Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl[Si](C)(C)C.[C:17]1([CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>C(Cl)Cl.C(N(CC)CC)C>[C:7]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([OH:9])=[O:8]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)CCCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccccc1)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(Aminomethyl)benzoic acid (3.6 g) is suspended in methylene chloride (100 mL), to which 15 mL triethylamine is added. Chlorotrimethylsilane (10 mL) is then added and the mixture allowed to stir at room temperature for 1 hr. The mixture is then cooled in an ice bath and 4-phenylbutyryl chloride (5.3 g) in methylene chloride (10 mL) is added dropwise and the resulting mixture stirred for 30 min. at 0° C., followed by an additional 3 hrs at ambient temperature. The mixture is treated with 75 mL 1N HCl, after which the organic layer is separated and extracted with 1N HCl. The precipitate which had formed is recovered by filtration and recrystallized two times from methanol/1N HCl to give pure N-(4-carboxybenzyl)-4-phenylbutyramide. M.p. 178°-179° C.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5].[H-].[Na+].[CH3:14][O:15][CH2:16]Cl>C1COCC1>[F:1][C:2]1[C:9]([O:10][CH2:14][O:15][CH3:16])=[CH:8][CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(I)ccc(O)c1F
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(I)c(C#N)c1F
Reaction time: 0.08 h
Yield: 72 %

Procedure:
A 0° C. solution of Example 68A (250 mg, 0.95 mmol) in THF (5 mL) at room temperature was treated with NaH (25 mg, 95%, 1.05 mmol), stirred for 5 minutes, treated with chloromethyl methyl ether (0.108 mL, 1.4 mmol), stirred overnight, and partitioned between water and ethyl acetate. The organic extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 2% ethyl acetate/hexanes to provide 0.21 g of the desired product. Rf=0.4 (10% ethyl acetate/hexanes).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@@H:40]2[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]2)=[O:37])=[O:30])[CH2:3]1.[CH3:46][C:47]([CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1)=O>>[CH:49]1([CH:47]([N:42]2[CH2:43][CH2:44][CH2:45][C@@H:40]([CH2:39][NH:38][C:36]([C@H:32]3[CH2:33][CH2:34][CH2:35][N:31]3[C:29]([C@@H:4]3[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]3[C:7](=[O:28])[CH2:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:30])=[O:37])[CH2:41]2)[CH3:46])[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: CC(=O)C1CCCCC1
Reactant: O=C(NC[C@@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C1CCCCC1)N1CCC[C@@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Step 3 of Example 17, using (2R)-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3R)-3-piperidylmethyl)pyrrolidine-2-carboxamide and cyclohexyl methyl ketone. The compound was obtained as a white solid.
Reaction SMILES: [CH3:1][NH2:2].F[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[N+:18]([O-:20])=[O:19].O>O1CCCC1>[CH3:1][NH:2][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[N+:18]([O-:20])=[O:19]
Reactant: CN
Reactant: COc1ccnc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc(-c2cc(OC)ccn2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methylamine in tetrahydrofuran (2M, 11 ml) was added 1-fluoro-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (289 mg). The mixture was stirred at ambient temperature for 2 hours and poured into water. The precipitate was collected by filtration and dried to give 1-methylamino-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (280 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10](I)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([Sn](CCCC)(CCCC)CCCC)=[CH2:25].CN(C=O)C>C(#N)C>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([CH:24]=[CH2:25])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=c1c(I)c(OCc2ccccc2)ccn1Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: C=Cc1c(OCc2ccccc2)ccn(Cc2ccccc2)c1=O
Temperature: 65 °C
Yield: 50 %

