Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:16](OC(=O)C)(=[O:18])[CH3:17].[CH3:23][CH2:24][O:25][C:26](OCC)(OCC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C.C1CCCCC1.CO>[C:16]([N:11]1[C:12]2[C:8](=[CH:7][C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:14][CH:13]=2)[C:9](=[C:26]([O:25][CH2:24][CH3:23])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:10]1=[O:15])(=[O:18])[CH3:17]
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: CC(C)C(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCOC(=C1C(=O)N(C(C)=O)c2ccc(C(=O)C(C)C)cc21)c1ccccc1

Procedure:
Prepared from 5-isobutyryl-2-indolinone, acetic anhydride and triethyl orthobenzoate Rf=0.55 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N+](=[CH:16][Si](C)(C)C)=[N-].CCCCCC.C(O)(=O)C>CO>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc(O)c(C(=O)O)cc1Br
Solvent: CO
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COC(=O)c1cc(Br)c(OC)cc1O
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-2-hydroxy-4-methoxybenzoic acid (2.00 g) in methanol (10.0 mL) was added 0.6M (diazomethyl)trimethylsilane/hexane solution (14.8 mL) under ice-cooling, and the mixture was stirred for 3 hr. To the reaction mixture was added acetic acid (0.12 mL), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.08 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:35]([NH:37]O)=[NH:36])=[CH:31][N:30]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:27][N:37]=[C:35]([C:32]5[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=5)[N:36]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(F)c3)nc12
Reactant: N=C(NO)c1cnc(N)nc1
Product: Nc1ncc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)c(F)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3-fluoro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.18) (197 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example B.5) (115 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (130 mg, 51%). MS (EI) 510.1 [(M)+]; mp 270° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].N12CCCN=C1CCCCC2.[NH:31]1[CH2:35][CH2:34][CH:33]([CH2:36][NH:37][CH2:38][CH2:39][OH:40])[CH2:32]1>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:31]3[CH2:35][CH2:34][CH:33]([CH2:36][NH:37][CH2:38][CH2:39][OH:40])[CH2:32]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: OCCNCC1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CNCCO)C3)c(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A mixture of 0.50 g (1.84 mmole) of 1-ethyl-6,7,8-trifluoro-4-oxo-quinoline-3-carboxylic acid, 5 ml acetonitrile, 0.28 g (1.84 mmole) 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.28 g (1.94 mmole) of 2-[(3-pyrrolidinylmethyl)amino]ethanol was refluxed one hour and then stirred at room temperature overnight. The reaction was filtered and the precipitate washed with ether until dry to give 0.58 g of 1-ethyl-6,8-difluoro-1,4-dihydro-7-[3-[[(2-hydroxyethyl)amino]methyl]-1-pyrrolidinyl]-4-oxo-3-quinoline carboxylic acid, mp 215°-216° C.
Reaction SMILES: N[C:2]1C=CC=C2[C:3]=1C(=O)N(C1CCC(=O)NC1=O)C(C)=N2.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[C:24]=1[C:25]([OH:27])=[O:26]>C(O)(=O)C>[CH3:2][C:3]1[O:26][C:25](=[O:27])[C:24]2[C:28]([N+:32]([O-:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:23]=2[N:22]=1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Solvent: CC(=O)O
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1

