of acetone in hexane, giving some unchanged starting compound (1.62 g, 15%), and then with a 30% v/v solution of acetone in hexane, giving the desired compound (12.6 g, 85%) in the form of a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([CH3:13])[CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:41]=[N+:42]=[N-:43])(=O)=O)(C)C.C(O)(=O)C>C1COCC1>[N:41]([C@@H:10]1[CH2:11][C@@H:12]([CH3:13])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:14])=[N+:42]=[N-:43]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: C[C@@H]1CCC(=O)N1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](N=[N+]=[N-])C(=O)N1Cc1ccccc1
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
To a solution of 13-3 (2.2 g, 11.6 mmol) in THF (45 mL) at -78° C. was added a solution of LDA (6.39 mL, 12.8 mmol; 2M/THF, ethylbenzene). The mixture was warmed to -15° C. for 20 minutes, then recooled to -78° C., and 2,4,6-triisopropylbenzenesulfonyl azide (4.31 g, 13.9 mmol, prepared as described in Harmon, et al, J. Org. Chem. 1973, 38, 11-16. ) was added rapidly as a solution in 40 mL THF at -78° C. After 10 minutes, glacial acetic acid (2.67 mL, 47 mmol) was added, and the resultant viscous liquid mixture allowed to warm to ambient temperature and stir for 1 hour. The solvent was then evaporated, the residue dissolved in CHCl3, washed with NaHCO3 (sat.), and dried over magnesium sulfate. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 25% ethyl acetate/hexanes) to give 13-4 as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[CH2:11][CH2:10][NH:9][CH2:8]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>C1COCC1>[C:42]([O:41][C:39]([CH2:38][N:9]1[CH2:8][C:7]2([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Br:1])=[CH:3][CH:4]=3)[N:12]([C:13](=[O:25])[N:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:15]2=[O:16])[CH2:11][CH2:10]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CNCCN12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Reaction time: 40 h

Procedure:
To a solution of 6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.11 g) in THF (5 mL) was added DIEA (0.1 mL) and tert-butyl bromoacetate (0.06 mL). Additional tert-butyl bromoacetate (0.040 mL) was added after 16 hours. After 40 hours, the reaction mixture was concentrated and the residue was diluted with EtOAc and washed with water, NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/5, Chromatotron) afforded the titled compound (0.124 g). MS (m/z) 582 (MH+). mp 74.7° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](NC(=O)[C@@H](N2C(=O)[C@@H](C3C=CC(OC)=CC=3)NC2=O)CC2C=CC([N+]([O-])=O)=CC=2)[S:8][CH:9]=1)=[O:4].C([O-])(=O)C.[Na+].C=O>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccc([N+](=O)[O-])cc2)N2C(=O)N[C@H](c3ccc(OC)cc3)C2=O)n1
Agent: [Pd]
Agent: C=O
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: COC(=O)c1cscn1
Reaction time: 72 h
Yield: 83.8 %

Procedure:
To a solution of 2-[(S)-2-[(R)-4-(4-methoxy-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (53.9 mg, 0.1 mmol) in tetrahydrofuran (10 mL) was added sodium acetate (60 mg, 0.44 mmol), 37% w/w aqueous formaldehyde solution (0.033 mL, 0.44 mmol) and 10% palladium on carbon (30 mg) and the mixture shaken under an atmosphere of hydrogen at 50 psi pressure in a Parr apparatus for 72 hours. The reaction mixture was filtered through a pad of Celite® and washed through with additional tetrahydrofuran. The filtrate was concentrated in vacuo, the residue was dissolved in dichloromethane, washed with water, saturated aqueous sodium bicarbonate, dried with sodium sulfate and concentrated in vacuo to give the crude product as a yellow solid. Purification by reverse phase HPLC using a C18 stationary phase gradient eluted from 10% up to 90% acetonitrile in water gave 2-(S)-3-(4-dimethylamino-phenyl)-2-[(R)-4-(4-methoxy-phenyl)-2,5-dioxo-imidazolidin-1-yl]-propionylamino}-thiazole-4-carboxylic acid methyl ester as a colorless solid (12 mg, 22%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>O>[N+:9]([C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)cc1
Solvent: O
Product: Cc1ccc(C)c([N+](=O)[O-])c1

