Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=O)[NH:5][C:6](=[O:15])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[NH2:22][C@@H:23]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:24]([N:26]([CH2:38][CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=[O:25]>>[CH2:1]([N:4]([C:16]([CH3:21])([CH3:20])[C:17]([NH:22][C@@H:23]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[CH:49][CH:48]=1)[C:24]([N:26]([CH2:38][CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:19])[NH:5][C:6]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:15])[CH:2]=[CH2:3]
Reactant: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: C=CCN(NC(=O)NCc1ccccc1)C(C)(C)C(=O)O
Product: C=CCN(NC(=O)NCc1ccccc1)C(C)(C)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2ccccc12)CC(OCC)OCC
Yield: 128 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, 2-(1-allyl-2-(benzylcarbamoyl)hydrazinyl)-2-methylpropanoic acid (Compound VI-4) (317 mg, 1.1 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) (502 mg, 0.73 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=97:3) to obtain the title compound (716 mg, 128%).
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[Cl:23])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[H][H]>N.CO.[Ni]>[NH2:2][CH2:1][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[Cl:23])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(Cl)c2Cl)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CN)(c2cccc(Cl)c2Cl)CC1

Procedure:
Tert-butyl 4-cyano-4-(2,3-dichlorophenyl)piperidine-1-carboxylate (2.30 g, 6.47 mmol) was dissolved in 75 ml of a 7M solution of NH3 in MeOH. Raney Nickel (˜2 g aq. suspension) was added and the mixture shaken on a PARR apparatus under 60 psi of hydrogen for 4 days. The catalyst was removed by filtration through a layer of Celite and the crude reaction mixture concentrated. The crude product (1.90 g yellow oil) was used in the next reaction (amide bond formation) “as is”.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino-methyl)-benzoic acid (1.005 g) and N-hydroxy-benzotriazole (HOBt)(0.642 g) in DMF (30 ml) are added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)(2.76 g) and triethylamine (2.005 ml). The mixture is stirred for 1 h at ambient temperature. This solution is added at 0° C. slowly to a solution of 1,4-diaminobenzene (0.43 g) and triethylamine (0.45 ml) in DMF (5 ml). After completion of the chemical reaction the mixture is evaporated at high vacuum and the residue is partitioned between ethyl acetate and an aqueous saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and the crude product is purified by silica gel flash chromatography. A colorless solid (0.735 g) is obtained in 55% yield.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:18])[CH:15]=3)[N:10]([CH3:19])[C:9]=2[C:8]([O:20][CH3:21])=[CH:7][CH:6]=1)=[O:4]>CO.[OH-].[Na+]>[Cl:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:19])[C:9]1[C:8]([O:20][CH3:21])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:17]2=1
Reactant: COC(=O)c1ccc(OC)c2c1c1cc(Cl)ccc1n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)c2c3cc(Cl)ccc3n(C)c12
Reaction time: 3 h

Procedure:
To a solution of methyl-6-chloro-1-methoxy-9-methyl-9H-4-carbazole carboxylate (390 mg 1.285 mmoles) in 20 mL methanol, 5 mL of 10% sodium hydroxide solution was added and stirred for 3 hrs. Methanol from the reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate (5 mL) and washed with 10% sodium hydroxide solution (2×2 mL). This aqueous layer is acidified with 1N HCl and extracted with ethyl acetate (2×25 mL), dried over sodium sulfate and concentrated to give 350 of the title compound
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[NH2:18][C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1>>[CH3:24][C:22]1[N:23]=[C:19]([NH:18][C:3]([C:5]2[C:10]([NH:11][C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)=[N:9][CH:8]=[CH:7][N:6]=2)=[O:4])[S:20][CH:21]=1
Reactant: Cc1csc(N)n1
Reactant: COC(=O)c1nccnc1Nc1cncnc1
Product: Cc1csc(NC(=O)c2nccnc2Nc2cncnc2)n1

