Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[Br:8].CN(C)C1C=CC=CC=1.[Br:20][CH2:21][C:22](Br)=[O:23]>C(Cl)Cl>[Br:10][C:3]1[C:2]([NH:1][C:22](=[O:23])[CH2:21][Br:20])=[C:7]([Br:8])[CH:6]=[C:5]([CH3:9])[N:4]=1
Reactant: O=C(Br)CBr
Reactant: Cc1cc(Br)c(N)c(Br)n1
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Cc1cc(Br)c(NC(=O)CBr)c(Br)n1
Reaction time: 0.08 h
Yield: 85 %

Procedure:
3-Amino-2,4-dibromo-6-methylpyridine (1.16 g, 4.38 mmol) was dissolved in methylene chloride (10 mL). N,N-dimethylaniline (0.77 g, 6.35 mmol) was added to the solution and then a solution of bromoacetyl bromide (1.03 g, 5.12 mmol) in dichloromethane (2 mL) was added dropwise thereto over 5 minutes with stirring and cooling with ice. After completion of addition, the temperature of the mixture was elevated to room temperature and stirred for 12 hours. The resultant mixture was washed sequentially with water, an aqueous saturated sodium hydrogencarbonate solution, and saturated brine. Subsequently, the mixture was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was crystallized from hexane-acetone, to thereby yield 1.44 g of N-[2,4-dibromo-6-methylpyridin-3-yl]-2-bromoacetamide as colorless crystals (yield 85.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH:5]=[N:6][OH:7].[Cl:12]N1C(=O)CCC1=O>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([Cl:12])=[N:6][OH:7])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)c1ccc(Cl)c(Cl)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 132.7 %

Procedure:
The title compound of Step A (3.7 g) was dissolved in 100 mL of dimethylformamide and 2.6 g of N-chlorosuccinimide was added. The reaction mixture was stirred at about 30° C. for 2 h and then at room temperature overnight. The mixture was diluted with 200 mL of water and extracted with three 100 mL portions of diethyl ether. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give 5.8 g of the title compound of Step B as an oil. 1H NMR (CDCl3): δ 10.41 (s,1H), 7.95 (d,1H,J=2 Hz), 7.69 (dd,1H,J=2, 8 Hz), 7.46 (d,1H,J=8 Hz). The crude oil also contained DMF. The crude material was triturated in hexane and collected by filtration to yield 5.2 g of white solid, still containing DMF, which was used in the next step without additional purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Br[C:11]1[CH:20]=[N:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:17]2[CH:18]=[N:19][CH:20]=[CH:11][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccncc1Br
Product: COC(=O)c1ccncc1NCc1ccc(Cl)cc1
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield from 4-chlorobenzylamine and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 7.94 (d, 1H, J=5.0 Hz), 7.82 (br s, 1H), 7.62 (d, 1H, J=5.0 Hz), 7.24-7.32 (m, 4H), 4.47 (d, 2H, J=5.7 Hz), 3.89 (s, 3H). [M+H] calc'd for C14H13ClN2O2, 277, 279. found 277, 279.
Reaction SMILES: Br[C@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[C@@H:3]1OC(=O)C.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)C=O.O>[N:27]([C:18]1[C:17](=[O:20])[CH:16]=[CH:15][C@@:14]2([CH3:21])[C:19]=1[CH:2]=[CH:3][C@@H:4]1[C@@H:13]2[CH2:12][CH2:11][C@@:9]2([CH3:10])[C@H:5]1[CH2:6][CH2:7][C:8]2=[O:22])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O[C@H]1[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C2[C@@H]1Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12C=CC(=O)C(N=[N+]=[N-])=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 100 °C
Yield: 73 %

Procedure:
To a stirred solution of 0.5 g of 6β-bromo-7α-acetoxyandrosta-1,4-dien-3,17-dione in 30 ml of dimethylformamide and 1.2 ml of water are added 0.11 g of sodium azide. The reaction mixture is heated at 100° C. for 45 minutes, cooled, poured into 500 ml of iced water and extracted with ethyl acetate. The combined extracts are washed with water, dried over sodium sulphate, filtered and evaporated in vacuo to give a residue which is purified by column chromatography on silica gel. Elution with n-hexane:ethyl acetate 70:30 yields 0.28 g of the title compound, m.p. 123°-125° C. (dec.);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH2:26][CH:27]([OH:30])[CH2:28][OH:29]>>[OH:30][CH:27]([CH2:28][OH:29])[CH2:26][NH:25][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[CH:5]=1
Reactant: NCC(O)CO
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Product: COc1ccc(C(=O)NCC(O)CO)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 3-amino-1,2-propanediol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.B(O)(O)[C:33]1[S:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[S:41]1[C:33]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:13])=[O:14])[CH:9]=3)[NH:4][N:3]=2)=[CH:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:40]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1
Yield: 35.8 %