Procedure:
A solution of 1-benzyl-4-(benzyloxy)-3-iodopyridin-2 (1H)-one (1.9 g, 4.56 mmol) and vinyl-tri-butyltin (2.5 mL) in acetonitrile (200 mL) containing DMF (2.0 mL) was degassed using house vacuum and purged with argon. Then added PdCl2(PPh3)2 (0.3 g) and the mixture was heated at 65° C. under argon atmosphere for 4 h, with stirring. The solvents were distilled in vacuo, and the residue was triturated with EtOAc and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by silica gel flash chromatography using 25% EtOAc in hexanes to give the title compound (0.75 g. 50%) as an orange colored solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37].[O:38]1[CH2:40][CH2:39]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[OH:38][CH2:39][CH2:40][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: C1CO1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1OCCO
Yield: 14.8 %

Procedure:
The title compound was prepared according to the procedure described in Example 15 by using N-(4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (5 g, 10 mmol), oxirane (5.8 mL, 100 mmol) and K2CO3 (2.74 g, 2 mmol) in DMF/H2O (24 mL/6 mL). The crude product was purified by a silica gel column chromatography (DCM/MeOH=30/1) to give the title compound as a pale white solid (0.8 g, 15%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[O:17]C)([CH3:9])[CH3:8])[CH3:2].B(Br)(Br)Br.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:24])[C:5]([OH:23])([C:19]([F:20])([F:21])[F:22])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[OH:17])([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1O)C(F)(F)F
Temperature: 3 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
A solution of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester (WO 00/32584) (10.83 g, 30.74 mmol) in dichloromethane (200 ml) is mixed with 1 M boron tribromide-chloroform solution (60 ml) while being cooled in an ice bath, and it is stirred for 3 hours at 2-4° C. The batch is poured onto ice and saturated NaHCO3 solution, and it is stirred for 30 minutes while being cooled with ice. The organic phase is separated, and the aqueous phase is extracted twice more with dichloromethane. The combined, organic extracts are washed with saturated NaCl solution, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography of the residue (silica gel) with hexane-ethyl acetate yields 5.36 g of product. Extraction of the aqueous phase with ethyl acetate yields 4.0 g of product again.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[NH2:7].[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15]>>[CH3:12][O:11][C:9]1[CH:10]=[C:4]([O:3][CH3:2])[CH:5]=[C:6]2[C:8]=1[C:13](=[O:17])[C:14](=[O:15])[NH:7]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(N)cc(OC)c1
Agent: Cl
Product: COc1cc2c(c(OC)c1)C(=O)C(=O)N2
Yield: 99.6 %

Procedure:
12 g (63 mmol) of 3,5-dimethoxyaniline hydrochloride and 20 ml (230 mol) of oxalyl chloride were stirred at 165° C. for 30 min. The excess of oxalyl chloride was distilled (the color of the reaction mixture changed from dark-red to green-yellow). The reaction mixture was cooled and methanol was added. The resulting suspension was heated then filtered, washed with methanol and dried to yield 13 g of 4,6-dimethoxyindole-2,3-dione (100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22](=[O:30])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:31][C:32]([OH:34])=[O:33])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22](=[O:30])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]3)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)CN(c1ccc2c(c1)CCN2C(=O)Nc1ccccc1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN(c1ccc2c(c1)CCN2C(=O)Nc1ccccc1)S(=O)(=O)c1cc(Cl)cc(Cl)c1

Procedure:
1.24 g tert.butyl [(3,5-dichloro-phenylsulphonyl)-(1-phenylcarbamoyl-2,3-dihydro-1H-indol-5-yl)-amino]-acetate are dissolved in 10 ml dichloromethane. 5 ml of trifluoroacetic acid is added with stirring. The mixture is stirred for 2 hours at ambient temperature and then the solvents are eliminated in vacuo. The residue is extracted from diisopropylether and cyclohexane.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[C:17](C(=O)C)[CH:16]=1)(=[O:14])[CH3:13].[OH-].[Li+].[OH-].[Na+]>ClCCl>[C:21]([C:19]1[CH:20]=[C:15]([C:12](=[O:14])[CH3:13])[CH:16]=[C:17]([OH:9])[CH:18]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1cc(C(C)=O)cc(C(C)(C)C)c1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)c1cc(O)cc(C(C)(C)C)c1
Reaction time: 4 h