Procedure:
The title compound, MS: m/e=314.0 (M+H+), was prepared in accordance with the general method of example 1, step 2 from 3-(pyrimidin-5-ylamino)-pyrazine-2-carboxylic acid methyl ester and 2-amino-4-methylthiazole.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].C([N:12](CC)CC)C.C(Cl)(=O)CCC(Cl)=O>O1CCCC1>[C:4]1(=[O:5])[NH:12][C:7](=[O:9])[CH2:2][CH2:3]1.[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCN(CC)CC
Agent: N[C@@H](CC(=O)O)C(=O)O
Agent: O=C(Cl)CCC(=O)Cl
Solvent: C1CCOC1
Product: O=C1CCC(=O)N1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
This example that demonstrates how this method could be performed. 9.4 g aspartic acid, 10 ml triethyl amine and 100 ml tetrahydrofuran are transferred into a 100 ml flask fitted with a condenser and nitrogen inlet. The mixture is cooled to 0° C. and 5 g succinyl chloride is added and the mixture stirred under nitrogen atmosphere for 5 min and refluxed for 6 hours. The triethyl amine hydrochloride is filtered and the filtrate is concentrated by removing the solvent under vacuum. The residue is used directly for the subsequent reaction. The residue can be purified by chromatography on silica gel.
Reaction SMILES: [CH3:1][CH:2]1[CH2:3][N:4](C(OC(C)(C)C)=O)[CH2:5][CH2:6]/[C:7]/1=[N:8]\[O:9][CH3:10].Cl.O1CCOCC1>CO>[CH3:10][O:9]/[N:8]=[C:7]1/[CH:2]([CH3:1])[CH2:3][NH:4][CH2:5][CH2:6]/1
Reactant: CO/N=C1\CCN(C(=O)OC(C)(C)C)CC1C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CO/N=C1\CCNCC1C
Reaction time: 8 h
Yield: 147.1 %

Procedure:
1,1-Dimethylethyl(4E)-3-methyl-4-[(methyloxy)imino]-1-piperidinecarboxylate (197 mg) was dissolved in methanol, treated with 4.0 N HCl/dioxane (4 mL) and stirred overnight. The reaction was then concentrated to provide the product as a white solid (170 mg). The crude material was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[S:10][C:11]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(#N)C>[O-:31][N+:20]1[CH:19]=[CH:18][C:17]([C:9]2[S:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1sc(-c2ccncc2)nc1-c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC#N
Product: CCOC(=O)c1sc(-c2cc[n+]([O-])cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.1 %

Procedure:
To a suspension of ethyl 4-phenyl-2-pyridin-4-yl-1,3-thiazole-5-carboxylate (2.6 g, 8.5 mmol) produced in the above in acetonitrile (300 mL) was added m-chloroperbenzoic acid (containing water, about 70%, 3.9 g, about 16.0 mmol), and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure to about 100 mL, and the obtained suspension was diluted with ethyl acetate (300 mL), and washed successively with saturated aqueous sodium bisulfite solution (150 mL×2) and saturated aqueous sodium carbonate solution (150 mL×2). The combined aqueous layer was extracted with ethyl acetate (200 mL×2). The combined organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate, and collected by filtration to give the title compound (2.0 g, 72%) as a yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([Cl:16])=[CH:11][C:10]=1[C:17]1[N:21](COCC[Si](C)(C)C)[N:20]=[C:19]([CH3:30])[C:18]=1[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[Cl:16][C:12]1[C:13]([F:15])=[CH:14][C:9]([OH:8])=[C:10]([C:17]2[NH:21][N:20]=[C:19]([CH3:30])[C:18]=2[C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH:11]=1
Reactant: COc1ccc(-c2c(C)nn(COCC[Si](C)(C)C)c2-c2cc(Cl)c(F)cc2OCc2ccccc2)cc1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2c(C)n[nH]c2-c2cc(Cl)c(F)cc2O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-(2-Benzyloxy-5-chloro-4-fluoro-phenyl)-4-(4-methoxy-phenyl)-3-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole (1 eq) was taken up in anhydrous dichloromethane and the solution was cooled under nitrogen to 0° C. 1M boron trichloride in dichloromethane (6 eq) was added dropwise and the solution was allowed to stir for 1 hour. The reaction mixture was added dropwise to sat. NaHCO3 (aq) and the resulting solution was extracted into dichloromethane. The organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative LC/MS, to give 4-chloro-5-fluoro-2-[4-(4-methoxy-phenyl)-5-methyl-2H-pyrazol-3-yl]-phenol as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:10][C:11]([CH3:15])([CH3:14])[C:12]#[CH:13]>[Pd+2].[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[NH2:10][C:11]([CH3:15])([CH3:14])[C:12]#[C:13][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: Fc1ccc(Br)cc1F
Reactant: C#CC(C)(C)N
Agent: [Cu]I
Agent: [Pd+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CC(C)(N)C#Cc1ccc(F)c(F)c1
Yield: 87.7 %