Procedure:
N-(3-Benzo[b]thiophen-2-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 0.5 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 300 mg of thianaphthene-2-boronic acid, 20 ml of dimethylformamide, 1.9 ml of a saturated aqueous solution of sodium hydrogencarbonate and 25 mg of tetrakis(triphenylphosphine)palladium[0]. 150 mg of N-(3-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 270° C. (analysis C22H17N3O4S3 % calculated C, 54.64; H, 3.54; N, 8.69; O, 13.23; S, 19.89. % found C, 54.59H: 3.47; N, 8.79; S, 19.98).
Reaction SMILES: Cl[P:2]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[O:3][CH2:4][CH3:5].[NH2:17][CH:18]1[CH2:23][S:22][C@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([CH2:30][C:31]([O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])=[O:32])[C:19]1=[O:40]>>[CH2:4]([O:3][P:2]([NH:17][CH:18]1[CH2:23][S:22][C@H:21]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:20]([CH2:30][C:31]([O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])=[O:32])[C:19]1=[O:40])([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])[CH3:5]
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Reactant: C[Si](C)(C)CCOC(=O)CN1C(=O)C(N)CS[C@@H]1c1ccccc1
Product: CCOP(=O)(CCCCc1ccccc1)NC1CS[C@H](c2ccccc2)N(CC(=O)OCC[Si](C)(C)C)C1=O

Procedure:
Chloro(4-phenylbutyl)phosphinic acid, ethyl ester is reacted with (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethylsilylethyl ester according to the procedure of Example 1(f) to yield (R)-dihydro-5-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethylsilylethyl ester.
Reaction SMILES: C(O[C:4](=[O:17])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8]CC)=O)C.S(O)(O)(=O)=O.[NH2:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:11]1([C:5]2[C:4]([OH:17])=[N:23][C:24]3[N:25]([CH:26]=[CH:27][N:28]=3)[C:6]=2[OH:8])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: Nc1ncc[nH]1
Agent: O=S(=O)(O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Oc1nc2nccn2c(O)c1-c1ccccc1

Procedure:
18.3 g (0.0776 mol) diethylphenylmalonate and 20.5 g (0.0776 mol) 2-aminoimidazole sulfate are dissolved in 93 ml DMF and 35 ml DBU and the mixture heated to 100° C. for 15 h. The solvent is removed, the residue dissolved in water and re-precipitated by adjusting the pH to 1 with 2 mol/l HCl. The precipitate is collected by filtration to obtain the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH3:18])=[CH:6]2.[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].O>CN(C)C=O>[C:19]([O:22][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH3:18])=[CH:6]2)(=[O:21])[CH3:20]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1nc2ccc(CBr)cc2cc1C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2ccc(COC(C)=O)cc2cc1C
Reaction time: 24 h
Yield: 69.3 %

Procedure:
To a solution of ethyl 6-bromomethyl-3-methylquinoline-2-carboxylate (700 mg) in dimethylformamide (7 ml) was added sodium acetate (373 mg) at ambient temperature, and the mixture was stirred for 24 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (n-hexane:ethyl acetate=1:2, V/V) to give ethyl 6-acetoxymethyl-3-methylquinoline-2-carboxylate (452 mg) as an oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:20]=[N:19][C:14]3[O:15][CH2:16][CH2:17][NH:18][C:13]=3[CH:12]=2)=[CH:3][N:2]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].C(N(CC)CC)C.Cl>ClCCl>[Br:21][C:22]1[CH:23]=[C:24]([C:25]([N:18]2[CH2:17][CH2:16][O:15][C:14]3[N:19]=[CH:20][C:11]([C:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=[N:2][CH:3]=4)=[CH:12][C:13]2=3)=[O:26])[CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32]
Reactant: c1ccc2c(-c3cnc4c(c3)NCCO4)cncc2c1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cncc5ccccc45)cc32)cc1Br
Reaction time: 3 h
Yield: 23.3 %

Procedure:
Under nitrogen atmosphere, in a 10 ml flask, 7-isoquinolin-4-yl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (22.6 mg, 0.085 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (42.2 mg, 0.129 mmol) were dissolved in dichloromethane (1.0 ml). After cooling to 0□, triethylamine (0.06 ml, 0.429 mmol) was added thereto at room temperature for 3 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of ethyl acetate and n-hexane. The fractions containing the product were collected and evaporated to obtain white solid (11.0 mg, 23%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:18])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:4][CH:3]=1.Br[CH:20]([CH3:28])[C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:20]([CH3:28])=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:18]=[C:9]2[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)C(C)Br
Reactant: N=C(Nc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Br)cc2)c1C
Temperature: 100 °C
Reaction time: 12 h
Yield: 47.2 %

