Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:7]=[C:6]([N:8](CC)CC)[CH:5]=[CH:4][C:3]=1[N:13]=[C:14]1[CH:23]=[CH:22][C:21](=[O:24])[C:20]2N=CC=C[C:15]1=2>O.C(O)C>[CH:23]1[C:14](=[N:13][C:3]2[CH:2]=[CH:7][C:6]([NH2:8])=[CH:5][CH:4]=2)[CH:15]=[CH:20][C:21](=[O:24])[CH:22]=1
Reactant: CCN(CC)c1ccc(N=C2C=CC(=O)c3ncccc32)c(C)c1
Solvent: CCO
Solvent: O
Product: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Then, a solution prepared by dissolving 285.3 mg of Ni(ClO4)2.6H2O in 50 ml of water, was added under a nitrogen atmosphere to a solution prepared by dissolving 100 mg of 5-(2'-methyl-4'-diethylaminophenylimino)quinoline-8-one obtained above in 50 ml of 99% ethanol, and the mixture was stirred at room temperature for about 30 minutes. Formed precipitates were subjected to suction filtration, washed with water and dried to obtain a metal-containing indoaniline compound having the formula: ##STR10##
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=O)=[CH:3][CH:2]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].N1CCCCC1>C(O)C>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[C:27]2[S:23][C:24](=[O:29])[NH:25][C:26]2=[O:28])=[CH:5][CH:6]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cccc(OCc3ccc(-c4ccccc4)cc3)c2)S1
Yield: 28.5 %

Procedure:
A mixture of the above benzaldehyde (500 g, 17 mmol), 2,4-thiazolidinedione (3.03 g, 26 mmol) and piperidine (0.35 ml, 3.5 mmol) in ethanol (75 ml) was stirred at reflux temperature for 16 h. The reaction mixture was cooled and the precipitated was filtered off and washed thoroughly with ethanol and dried in vacuo at 50° C. The solid was first washed with a mixture of ethyl acetate, heptane and dichloromethane (1:1:6, 40 ml) and then washed with dichloromethane (20 ml). Drying in vacuo at 50° C. afforded 1.88 g (28%) of the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24](Cl)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([C:48]4[CH:49]=[CH:50][C:45]([C:43]([O:42][CH3:41])=[O:44])=[CH:46][CH:47]=4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1c(C)nc(Cl)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(C)nc(-c2ccc(C(=O)OC)cc2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Yield: 72.8 %

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-chloro-6-methylpyrimidine-5-carboxylate (0.8 g, 1.63 mmol), K2CO3 (0.56 g, 4 mmol), Pd(PPh3)4 (0.28 g, 0.24 mmol) were dissolved in dioxane/water (20:1), 4-(methoxycarbonyl)phenylboronic acid (0.38 g, 2.1 mmol) was added the mixture was heated to 100° C. for 3 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography over silica gel using 30% EtOAc/hexanes as eluent to give the desired product (0.7 g). 1H NMR (400 MHz, DMSO-d6): δ 9.88 (s, 1H), 8.43 (d, J=8.0 Hz, 2H), 8.10 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.39 (q, J=6.8 Hz, 2H), 3.89 (s, 3H), 3.49 (s, 2H), 2.68 (m, 4H), 2.50 (s, 3H), 2.33 (m, 4H), 1.91 (t, J=6.8 Hz, 3H), 1.39 (s, 9H); MS m/z 590.2 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[O:15]1[C:19]2([CH2:24][CH2:23][CH:22]([CH:25]3[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]3)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:3]([C:4]1[CH:9]=[CH:8][C:7]([C@H:28]2[CH2:27][CH2:26][C@H:25]([CH:22]3[CH2:21][CH2:20][C:19]4([O:18][CH2:17][CH2:16][O:15]4)[CH2:24][CH2:23]3)[CH2:30][CH2:29]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Reactant: BrCCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1ccc([C@H]2CC[C@H](C3CCC4(CC3)OCCO4)CC2)cc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
4-Bromoethylbenzene (s4) (30.0 g) and THF (1,000 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. n-Butyllithium (1.57M in n-hexane; 124 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 4-(1,4-Dioxaspiro[4.5]decan-8-yl)-cyclohexanone (s5) (38.6 g) in THF (200 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The resulting reaction mixture was poured into a vessel containing an aqueous solution of ammonium chloride (500 ml) and ethyl acetate (500 ml), and mixed with them. The mixture was allowed to stand and separate into organic and aqueous layers, and the latter was extracted. The separated organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure. p-Toluenesulfonic acid (1.6 g) and toluene (300 ml) were added to the residue, and the mixture was heated to reflux for 2 hours, while distilled water was removed. After the reaction mixture had been