Procedure:
155 g (0.8 mol) of 3,4-difluoro-bromobenzene and 75 g (0.9 mol) of 3-amino-3, 3-dimethyl-1-propine are introduced into 900 ml of triethylamine. After 2.81 g (0.004 mol) of palladium(II)-bis(triphenylphosphine) dichloride, 3.05 g (0.016 mol) of copper(I) iodide and 8.4 g (0.032 mol) of triphenylphosphine have been added, the reaction mixture is refluxed for 4 hours. It is subsequently filtered, the filtrate is concentrated under a water-pump vacuum, and the residue is distilled under an oil-pump vacuum. 137 g (86% of theory) of 3-amino-3,3-dimethyl-1-(3,4-difluoro-phenyl)-1-propine of boiling point 75° C. at 1.5 mbar are obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH2:13][N:14]([CH2:16][C:17]1[C:21]([F:22])=[C:20]([C:23]2[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=2)[NH:19][CH:18]=1)[CH3:15].C1OCCOCCOCCOCCOC1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([S:51](Cl)(=[O:53])=[O:52])[CH:46]=1>O1CCCC1>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH2:13][N:14]([CH2:16][C:17]1[C:21]([F:22])=[C:20]([C:23]2[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=2)[N:19]([S:51]([C:47]2[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=2)(=[O:53])=[O:52])[CH:18]=1)[CH3:15]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COc1ccc(CN(C)Cc2c[nH]c(-c3cccnc3F)c2F)c(OC)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(C)Cc2cn(S(=O)(=O)c3cccnc3)c(-c3cccnc3F)c2F)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
To a suspension of sodium hydride (60% in oil, 1.57 g) in tetrahydrofuran (100 mL) was added dropwise a solution of 1-(2,4-dimethoxyphenyl)-N-{[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}-N-methylmethanamine (9.8 g) in tetrahydrofuran (30 mL) under ice-cooling. The reaction mixture was stirred at the same temperature for 10 min, and 15-crown-5 (8.66 g) was added dropwise. After further stirring for 10 min, pyridine-3-sulfonyl chloride (6.98 g) was added dropwise. After stirring for 15 min at the same temperature, ice water was added and the reaction mixture was extracted with ethyl acetate. The aqueous layer was weakly basified with saturated aqueous sodium hydrogen carbonate solution (100 mL), and extracted again with ethyl acetate. The combined extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=6:1→3:1), and washed with diisopropyl ether to give the title compound as colorless crystals (yield 9.25 g, 69%).
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][CH:6]1[O:11][CH:10](Br)[CH:9]([O:13][C:14]([CH3:16])=[O:15])[CH:8]([O:17][C:18]([CH3:20])=[O:19])[CH:7]1[O:21][C:22]([CH3:24])=[O:23])=[O:3].[CH2:25]([OH:28])[CH:26]=[CH2:27]>>[C:14]([O:13][C@@H:9]1[C@@H:8]([O:17][C:18](=[O:19])[CH3:20])[C@@H:7]([O:21][C:22](=[O:23])[CH3:24])[C@@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[O:11][C@H:10]1[O:28][CH2:25][CH:26]=[CH2:27])(=[O:15])[CH3:16]
Reactant: CC(=O)OCC1OC(Br)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Reactant: C=CCO
Product: C=CCO[C@@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
Acetobromogalactose (2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide) was mixed with allyl alcohol and mercuric cyanide via the Koenigs-Knorr glycosylation to obtain allyl β-D-galactopyranoside tetraacetate. This was followed by oxidation with 3-chloroperoxybenzoic acid in dichloromethane to obtain 2,3-epoxypropyl-β-D-galactopyranoside, 2,3,4,6-0-tetracetate.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[CH2:13]([N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C@@H:21]1[C:26]([NH:28][CH:29]([CH:37]([OH:43])[C:38]([NH:40][O:41][CH3:42])=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CS(C)=O.O.C(Cl)Cl.C(OCC)C>[CH2:13]([N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C@@H:21]1[C:26]([NH:28][CH:29]([C:37](=[O:43])[C:38]([NH:40][O:41][CH3:42])=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Agent: O=C(O)c1ccccc1I(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CONC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Reaction time: 2 h