Procedure:
To a magnetically stirred solution of above imidamide from step A (2.45 g, 7 mmol) in 30 mL anhydrous toluene were added ethyl 3-bromo-2-oxobutanoate (1.48 g, 7 mmol) and Na2CO3 (0.74 g, 7 mmol). The contents were stirred at 100° C. for 12 hours. The reaction was brought to RT. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined extracts were dried over anhydrous MgSO4, filtered and evaporated under reduced pressure. Purification by column chromatography gave the ester as pale white solid (1.5 g, 46.4%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)=[O:5])[CH3:2].Br[CH2:19][CH2:20][CH2:21][Cl:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:16]=[C:15]([O:17][CH2:19][CH2:20][CH2:21][Cl:22])[CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(=O)c2ccc(OCCCCl)cc2o1
Yield: 72.4 %

Procedure:
A mixture of 23.4 g (0.1 mole) of 7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester, 31.6 g (0.2 mole) of 1-bromo-3-chloropropane and 41.5 g (0.3 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 20 hr. The mixture was cooled and filtered through Celite®. The filtrate was concentrated under reduced pressure to give a solid residue. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration, and recrystallized from 2-propanol to yield 22.5 g (73%) of white solid, m.p. 107°-108° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.[I-:19].[K+].C1(C)C=CC=CC=1.Cl>CN(C)P(N(C)C)(N(C)C)=O.[Cu]I>[I:19][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1
Reactant: CN1CCN(c2cccc3cc(Br)cnc23)CC1
Reactant: [I-]
Agent: [Cu]I
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN1CCN(c2cccc3cc(I)cnc23)CC1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
A mixture of 3-bromo-8-(4-methyl-piperazin-1-yl)-quinoline (D1)(1.75 g, 5.7 mmol), copper (I) iodide (5.4 g, 28.5 mmol) and potassium iodide (9.6 g, 57.8 mmol) in hexamethylphosphoramide (20 ml) was heated in an oil bath at 150° C. for 21 h under argon. To the cooled reaction mixture was added toluene (120 ml) and 1M hydrochloric acid (120 ml) and the whole was shaken vigorously for 5 minutes. The insoluble brown solid was then collected by filtration, washed with methanol (3×40 ml) and resuspended in a mixture of dichloromethane (150 ml) and 2M sodium hydroxide (150 ml). After shaking the mixture vigorously, the insoluble material was filtered, washed with dichloromethane (2×50 ml) and discarded. The filtrate and washings were transferred to a separating funnel and the layers were separated. The aqueous phase was extracted with dichloromethane (2×100 ml) and the combined organic extracts were dried (MgSO4) and concentrated to a brown oil (1.5 g) which was identified by NMR spectroscopy as a mixture of the title compound (D2) and 3-bromo-8-(4-methyl-piperazin-1-yl)-quinoline (D1) in a ratio of 4:1. This mixture was used directly in the next stage (see Example 1).
Reaction SMILES: C(OC([N:8]1[CH2:40][C@@H:39]2[C@@H:10]([CH2:11][C:12]3[N:13]([CH2:38]2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]=3[C:21]2[C:22](=[O:37])[O:23][C:24](=[O:36])[C:25]=2[C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:35])[CH:27]=2)[CH2:9]1)=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH2:9]1[C@@H:10]2[CH2:11][C:12]3[N:13]([CH2:38][C@@H:39]2[CH2:40][NH:8]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=1[C:20]=3[C:21]1[C:22](=[O:37])[O:23][C:24](=[O:36])[C:25]=1[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH3:35])[CH:27]=1
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@@H]3C4)C(=O)OC2=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)C[C@@H]3CNC[C@@H]3C4)C(=O)OC2=O)c2ccccc21