Procedure:
In one particular embodiment, provided herein is a method for preparing 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; comprising the steps of (a) reacting 2-amino-6-nitrobenzoic acid with an activated acetic acid in a solvent to form 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one; (b) reacting 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one with 3-aminopiperidine-2,6-dione or a salt thereof in a solvent in the presence of a coupling reagent to form 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione; and (c) reducing 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione via transfer hydrogenation in a solvent to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; and wherein steps (a), (b), and (c) are each as described herein elsewhere.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[N:27][CH:28]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]([CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)[C:5](=[O:7])[CH3:6])=[N:27][CH:28]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc(NCCN4CCCC4)nc3)nc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N(CCN1CCCC1)c1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
45 μL (0.48 mmol) acetic anhydride is added to a solution of 89 mg (0.22 mmol) {5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-(2-pyrrolidin-1-yl-ethyl)-amine in 2 mL DCM. The reaction solution is stirred for 16 h at RT. The solvent is eliminated i.vac. and further purification is carried out by HPLC-MS.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:28]1[CH:42]=[CH:41][C:31]([C:32]([C:34]2[CH:39]=[CH:38][C:37](F)=[CH:36][CH:35]=2)=[O:33])=[CH:30][CH:29]=1.C1(C)C=CC=CC=1>O.CN(C)C(=O)C>[CH2:1]1[CH2:6][CH2:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])[C:31]1[CH:41]=[CH:42][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: Oc1ccc(C2(c3ccc(O)cc3)CCCCC2)cc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In a three neck 500 mL round-bottom flask was weighed bisphenol-Z (35.0000 g, 130.42 mmol), potassium carbonate (36.0505 g, 260.45 mmol), 4,4′-difluorobenzophenone (28.4587 g, 130.42 mmol), toluene (115 g) and N,N-dimethylacetamide (233 g). The flask was fitted with a condenser and a thermometer. The light yellow mixture was stirred and heated to reflux. The water formed was azeotropically distilled with toluene. On complete removal of water and toluene, the solution was stirred at reflux for about 2 hours. The viscous polymer solution was precipitated in water, and a white fibrous polymer was isolated by filtration. The white polymer was stirred in boiling water for about 1 hour, filtered, and then stirred in boiling methanol for about 1 hour and filtered. The fibrous white polymer was then dried in an vacuum oven for about 16 hours at 100° C. The yield was about 54.35 g. The number average molecular weight of the polymer was about 11.5 K.
Reaction SMILES: C(OC(C1CCCN1C(=O)C(NC(=O)C1C=CC(N)=C(Cl)C=1)C)=O)(C)(C)C.[O:28]=[C:29]1[O:33][CH:32]([O:34][CH2:35][CH2:36][C:37]2C=CC=[CH:39][CH:38]=2)[CH:31]([NH:43][C:44]([CH:46]2[CH2:50][CH2:49][CH2:48][N:47]2[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=2)[CH3:53])=[O:45])[CH2:30]1>>[CH:35]1([O:34][CH:32]2[CH:31]([NH:43][C:44]([CH:46]3[CH2:50][CH2:49][CH2:48][N:47]3[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]3[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=3)[CH3:53])=[O:45])[CH2:30][C:29](=[O:28])[O:33]2)[CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OC1CCCC1
Yield: 59 %

Procedure:
Prepared from 97a and syn-(2-cyclopentyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford the title compound as an off-white solid (0.19 g, 59% yield). 1H-NMR (500 MHz, CDCl3) δ 1.2-2.4 (m, 15H), 2.4-3.1 (m, 2H), 3.6-3.9 (m, 2H), 4.2-4.4 (m, 2H), 4.5-5.0 (m, 4H), 5.40 (d, J=5.0 Hz, 0.35H), 5.55 (d, J=5.0 Hz, 0.65H), 6.8-8.2 (m, 5H) ppm. Analytical HPLC (C18 column) 14.065 min. LC-MS (ES+): m/e=507 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:25])([F:24])[O:16][C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[C:10]([F:26])[CH:9]=2)=[C:4](F)[CH:3]=1.[CH2:28]([OH:34])[CH2:29][CH2:30][CH2:31][C:32]#[CH:33].[OH2:35].Cl>C(N(CC)CC)C.C1(C)C=CC=CC=1.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.[Cu]I>[F:25][C:15]([F:24])([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:33]#[C:32][CH2:31][CH2:30][CH2:29][CH2:28][OH:34])=[CH:19][CH:18]=1)[C:11]1[C:12]([F:14])=[CH:13][C:8]([C:5]#[C:4][CH2:3][CH2:2][CH2:7][CH2:6][OH:35])=[CH:9][C:10]=1[F:26]
Reactant: C#CCCCCO
Reactant: O
Reactant: Fc1cc(Br)ccc1-c1cc(F)c(C(F)(F)Oc2ccc(I)cc2)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCCCCC#Cc1ccc(OC(F)(F)c2c(F)cc(C#CCCCCO)cc2F)cc1