Procedure:
m-Chloroperbenzoic acid (382 g, 2.21 mol) was added to a solution of 1,3-bisacetyl-5-tert-butylbenzene (O4.106; 169 g, 776 mmol) in dichloromethane (1.7 l). The resulting suspension was heated to reflux temperature for 24 h. Once the suspension had cooled, the solids were filtered off and the filtrate was admixed with saturated aqueous NaHSO3 solution (500 ml). The phases were separated, the organic phase was dried (MgSO4) and the solvent was removed under reduced pressure. The residue was dissolved in THF (500 ml) and admixed with lithium hydroxide (34.9 g, 1.46 mol). After 4 h at RT, aqueous sodium hydroxide solution (1 M, 500 ml) was added and the mixture was washed with MtB ether (3×500 ml). The aqueous phase was acidified (pH 3) with HCl (1 M), and extracted with EA (3×500 ml). The combined organic phases were dried (MgSO4), and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (met. C). The product was obtained as a colorless oil which crystallized slowly (36.5 g).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:25]([O:27][C:28]([N:30]=[C:31]=[S:32])=[O:29])[CH3:26]>O1CCCC1>[NH2:20][C:18]([C:17]1[CH:16]=[N:15][N:14]2[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:21])([F:1])[F:22])[CH:4]=3)=[CH:10][CH2:11][N:12]([C:31]([NH:30][C:28](=[O:29])[O:27][CH2:25][CH3:26])=[S:32])[C:13]=12)=[O:19]
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)N=C=S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)N1CC=C(c2cccc(C(F)(F)F)c2)n2ncc(C(N)=O)c21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3.0 g of 4,5-dihydro-7[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared as described in Example 4) in 90 ml of dry tetrahydrofuran, cooled to -78° C. was added 584 mg of sodium hydride (60% dispersion in mineral oil) in one portion. The reaction mixture was stirred at -78° C. for one hour followed by the addition of 2.55 g of ethoxycarbonyl isothiocyanate. The mixture was stirred at -78° C. for 2 hours then was allowed to warm slowly to room temperature. The reaction mixture was stirred at room temperature for 48 hours, then was quenched with water and extracted with ether. The aqueous layer was separated, neutralized with 5% hydrochloric acid and extracted with chloroform. The chloroform extracts were evaporated in vacuo to give the product of the example as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[Br:27][C:28]1[C:37]([CH3:38])=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([CH:39]=O)=[N:35]2)=[CH:30][CH:29]=1>>[Br:27][C:28]1[C:37]([CH3:38])=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([C:39]3[N:6]4[CH:5]=[C:4]([C@@H:3]([N:12]5[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]5)[C:2]([F:25])([F:1])[F:26])[CH:9]=[CH:8][C:7]4=[N:10][N:11]=3)=[N:35]2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: Cc1c(Br)ccc2ccc(C=O)nc12
Product: Cc1c(Br)ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Yield: 78.3 %

Procedure:
Prepared as described in Example 9B, Step F, using tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.80 g, 2.13 mmol) and 7-bromo-8-methylquinoline-2-carbaldehyde (0.533 g, 2.13 mmol) in place of 8-methoxyquinoline-2-carbaldehyde to provide tert-butyl (S)-1-((R)-1-(3-(7-bromo-8-methylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (1.01 g, 79%).
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[CH2:13][C:14]#N.[OH2:16]>C(O)C>[C:14]([CH2:13][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[Cl:3])[C:8]([OH:10])=[O:9])([OH:16])=[O:1]
Reactant: [OH-]
Reactant: O
Reactant: N#CCc1cc(C(=O)O)ccc1Cl
Agent: [K+]
Solvent: CCO
Product: O=C(O)Cc1cc(C(=O)O)ccc1Cl