Procedure:
IBX (293 mg, 0.472 mmol) was added to a solution of (2R)-1-benzyl-N-(3-hydroxy-4-(methoxyamino)-4-oxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (143 mg, 0.337 mmol) in DMSO (5 mL). After stiffing for 2 h more IBX (105 mg, 0.169 mmol) was added and the stirring continued overnight. The saturated aqueous NaHCO3 solution was added and the reaction mixture was diluted with water and DCM. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with water and dried (MgSO4). The crude product obtained was dissolved in a minimal amount of DCM and diethylether was added. The precipitate formed was isolated and dried in vacuo. The title compound was obtained as a colourless solid (12 mg, 8%)
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[CH2:18]([NH:21][S:22]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)(=[O:24])=[O:23])[CH:19]=[CH2:20]>>[CH2:18]([NH:21][S:22]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:30][CH:31]=1)(=[O:24])=[O:23])[CH:19]=[CH2:20]
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: C=CCNS(=O)(=O)Cc1ccc(N)cc1
Product: C=CCNS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and N-allyl-4-aminophenylmethane sulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 11.1 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 7.5 (q, 4H), 7.3 (t, 1H), 7.1 (d, 1H), 5.8 (m, 1H), 5.2 (d, 1H), 5.1 (d, 1H), 4.4 (s, 2H), 3.6 (t, 2H); APCI−MS m/z 427 (M+H)+.
Reaction SMILES: C12OC(CC1)CN(C1N=C(C3C=CC(N)=CC=3)N=C3N(C(COC)COC)N=CC=13)C2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH2:44]([OH:47])[CH2:45][OH:46].[CH3:48][O:49][CH2:50][CH:51]([N:55]1[C:59]2=[N:60][C:61]([C:72]3[CH:77]=[CH:76][C:75]([N:78]=[C:79]=[O:80])=[CH:74][CH:73]=3)=[N:62][C:63]([N:64]3[CH2:70][CH:69]4[O:71][CH:66]([CH2:67][CH2:68]4)[CH2:65]3)=[C:58]2[CH:57]=[N:56]1)[CH2:52][O:53][CH3:54]>ClCCl.C(N(CC)CC)C>[OH:46][CH2:45][CH2:44][O:47][C:79](=[O:80])[NH:78][C:75]1[CH:74]=[CH:73][C:72]([C:61]2[N:60]=[C:59]3[N:55]([CH:51]([CH2:50][O:49][CH3:48])[CH2:52][O:53][CH3:54])[N:56]=[CH:57][C:58]3=[C:63]([N:64]3[CH2:65][CH:66]4[O:71][CH:69]([CH2:68][CH2:67]4)[CH2:70]3)[N:62]=2)=[CH:77][CH:76]=1
Reactant: COCC(COC)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N=C=O)cc3)nc21
Reactant: OCCO
Agent: COCC(COC)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(COC)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)OCCO)cc3)nc21
Reaction time: 3 h
Yield: 53 %