Procedure:
A mixture of p-xylene (25 ml), and Fe3+ montmorillonite or Zn2+ montmorillonite (0.5 g) were taken in a 50 ml two-necked round-bottomed flask equipped with Dean-Stark apparatus. Fuming nitric acid (5 ml) was added dropwise into the reaction mixture. The reaction mixture was heated to reflux where upon the required amount of liberated water was collected in the Dean-Stark apparatus which usually takes 1.5 hr. Later on, the catalyst was filtered and the reaction mixture was concentrated to obtain the nitro p-xylene.
Reaction SMILES: Cl.N[C@H]1C(=O)NC2C=CC=CC=2OC1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([NH:27][C@@H:28]1[C:34](=[O:35])[NH:33][C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[O:30][CH2:29]1)=[O:26])=[CH:19]2.Cl.N[C@@H]1C(=O)NC2C=CC=CC=2OC1>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([NH:27][C@H:28]1[C:34](=[O:35])[NH:33][C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[O:30][CH2:29]1)=[O:26])=[CH:19]2
Reactant: O=C(N[C@H]1COc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Agent: N[C@@H]1COc2ccccc2NC1=O
Agent: N[C@H]1COc2ccccc2NC1=O
Product: O=C(N[C@@H]1COc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
The title compound was prepared from (R)-3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one hydrochloride salt by the procedures described for the preparation of (S)-3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (Example 20) from (S)-3-amino-2,3dihydro-1,5-benzoxazepin-4(5H)-one hydrochloride salt. HPLC/MS [M+H]+, 356.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([C:12](OCC)=[O:13])=[CH:8][C:7]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:6]2)[CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([C:12](=[O:13])[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:8][C:7]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[N:6]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC2CC2)c1=O
Reactant: Nc1ccccc1
Product: COc1ccc(-c2cc(C(=O)Nc3ccccc3)c(=O)n(CC3CC3)n2)cc1
Yield: 12.2 %

Procedure:
2-Cyclopropylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and aniline were processed as in Example 70, whereby the title compound was obtained in a yield of 12.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:26]=1[CH3:36])=O.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:26]=1[CH3:36])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one(1 g, 2.82 mmol), 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (548 mg, 1 eq.) and piperidine (0.416 mL, 1.5 eq.) in ethanol (5 mL) was stirred at rt for 5 days. The reaction was concentrated, acidified with 2M HCl (pH 3), stirred for 15 mins, diluted with water and filtered. The solid was washed with water and triturated with ethanol to give the titled compound as a pale orange solid.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[C:20]([O:22][CH3:23])=[O:21])=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11](=[O:19])[C:10]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1c(NCc2ccc(OC)cc2)c2ccccc2[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(N)c2ccccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
Methyl 4-(4-methoxybenzylamino)-2-oxo-1,2-dihydroquinoline-3-carboxylate (Example 68a) (0.841 g, 2.49 mmol) was dissolved in TFA (5 mL) and stirred at room temperature for 30 minutes. The TFA was removed under reduced pressure, and the residue was dissolved in dichloromethane, then precipitated out by adding excess diethyl ether. The resultant solid was collected by filtration, suspended in dichloromethane, and washed with concentrated sodium bicarbonate. The solid was collected to give methyl 4-amino-2-oxo-1,2-dihydroquinoline-3-carboxylate (0.230 g, 42%) as a white solid. M.p.: 236° C. 1H NMR (400 MHz, DMSO-d6) δ 3.73 (s, 3H), 7.12 (t, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.38 (bs, 2H), 10.88 (bs, 1H). MS 219 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)[CH2:14][CH2:13][C:12]2=[O:28])C.[OH-].[K+].CO>O>[O:28]=[C:12]1[C:11]2[C:15](=[CH:16][C:17]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=3)=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3])[CH:10]=2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)CCCOc1cc2c(cc1-c1ccc(C(F)(F)F)cc1)CCC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCOc1cc2c(cc1-c1ccc(C(F)(F)F)cc1)CCC2=O