Procedure:
Potassium hydroxide (1.549 g) in water (15 mL) was added to a suspension of 4-chloro-3-(cyanomethyl)benzoic acid (2.07 g) in ethanol (15 mL) and the resulting solution was heated at reflux for 4 hours, then allowed to cool. The mixture was concentrated in vacuo to remove the ethanol and then diluted with water and washed twice with ethyl acetate. The organic phases were discarded, whilst the aqueous phase was acidified to pH 1 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the subtitled compound as a pale brown solid. Yield 2.06 g.
Reaction SMILES: C[O-].[Na+].CO.[C:6]12([C:16]3[CH:36]=[CH:35][C:19]([C:20]([CH2:22][O:23][C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=4[I:34])[C:27]([O:29][CH3:30])=[O:28])=O)=[CH:18][C:17]=3[O:37][CH3:38])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.[Br-].[CH3:40]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[I:34][C:33]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:23][CH:22]=[C:20]([C:19]1[CH:35]=[CH:36][C:16]([C:6]23[CH2:13][CH:12]4[CH2:14][CH:8]([CH2:9][CH:10]([CH2:11]4)[CH2:15]2)[CH2:7]3)=[C:17]([O:37][CH3:38])[CH:18]=1)[CH3:40]
Reactant: COC(=O)c1ccc(I)c(OCC(=O)c2ccc(C34CC5CC(CC(C5)C3)C4)c(OC)c2)c1
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(I)c(OC=C(C)c2ccc(C34CC5CC(CC(C5)C3)C4)c(OC)c2)c1

Procedure:
A solution of 30% sodium methoxide in methanol (0.3 ml, 1.6 mmol) is added over 8 hours to a mixture of methyl 3-[4-(1-adamantyl)-3-methoxybenzoylmethyloxy]-4-iodobenzoate (870 mg, 1.55 mmol) and methyltriphenylphosphine bromide (790 mg, 2.21 mmol) in THF (10 ml).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[CH:23]([CH:25]=O)=[O:24]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[CH:25][CH:23]=[O:24]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Reactant: O=CC=O
Product: CC1=C(CCON=CC=O)c2cc(F)ccc2/C1=C\c1ccncc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with glyoxal by the method of Example 1.
Reaction SMILES: I[C:2]1[N:14]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:5]2=[N:6][CH:7]=[C:8]3[CH:12]=[N:11][N:10]([CH3:13])[C:9]3=[C:4]2[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:31]=[C:30]2B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+].O>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:31]=[C:30]2[C:2]1[N:14]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=2)(=[O:17])=[O:16])[C:5]2=[N:6][CH:7]=[C:8]3[CH:12]=[N:11][N:10]([CH3:13])[C:9]3=[C:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c4c(cnc32)cnn4C)cc1
Reactant: COc1ccc2c(c1)c(B1OC(C)(C)C(C)(C)O1)cn2C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2C(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 100.4 %

Procedure:
A flask was charged with 7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.80 g, 1.76 mmol, Preparation #1), tert-butyl 5-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (0.792 g, 2.12 mmol, prepared using H from tert-butyl 3-bromo-5-methoxy-1H-indole-1-carboxylate (SynChem) with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane), Cs2CO3 (1.44 g, 4.42 mmol), PdCl2(PPh3)2 (0.074 g, 0.106 mmol), water (2.6 mL) and 1,4-dioxane (8.0 mL). The mixture was heated to about 85° C. for about 2 h and then cooled to rt. The mixture was diluted with DCM (60 mL) and washed with water (30 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with a gradient of 0 to 20% EtOAc/DCM to afford tert-butyl 5-methoxy-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indole-1-carboxylate (1.01 g, 100%): LC/MS (Table 2, Method c) Rt=1.71 min; MS m/z 572 (M+H)+.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([NH2:30])[CH3:29])=[CH:20][CH:19]=1.CCO.CC#N>C(O)(C(F)(F)F)=O>[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([NH:30][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH3:29])=[CH:20][CH:19]=1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Reactant: CC(N)CCCCCOc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CC#N
Product: CC(CCCCCOc1ccc(Cl)cc1)Nc1c(Nc2cccnc2)c(=O)c1=O
Yield: 12 %