Procedure:
A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1,3-dimethoxypropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (65 mg, 0.15 mmol) in dichloromethane (1.5 mL) was treated with triethylamine (0.2 mL), followed by a solution of triphosgene (23 mg, 0.08 mmol) in dichloromethane (1 mL). After the passage of 10 minutes, the appropriate nucleophile—in the case, ethylene glycol (84 μL, 1.5 mmol)—was added to the 3-(1-(1,3-dimethoxypropan-2-yl)-6-(4-isocyanatophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (“isocyanate”) mixture. After 3 hours, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 2-hydroxyethyl(4-{1-[2-methoxy-1-(methoxymethyl)ethyl]-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)carbamate (41 mg, 53%). MS (ES+): 513.2 (M+H)+
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:31][N:30]([C:32]3[CH:37]=[C:36]([CH:38]([CH3:40])[CH3:39])[CH:35]=[CH:34][C:33]=3[CH3:41])[CH2:29][CH2:28][C:4]=2[N:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:27])=[CH:11][N:12]3[S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:7]=1.[CH3:42][O-:43].[Na+].[OH-].[K+].[OH-].[NH4+]>CO.CCOC(C)=O.O.ClCCl.[Cl-].[Na+].O>[CH:38]([C:36]1[CH:35]=[CH:34][C:33]([CH3:41])=[C:32]([N:30]2[CH2:29][CH2:28][C:4]3[N:5]=[C:6]([C:8]4[CH:16]=[CH:15][CH:14]=[C:13]5[C:9]=4[C:10]([CH3:27])=[CH:11][N:12]5[S:17]([C:20]4[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=4)(=[O:18])=[O:19])[N:7]=[C:2]([O:43][CH3:42])[C:3]=3[CH2:31]2)[CH:37]=1)([CH3:40])[CH3:39]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(Cl)c5c(n4)CCN(c4cc(C(C)C)ccc4C)C5)cccc32)cc1
Reactant: C[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(c1cc(C(C)C)ccc1C)CC2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4-chloro-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, prepared as described in Example 17 (110 mg, 0.188 mmol) in methanol (5 mL) was added 25% sodium methoxide in methanol (40.6 mg, 0.188 mmol). The reaction was stirred for ca. 40 minutes at room temperature at which time the mixture was diluted with EtOAc and water. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was added to a microwave vial, and diluted with EtOH (2 mL) and charged with KOH (ca. 100 mg, 1.75 mmol) and 28% ammonium hydroxide in water (1 mL, 7.25 mmol). The vial was sealed and heated via microwave irradiation at 100° C. for 45 minutes. The reaction mixture was cooled to room temperature and diluted with dichloromethane and brine. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (0-100% ethyl acetate/heptanes) and then further purified by reverse phase HPLC (20-100% MeCN/0.1% NH4OH in water to afford 6-(5-isopropyl-2-methylphenyl)-4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Mg+2:5].[P:6](=[O:10])([OH:9])([OH:8])[OH:7]>>[P:6]([O-:10])([O-:9])([OH:8])=[O:7].[Mg+2:5].[C:1](=[O:2])([O-:4])[O-:3]
Reactant: O=P(O)(O)O
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Product: O=P([O-])([O-])O

Procedure:
By the reaction of magnesium carbonate in an aqueous, 10-40% suspension with technical phosphoric acid at a molar ratio of 2:1 there is obtained magnesium hydrogen phosphate with a carbonate proportion of 50 mole-%. The reaction may be carried out at temperatures between room temperature and heat of boiling of the mixture, but it is carried out preferably, in the case of an amount of a few kilograms, at temperatures of from 30° to 50° C. for a period of time of 30 minutes, with the period of time, but also the temperature, depending upon the converted amount. In the case of a production charge of about 5 t, for instance, the temperature increases on account of the resultant heat of reaction to about 90° C., and the reaction lasts for about 3 hours. Hence, the duration of the reaction and the reaction temperature are the longer and higher, the larger the amount used is. The increase in temperature also has the advantageous effect that the time of reaction can be kept within reasonable limits. The precipitated pigments are filtered off in customary manner, manner, are dried at 105° C. and ground.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[C:12]([CH3:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:15])[C:4]=1[NH:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])=O.[NH3:26]>>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[N:26]=[CH:1][C:3]2[C:4](=[C:5]([CH3:15])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH3:14])[CH:13]=2)[N:16]=1
Reactant: CCOC(=O)c1c(C)cc(C=O)c(NC(=O)c2ccccc2F)c1C
Reactant: N
Product: CCOC(=O)c1c(C)cc2cnc(-c3ccccc3F)nc2c1C
Yield: 28 %

Procedure:
Instead of the compound of formula (II) used in Example 1, ethyl 4-formyl-2,6-dimethyl-3-(o-fluorobenzoylamino)benzoate was used and reacted with ammonia in the same way as in Example 1. The reaction product was chromatographed on a silica gel column in the same way as in Example 1. The solvent was evaporated, and the residue was recrystallized from ethanol/water to give 2-(o-fluorophenyl)-7-ethoxycarbonyl-6,8-dimethylquinazoline having a melting point of 98° to 100° C. in a yield of 28%.