cooled to 30° C., water (500 ml) and toluene (900 ml) were added and mixed with it. The mixture was allowed to stand and separate into two layers of organic and aqueous layers, and the latter was extracted. The organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The resulting solution was purified by fractionation using column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The product was dissolved in a mixed solvent of toluene (250 ml) and Solmix A-11 (250 ml), to which Pd/C (0.3 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The resulting residue was purified by fractionation using column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and by recrystallization from heptane, and then dried to give 8-(trans-4-(4-ethylphenyl)cyclohexyl)-1,4-dioxaspiro[4.5]decane (s6) (33.2 g). The yield based on the compound (s1) was 62.3%.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([O:10]CC)=O.O.[NH2:14][NH2:15]>CC(O)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([NH:14][NH2:15])=[O:10]
Reactant: CCOC(=O)[C@@H]1CCCC[C@H]1O
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: NNC(=O)[C@@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a one-liter four-necked flask were added 102.5 g (595 mmol) of ethyl (R,R)-2-hydroxycyclohexanecarboxylate and 400 mL of 2-propanol and stirring was started. Hydrazine monohydrate (44.7 g; 893 mmol) was dropped thereinto at 13° C. taking 30 minutes. After the dropping, the mixture was stirred at 80° C. for 9.5 hours. Followed by, heating was stopped and the mixture was cooled to room temperature to precipitate the crystals. The crystals were filtered and washed with a small amount of 2-propanol. The resulting crystals were dried to give 30.10 g of the title compound. The yield was 32%.
Reaction SMILES: [C:1]([CH:3]([O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])#[CH:2].[CH2:19]([SnH:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])/[CH:2]=[CH:1]/[CH:3]([O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:29][CH2:30][CH3:31]
Reactant: C#CC(CCCCCCCC)OC1CCCCO1
Reactant: CCCC[SnH](CCCC)CCCC
Product: CCCCCCCCC(/C=C/[Sn](CCCC)(CCCC)CCCC)OC1CCCCO1
Temperature: 110 °C

Procedure:
To 0.05 g (0.19 mmol) of the titled product of Example 8 is added 0.6 ml (0.22 mmol) of tri-n-butyltin hydride, and 20 mg of azoisobutyronitrile (AIBN). The reaction mixture was heated at 110° C. for 3 hours, whereupon thin layer chromatography indicated that the reaction was complete, producing the titled product. The product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:15](O)[CH2:16][OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1([O:17][CH2:16][CH2:15][O:13]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCCO
Reactant: COC(=O)CCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)CCC1(c2ccccc2)OCCO1

Procedure:
To a solution of 2.0 g of 3-benzoylpropionic acid methyl ester in 50 ml of dry benzene were added 0.7 ml of ethylene glycol and 0.01 g of anhydrous-p-toluene-sulfonic acid and the mixture was heated under reflux for 17 hours while removing water formed during the reaction by using a molecular sieve. After cooling, the reaction mixture was washed with a saturated sodium chloride aqueous solution, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene/hexane=1/1 by volume) to obtain 1.8 g of 4,4-ethylenedioxy-4-phenylbutyric acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.Br[CH2:23][CH:24]1[CH2:26][CH2:25]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[N:9]1[CH2:23][CH:24]1[CH2:26][CH2:25]1
Reactant: BrCC1CC1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3Cl)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccccc2Cl)n1CC1CC1
Temperature: 100 °C
Yield: 33 %

Procedure:
A mixture of (4S,7R)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 10; 154 mg, 0.51 mmol), tetrabutylammonium iodide (752 mg, 2.0 mmol), and (bromomethyl)cyclopropane (Lancaster; 195 μL, 2.0 mmol) in dimethylformamide (4.3 mL) was heated in an oil-bath at 100° C. for 16 h. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with water (5×100 mL) and aqueous sodium thiosulfate (100 mL). The solvent was evaporated and the residue was purified using an ISCO 120 g column, eluting with 65-100% ethyl acetate/hexanes to give (4S,7R)-2-(2-chloro-phenyl)-1-cyclopropylmethyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (60 mg, 33%) as a yellow gum. ES(+)-MS (M+H) 357.