Procedure:
The title compound was prepared from 3-ethoxy-4-(pyridine-3-yl-amino)-3-cyclobutene-1,2-dione (164 mg, 0.75 mmol) prepared according to example 1A and crude 6-(4-chlorophenoxy)-1-methyl-hexylamine (738 mg) in refluxing EtOH (15 ml). After 36 h the solvent was evaporated and the product was isolated by preparative HPLC chromatography using a gradient of 30 to 50% MeCN in 0.01% aq. TFA and subsequent freeze drying of the product containing fractions.
Reaction SMILES: C(O[C:9]([N:11](C)[C@H:12]([C:14]([NH:16][C@H:17]([C:19]([NH:21][C@H:22]([C:24]([NH:26][C@H:27]([P:29](=[O:32])([OH:31])[OH:30])[CH3:28])=[O:25])[CH3:23])=[O:20])[CH3:18])=[O:15])[CH3:13])=O)C1C=CC=CC=1.CO>C(O)C>[CH3:9][NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:19]([NH:21][C@H:22]([C:24]([NH:26][C@H:27]([P:29](=[O:30])([OH:32])[OH:31])[CH3:28])=[O:25])[CH3:23])=[O:20])[CH3:18])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)N(C)C(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: CO
Solvent: CCO
Product: CN[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 19(B)(ii), from (1R)-1-[(N-benzyloxycarbonyl-N-methyl-L-alanyl-L-alanyl-L-alanyl)amino]-ethylphosphonic acid, but carrying out the hydrogenation in aqueous ethanol instead of aqueous methanol, there was obtained (1R)-1-(N-methyl-L-alanyl-L-alanyl-L-alanylamino)-ethylphosphonic acid of melting point 318°-320° C. (decomposition); [α]D20 =-121°; [α]36520 =-418° (c=0.5% in water).
Reaction SMILES: O.CO[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([CH:12]=[O:13])=[O:11].[CH3:14][CH:15]([NH2:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]2[O:23][CH2:24][O:25][C:19]=2[CH:18]=1.[CH3:27]S(C)=O>>[CH3:14][CH:15]([N:26]=[C:12]([O:13][CH3:27])[C:10]([C:5]1[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:11])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]2[O:23][CH2:24][O:25][C:19]=2[CH:18]=1
Reactant: CS(C)=O
Reactant: CC(N)Cc1ccc2c(c1)OCO2
Reactant: COc1ccccc1C(=O)C=O
Solvent: O
Product: COC(=NC(C)Cc1ccc2c(c1)OCO2)C(=O)c1ccccc1

Procedure:
5 g of 2-methoxyphenylglyoxal hydrate (crude oil) are dissolved in 15 ml of dimethylsulfoxide, and 4.83 g of α-methyl-3,4-methylenedioxyphenethylamine are added thereto. The mixture is treated in the same manner as described in Example 1-(2), whereby a solution of α-(α-methyl-3,4-methylenedioxyphenethylimino)-2-methoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[C:6]=2[CH2:5][CH2:4][CH2:3]1.[O:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]1[CH2:25][CH2:26][CH2:27][CH:28]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:13][O:12][C:7]1[C:6]2[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][CH2:28][CH2:27][CH2:26][CH2:25][N:16]3[C:17](=[O:24])[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:15]3=[O:14])[C:11]=2[N:10]=[CH:9][CH:8]=1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Reactant: COc1ccnc2c1CCCC2N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccnc2c1CCCC2NCCCCN1C(=O)c2ccccc2C1=O
Yield: 54.4 %

Procedure:
Using General Procedure B: Reaction of 8-amino-4-methoxy-5,6,7,8-tetrahydroquinoline (0.297 g, 1.67 mmol) and 4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (0.371, 1.71 mmol) with NaBH(OAc)3 (0.493 g, 2.33 mmol) in CH2Cl2 (8 mL) for 60 minutes followed by purification of the crude material by column chromatography on silica gel (20:1 CH2Cl2—CH3OH) provided 0.345 g (54%) of 2-[4-(4-Methoxy-5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione as an off-white solid.