Procedure:
6.00 g (10.8 mmol) of 4′-bromo-4-[difluoro-(4-iodophenoxy)methyl]-3,5,2′-trifluorobiphenyl and 4.00 g (40.8 mmol) of hex-5-yn-1-ol are initially introduced in 6 ml of triethylamine and 300 ml of toluene, 0.700 g (1.00 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.100 g (0.525 mmol) of copper(I) iodide are added, and the mixture is heated under reflux overnight. The batch is subsequently added to water, neutralised using 2 N hydrochloric acid and extracted three times with toluene. The combined org. phases are dried over sodium sulfate, the solvent is removed in vacuo, and the residue is chromatographed on silica gel firstly with toluene and then with toluene/ethyl acetate (4:1), giving 6-(4-{difluoro-[4-(6-hydroxyhex-1-ynyl)phenoxy]methyl}-3,5-difluorophenyl)hex-5-yn-1-ol as a colourless solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([CH3:3])[CH3:2].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13]>C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:13][CH2:12][C:11]([OH:15])=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1S
Reactant: C=CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)c1ccccc1SCCC(=O)O
Temperature: 25 °C
Reaction time: 71.8 h
Yield: 98.5 %

Procedure:
2-Isopropylthiophenol (4.77 g, 31 mmol) was placed in a flask with acrylic acid (2.37 g, 33 mmol) and stirred at room temperature for 71.8 hours. The reaction mixture solidified, was dissolved in ethyl acetate and extracted with 5% NaOH. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ethyl acetate, dried over MgSO4, and concentrated in vacuo to give 3-(2-isopropylphenylthio)propanoic acid (6.85 g), contaminated with some acrylic acid, as a yellow solid which was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1.O>[F:1][C:2]1[S:6][C:5]([C:7]([N:12]([O:13][CH3:14])[CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)s1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(F)s1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a stirred solution of 5-fluorothiophene-2-carboxylic acid (33.95 g, 232.3 mmol) in tetrahydrofuran (465 mL) at 0° C. under nitrogen is added N,O-dimethylhydroxylamine hydrochloride (45.32 g, 464.6 mmol), 1-hydroxybenzotriazole monohydrate (53.36 g, 348.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89.1 g, 464.6 mmol), and diisopropylethylamine (162 mL, 929 mmol). The mixture is allowed to warm to room temperature over 18 hours. The mixture is diluted with water (500 mL) and extracted with ethyl acetate (500 mL). The aqueous phase is re-extracted twice with ethyl acetate (300 mL). The combined organic extracts are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The liquid residue is purified by silica gel chromatography eluting with hexanes/ethyl acetate (3:1) to give the title compound (38.28 g, 87%) as a pale yellow liquid. ES/MS (m/e): 190 (M+H).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[CH2:7]([C:8]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 44 °C
Reaction time: 0.5 h

Procedure:
To a 2 liter 4 necked flask equipped with a mechanical stirrer, thermometer, and reflux condensor was added 155 g (1.0 mole) of phenyl acetyl chloride and 500 ml (4.9 mole) of chlorobenzene. A total of 145 g (1.08 mole) of anhydrous aluminum chloride was added portionwise over 10 minutes. The mixture self warmed to 44° C. and evolved HCl gas over the course of the next 30 minutes The mixture was stirred at about 50° C. for an additional 30 minutes and then poured onto about 500 g of ice and 110 ml of concentrated aqueous HCl. The organic layer (lower) was separated and the aqueous layer was washed with ethyl ether. The combined organic layers were washed with water, dilute aqueous NaOH, and water and then concentrated in vacuo. The resulting crude solid was recrystalized from 2200 ml of hexane yielding 132 g of 4-chlorophenyl benzyl ketone, mp 85°-90° C. NMR data was consistent with the structure.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=O.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].CC(C)=O.C(N(CC)CC)C>C(#N)C>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[CH:20]=[C:15]2[N:14]([CH:2]=1)[CH:19]=[CH:18][CH:17]=[CH:16]2)([O-:13])=[O:12]
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reactant: Cc1ccccn1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1-c1cc2ccccn2c1
Temperature: 25 °C

Procedure:
First, 4.1 mmol of 2-bromo-2′-nitroacetophenone and 5.33 mmol (1.3 eq.) of picoline are dissolved into 12 ml of acetone and the reaction mixture is allowed to react at 90° C. for 3 hours. After the completion of the reaction, the reaction mixture is cooled at room temperature and filtered, and then the filtered solid is washed with 5 ml of dichloromethane. To 20 ml of acetonitrile, 4.1 mmol of the obtained solid and 20.5 mmol (5 eq.) of triethylamine are added. Then, the reaction mixture is allowed to react at 60° C. for 16 hours. After the completion of the reaction, the reaction mixture is concentrated under reduced pressure, and then the concentrated reaction mixture is purified by silica gel column chromatography using hexane:ethyl acetate:dichloromethane=30:1:2 as a solvent to obtain the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17].N1CC[CH2:23][CH2:22]1>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH:12]=[CH:18][N:16]1[CH2:15][CH2:23][CH2:22][CH2:17]1
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Reactant: C1CCNC1
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)cc(Br)c1C=CN1CCCC1
Temperature: 110 °C