Reaction SMILES: CN1C(=O)[C:5](=O)[CH:4]([C:9](F)(F)F)N1.[CH:13]([N:16]1[C:20](=[O:21])[C:19](=[O:22])[CH:18]([C:23]([F:26])([F:25])[F:24])[NH:17]1)([CH3:15])[CH3:14].C(N1C(=O)C(=O)C(C(F)(F)F)N1)C.FC(F)(F)C1C(=O)C(=O)NN1>>[C:13]1([N:16]2[C:20](=[O:21])[C:19](=[O:22])[CH:18]([C:23]([F:26])([F:25])[F:24])[NH:17]2)[CH:15]=[CH:9][CH:4]=[CH:5][CH:14]=1
Reactant: CC(C)N1NC(C(F)(F)F)C(=O)C1=O
Reactant: CN1NC(C(F)(F)F)C(=O)C1=O
Agent: CCN1NC(C(F)(F)F)C(=O)C1=O
Agent: O=C1NNC(C(F)(F)F)C1=O
Product: O=C1C(=O)N(c2ccccc2)NC1C(F)(F)F

Procedure:
1-methyl-3-trifluoromethyl-4,5-pyrazolinedione; 1-isopropyl-3-trifluoromethyl4,5-pyrazolinedione; 1-ethyl-3-trifluoromethyl-4,5-pyrazolinedione; 3-trifluoromethyl-4,5-pyrazolinedione;
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C@@H:27]2[CH2:31][CH2:30][C@@H:29]([NH2:32])[CH2:28]2)[CH:22]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][C@H:29]2[CH2:30][CH2:31][C@H:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: N[C@@H]1CC[C@@H](c2cccnc2)C1
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H]1COc2c(N[C@H]3CC[C@H](c4cccnc4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 91 °C
Reaction time: 7 h
Yield: 16.3 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (1.00 g, 3.61 mmol), (1R,3R)-3-(3-pyridyl)cyclopentylamine (702 mg, 4.33 mmol) and diisopropylethylamine (1.38 mL, 7.94 mmol) in anhydrous DMSO (18 mL) was stirred at 91° C. for 7 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[(1S,3S)-3-(3-pyridyl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (247 mg, 16%) as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:9])[CH:8]=1)[NH2:5].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[CH2:10]([NH:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:8]=[C:7]([Br:9])[CH:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cc(Br)cc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Brc1cc(Br)cc(NCc2ccccc2)c1
Yield: 69.5 %

Procedure:
The same procedure as described above was used in a scale up reaction where 3,5-dibromoaniline (273) (3.85 g, 15.35 mmol), benzaldehyde (274) (1.61 g, 15.35 mmol), Na(OAc)3BH (6.47 g, 30.7 mmol), AcOH (1.11 g, 18.42 mmol) and DCE (38 mL) were used. After 3 h reaction and purification (flash chromatography), benzyl-(3,5-dibromo-phenyl)-amine (275) (3.64 g, 10.67 mmol) was obtained in 69.6% isolated yield.