Procedure:
1.2 g (3 mmol) of ethyl4-[3-oxo-6-(4-trifluoromethylphenyl)indan-5-yloxy]butyrate are mixed with 250 mg (45 mmol) of potassium hydroxide, 40 ml of methanol and 10 ml of water. The mixture is heated at reflux for 2 hours and the methanol is then evaporated off. The solution obtained is washed with ether; the aqueous phase is acidified and extracted with dichloromethane. The organic phase is dried (Na2SO4) and the solvents are evaporated off: yellow solid (0.95 g). Purification of the compound by flash chromatography (98/2 dichloromethane/methanol) [lacuna] (0.56 g; 50%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl.N.CO.O>[Fe].CC(=O)OCC>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(O[C@H]4CCOC4)c([N+](=O)[O-])cc23)c1
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: C#Cc1cccc(Nc2ncnc3cc(O[C@H]4CCOC4)c(N)cc23)c1
Temperature: 70 °C
Yield: 47.2 %

Procedure:
(S)—N-(3-ethynylphenyl)-6-nitro-7-(tetrahydrofuran-3-yloxy)quinazolin-4-amine (4 g, 0.011 mol) and ammonia hydrochloride (2.4 g, 0.045 mol) was mixed in a solution of 150 mL methanol, 75 mL H2O, 50 ml EA, and then was heated to 70° C. Fe (4.8 g, 0.085 mol) was added and the reaction mixture was heated to reflux for 4 hours. The resulting reaction solution was filtered and concentrated under reduced pressure to remove most of solvent. The residue was diluted in 100 mL H2O, extracted with ethyl acetate (3×100 mL), the organic layers were concentrated to give (S)—N4-(3-ethynylphenyl)-7-(tetrahydrofuran-3-yloxy)quinazoline-4,6-diamine as grey solid 1.8 g (48.9% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1(C)C=CC(S([N:16]2[C:32]3[C:19]4=[C:20]([CH:29]=[CH:30][CH:31]=3)[C@H:21]3[O:26][CH2:25][C:24](=O)[NH:23][C@@H:22]3[CH2:28][C:18]4=[CH:17]2)(=O)=O)=CC=1.O>O1CCCC1>[CH:29]1[C:20]2[C@H:21]3[O:26][CH2:25][CH2:24][NH:23][C@@H:22]3[CH2:28][C:18]3[C:19]=2[C:32]([NH:16][CH:17]=3)=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(cccc42)[C@H]2OCC(=O)N[C@@H]2C3)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1cc2c3c(c[nH]c3c1)C[C@H]1NCCO[C@H]21
Yield: 41.6 %

Procedure:
To a stirred slurry of lithium aluminum hydride (3.0 gms) in tetrahydrofuran (200 ml) is added trans-4-(p-tolylsulphonyl)-4,6,6a,8,9,10a hexahydro-7H-indolo-[3,4-gh]-[1,4]-benzoxazin-8-one (3.0 gms) in portions over 5 minutes. The resulting mixture is refluxed for 17 hours. The cooled slurry is hydrolyzed with water (6 ml), and the organic phase is separated from the solid inorganics by filtration. The solid is rinsed with ether (3×100 ml). The organic solvents are dried over anhydrous sodium sulfate. After filtration, the solvents are removed under reduced pressure (20 mm). The resulting oil is purified by column chromatography silica; CHCl3 (sat. with NH4OH) to yield 700 mg of trans 4,6,6a,8,9,10a-Hexahydro-7H-indolo-[3,4 gh]-[1,4]-benzoxazine; which after recrystalization from methanol gives 540 mg (25%) m.p. 175°-177° C. with previous softening.