Procedure:
A stirred solution of 5 g of cis-3-[2-(tertbutoxycarbonyl)-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]-pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione [prepared as described in Example 5(viii)] in 200 ml of dichloromethane was treated with 30 ml of trifluoroacetic acid. After 0.5 hour the solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel using dichloromethane/methanol/acetic acid/water (90:18:3:2) for the elution. Removal of the solvent gave 4.5 g of cis-3-[2,3,3a,4,11, 11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione trifluoroacetate of melting point 199°-201° C.
Reaction SMILES: ClCCl.[NH2:4][CH2:5][C:6]([CH3:9])([OH:8])[CH3:7].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]>C(N(CC)CC)C>[CH3:7][C:6]([OH:8])([CH3:9])[CH2:5][NH:4][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(O)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
To a stirred solution of 150 mL of dichloromethane, 10 mL of triethylamine and 6.7 g (0.075 mole) of 1-amino-2-methyl-2-propanol was added 10.4 g (0.05 mole) of 4-chloro-3-nitroquinoline. The solution was heated on a steam bath for about one hour then evaporated to remove the solvent. The residue was dissolved in dilute hydrochloric acid and filtered. The filtrate was made basic with concentrated ammonium hydroxide to reprecipitate the product. The product was separated by filtration and recrystallized twice from ethanol to provide the novel yellow solid 2-methyl-1-[(3-nitro-4-quinolinyl)amino]-2-propanol, m.p. 244°-246° C. (dec.). Analysis: Calculated for C13H15N3O3 : %C, 59.8; %H, 5.8; %N, 16.0; Found: %C, 59.8; %H, 5.9; %N 16.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[C:5]([F:17])=[CH:4][C:3]=1[N:18]1[C:22](=[O:23])[CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]1.[C:27](N1C=CN=C1)([N:29]1C=CN=C1)=O.CN>>[CH3:27][NH:29][C:24]([CH:20]1[CH2:21][C:22](=[O:23])[N:18]([C:3]2[CH:4]=[C:5]([F:17])[C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)=[CH:7][C:2]=2[F:1])[CH2:19]1)=[O:26]
Reactant: O=C(O)C1CC(=O)N(c2cc(F)c(OCc3cccc(F)c3)cc2F)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Product: CNC(=O)C1CC(=O)N(c2cc(F)c(OCc3cccc(F)c3)cc2F)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A solution of 365 mg (1.0 mmol) of (RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid is treated with 178 mg (1.1 mmol) of 1,1′-carbonyl-diimidazole, and the mixture is heated at 50° C. for 2 hours. Thereafter, the solution is cooled to RT and 47 mg (1.5 mmol) of methylamine (33% solution in ethanol) are added. After 18 hours the reaction is not complete, so that another 47 mg (1.5 mmol) of methylamine (33% solution in ethanol) are added and stirring is continued for 24 hours at 50° C. For the working-up, the reaction mixture is evaporated under reduced pressure. For purification, the material obtained is chromatographed on silica gel using a 95:5-mixture of dichloromethane and methanol as the eluent. There are obtained, after crystallization from ether, 136 mg (36% of theory) of the (RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide as an off-white solid. MS: m/e=379 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Br:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][C:18]=1[OH:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:20](OC=C)(=O)[CH3:21]>C1(C)C=CC=CC=1>[Br:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][C:18]=1[O:19][CH:20]=[CH2:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: C=COC(C)=O
Reactant: CCOC(=O)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COc1ccc(C(=O)OCC)cc1Br
Temperature: 100 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a toluene (8 mL) solution of [IrCl(cod)]2 (54 mg, 0.08 mmol) and sodium carbonate (506 mg, 4.8 mmol) was added ethyl 3-bromo-4-hydroxybenzoate (CAS 37470-58-9) (1.95 g, 7.96 mmol) followed by vinyl acetate (1.5 mL, 15.9 mmol) under argon. The mixture was stirred at 100° C. for 2 hours. The mixture was cooled to room temperature, quenched with wet ether. Solid was filtered off and washed with ether. Column chromatography (3% ethyl acetate/hexane) gave ethyl 3-bromo-4-(vinyloxy)benzoate (1.77 g, 79%) as a yellow oil.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]1=[O:13].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C(N(C(C)C)CC)(C)C>O1CCOCC1>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]([N:1]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]2=[O:19])[C:3](=[O:13])[CH:4]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nn1c(=O)cc(O)c2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1n1c(=O)cc(O)c2ccccc21
Temperature: 100 °C
Yield: 65.3 %

Procedure:
A mixture of the product of Example 350A (0.54 g, 3 mmol), phthalic anhydride (1.36 g, 2.2 eq.) and diisopropylethylamine (1.97 g, 5 eq.) in dioxane (20 mL) was heated at 100° C. for 2 hours, cooled to 25C and concentrated. The residue was triturated with water and ether. The resulting solids were filtered and dried in vacuum to give the title compound (0.6 g, 64% crude yield) which was used directly for the next step. 1H NMR (300 MHz, DMSO-d6) δ 5.95 (s, 1H), 7.37 (m, 1H), 7.6 (m, 2H), 7.95-8.1 (m, 5H), 12.18 (s, 1H). MS (DCI+) m/z 306 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH:37]C(OC(C)(C)C)=O)[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:7]=1>C(O)=O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH2:37])[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nccs2)cc1)NC(=O)OC(C)(C)C)C(C)C
Solvent: O=CO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1)C(C)C

Procedure:
0.94 9 (1.5 mmol) of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane and 18 ml of formic acid are stirred at room temperature for 6 hours and worked up analogously to Example 2d to form the title compound: FAB MS (M+H)+ =526.