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[NH2:17][C@H:18]([C:26]([O-:28])=[O:27])[CH2:19]C1C=CC=CC=1.C([S+]1CCCC1)C1C=CC=CC=1.Cl>C(#N)C>[O:9]([C:1]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH3:19])=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)[O-]
Agent: Cl
Agent: c1ccc(C[S+]2CCCC2)cc1
Solvent: CC#N
Product: C[C@H](NC(=O)Oc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 428 mg (2 mmol) of diphenyl carbonate and 5 mL of acetonitrile were loaded into a round bottom flask having a volume of 100 mL, and then the mixture was stirred at room temperature. Next, 618 mg (2 mmol) of S-benzyltetrahydrothiophenium phenylalanine salt and 15 mL of acetonitrile were dropped to the solution, and then the mixture was stirred for 30 minutes. After that, a 1M aqueous HCl solution was added to the reaction solution to terminate the reaction, and then the resultant was concentrated with an evaporator. Next, water was added to the concentrated product, and then the resultant was extracted with ethyl acetate. The resultant organic layer was washed with water and brine, and was then dried with sodium sulfate. After that, the dried product was concentrated with an evaporator. Thus, a crude product was obtained. Next, the crude product was purified by column chromatography. Thus, N-phenoxycarbonyl-L-alanine was obtained. An isolation amount and an isolation yield were 456.2 mg and 80%, respectively.
Reaction SMILES: I[C:2]1[N:3]([CH3:13])[CH:4]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:6]=1.[CH3:14][C:15]1[S:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CN(C=O)C>[CH3:13][N:3]1[CH:4]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:6]=[C:2]1[C:18]1[S:19][C:15]([CH3:14])=[CH:16][CH:17]=1
Reactant: Cc1ccc(-c2cn(C)c(I)n2)s1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cn(C)c(-c3ccc(C)s3)n2)s1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A mixture of 2-iodo-1-methyl-4-(5-methylthiophen-2-yl)-1H-imidazole 6 (1.31 g, 4.31 mmol), 5-methylthiophene-2-boronic acid pinacol ester (1.35 g, 6.03 mmol), Na2CO3 (1.80 g, 17.2 mmol) in H2O (10 mL) and DMF (40 mL) was degassed (N2 bubbling). Pd(PPh3)4 (125 mg) was added and the mixture was heated to reflux for 5 h. The mixture was allowed to cool to room temperature and concentrated. The mixture was diluted with EtOAc and H2O and the organic phase was separated. The aqueous phase was re-extracted (EtOAc) and the combined organics were washed (saturated aqueous NaCl), dried (MgSO4), filtered and concentrated to give a residue. The residue was purified by flash chromatography (EtOAc/hexanes 10:90 then 15:85 then 20:80) to give 1-methyl-2,4-bis(5-methylthiophen-2-yl)-1H-imidazole 7 (930 mg, 79%) as a colourless solid. A portion of this material was further purified by, firstly, recrystallisation (EtOAc/hexanes) and, secondly, by sublimation (130° C., 10−6 mBar): m.p. 138-140° C. 1H NMR (CDCl3, 400 MHz) δ2.48 (d, J=0.7 Hz, 3H), 2.51 (d, J=0.7 Hz, 3H), 3.76 (s, 3H), 6.64-6.67 (m, 1H), 6.73-6.77 (m, 1H), 7.00 (s, 1H), 7.10 (d, J=3.4 Hz, 1H), 7.14 (d, J=3.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ15.2, 15.3, 34.5, 117.0, 122.1, 125.5, 125.6, 126.7, 136.3, 137.7, 141.5, 142.4; HRMS (EI) m/z 274.0589 C14H14N2S2 [M]+. requires 274.0593.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:41])[CH2:21][NH:22][C:23]2([CH2:26][CH2:27][N:28]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[C:31]([CH3:39])([CH3:38])[O:30][C:29]3=[O:40])[CH2:25][CH2:24]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:41][CH:20]([C:12]1[C:13]2[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=2[C:9]([OH:8])=[CH:10][CH:11]=1)[CH2:21][NH:22][C:23]1([CH2:26][CH2:27][N:28]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]([CH3:39])([CH3:38])[O:30][C:29]2=[O:40])[CH2:24][CH2:25]1
Reactant: [H][H]
Reactant: CC1(C)OC(=O)N(CCC2(NCC(O)c3ccc(OCc4ccccc4)c4c3OCC(=O)N4)CC2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC(=O)N(CCC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)c2ccccc21

Procedure:
650 mg (1.17 mmol) 1-(2-{1-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one are dissolved in 30 mL methanol, combined with palladium on charcoal (10%) and hydrogenated at ambient temperature and 3 bar hydrogen pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[NH:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17].[CH3:25][O:26][C:27]([N:29]1[C:37]2[C:32](=[CH:33][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH2:31][CH2:30]1)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:38]([C:34]1[CH:33]=[C:32]3[C:37](=[CH:36][CH:35]=1)[N:29]([C:27]([O:26][CH3:25])=[O:28])[CH2:30][CH2:31]3)(=[O:39])=[O:40])[C:6](=[O:11])[C:5]2([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[NH:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17]
Reactant: COC(=O)N1CCc2cc(S(=O)(=O)Cl)ccc21
Reactant: COCCCNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Product: COCCCNC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc3c(c2)CCN3C(=O)OC)c2ccc(Cl)cc21
Yield: 69.8 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 222 from 1.3 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-[(3-methoxypropyl)amino]indol-2-one and 0.980 g of 1-(methoxycarbonyl)-indoline-5-sulfonyl chloride. 1.5 g of the expected product are obtained after crystallization from a DCM/ iso ether/hexane mixture. M.p.=98° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[CH3:11].C(N(CC)CC)C.[C:19]([O:23][C:24]([NH:26][NH2:27])=[O:25])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([O:23][C:24]([NH:26][NH:27][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1cc(C(=O)Cl)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
11.2 g 4-fluoro-3-methyl-benzoyl chloride was added to 6.1 g triethylamine and 8 g hydrazinecarboxylic acid tert-butyl ester in 150 mL dichlormethane. The reaction was stirred for 1 h at RT and extracted with water. The organic layer was evaporated and the residue was crystallized from diisopropylether to yield 13 g of the desired product. Rt: 1.22 min (method B) (M+H)+: 269
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].O>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[N:32]([C:38]2([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:31]3=[O:47])=[O:10])=[CH:6][N:5]=1)[CH3:2]
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: CCOc1ccc(C(=O)O)cn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A stirred mixture of 6-ethoxy-nicotinic acid (0.33 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. The solvent was removed in vacuo and the crude product was purified by column chromatography (80/20, EtOAc/hexanes). The product fractions were combined, concentrated and the residue was triturated in Et2O. The product was isolated by filtration and dried in vacuo to give 6-ethoxy-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-nicotinamide as a white solid (0.77 g, 86% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.56 min (99.14%); mp: 174-176° C.; 1H NMR (DMSO-d6) δ 1.33 (t, J=6.9 Hz, 3H), 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2.54-2.73 (m, 3H), 4.34 (dd, J=7.2, 14.1 Hz, 2H), 4.62 (d, J=6.0 Hz, 2H), 6.88 (d, J=8.7 Hz, 1H), 7.77-7.83 (m, 3H), 8.14 (dd, J=2.4, 8.7 Hz, 1H), 8.70 (d, J=2.1 Hz, 1H), 9.20 (t, J=6.0 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 14.40, 21.00, 28.60, 29.10, 42.50, 58.70, 61.80, 110.30, 121.60, 123.00, 123.20, 129.60, 131.40, 133.40, 138.10, 147.10, 147.30, 164.70, 165.00, 167.70, 167.90, 172.10, 172.20; LCMS: MH=451; Anal Calcd for C23H22N4O6+0.3H2O: C, 60.60; H, 5.00; N, 12.29. Found: C, 60.24; H, 4.86; N, 12.15.