Procedure:
To a solution of 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (1.78 g) in dimethylfornamide (15 ml) was added dimethylformamide dimethyl acetal (3.0 ml) followed by pyrrolidine (0.63 ml) and heated to 110° C. After 24 hours the cooled reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (MgSO4) and the solvent removed in vacuo to yield crude 1-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-vinyl]-pyrrolidine.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:38][OH:39].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:26])[NH:38][OH:39])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NO)cc1)n2C)c1ccccc1
Reaction time: 5 h
Yield: 39 %

Procedure:
1.44 g (3.0 mmol) of 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, 0.625 g (9.0 mMol) of hydroxylamine hydrochloride and 0.425 g (4.0 mMol) of sodium carbonate were dissolved in 80 ml of ethanol and refluxed for 7 hours. Then a further 210 mg of hydroxylamine hydrochloride and 170 mg of sodium carbonate were added, the mixture was boiled for a further 5 hours and then evaporated down in vacuo. The residue was dissolved in about 30 ml of dichloromethane, the solution obtained was washed with 20 ml of water, the organic phase was dried and evaporated down. The crude product thus obtained was purified by column chromatography (200 g silica gel, dichloromethane+4% ethanol). Yield: 39 % of theory, C28H30N6O4 (514.6) Rf value: 0.15 (silica gel; dichloromethane/ethanol=19:1) ##EQU67##
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[ClH:34].[NH2:35][C:36]1[CH:37]=[C:38]([C:42]2[C:50]3[S:49][C:48]([C:51]([NH:53][C@@H:54]4[CH:59]5[CH2:60][CH2:61][N:56]([CH2:57][CH2:58]5)[CH2:55]4)=[O:52])=[CH:47][C:46]=3[CH:45]=[CH:44][CH:43]=2)[CH:39]=[CH:40][CH:41]=1.[CH3:62][O:63][CH2:64][C:65](O)=[O:66]>CN(C=O)C>[ClH:34].[N:56]12[CH2:57][CH2:58][CH:59]([CH2:60][CH2:61]1)[C@@H:54]([NH:53][C:51]([C:48]1[S:49][C:50]3[C:42]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([NH:35][C:65](=[O:66])[CH2:64][O:63][CH3:62])[CH:37]=4)=[CH:43][CH:44]=[CH:45][C:46]=3[CH:47]=1)=[O:52])[CH2:55]2
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: COCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
96.4 mg (0.25 mmol) of HATU and 71.5 μl (0.41 mmol) of N,N-diisopropylethylamine are added to a solution of 50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 81) and 18.5 μl (0.24 mmol) of methoxyacetic acid in 0.5 ml of DMF at 0° C. The mixture is stirred at room temperature for 3 h. Purification by preparative HPLC is followed by concentration of the product fractions and, after addition of a 3:1 mixture of acetonitrile and 1 N hydrochloric acid, concentration again. Drying under high vacuum results in 7 mg (11% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].C(OC([NH:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][NH:30][CH2:29]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][N:30]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:29]1
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C[C@H]1N
Reaction time: 0.67 h
Yield: 8.9 %

Procedure:
A mixture of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.7 g), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.62 g), DBU (0.43 g) and anhydrous acetonitrile (30 ml) was refluxed for 52 hours. After cooling, the resulting precipitate was collected by filtration, washed with chilled acetonitrile and this was added to concentrated hydrochloric acid-methanol (1:1, 5 ml) and stirred for 40 minutes at elevated temperature. The reacting mixture was collected by filtration, washed with chilled water sufficiently and recrystallized from chloroform-methanol-concentrated aqueous ammonia (10:10:3) to give the title compound (0.076 g) as pale yellow prisms, mp 268°-270° C. (decompd.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:16](=[O:28])[NH:17][C:18]2=[O:27])=[N:13]1.Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:16](=[O:28])[N:17]([CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:18]2=[O:27])=[N:13]1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Cn1c(=O)n(CCN2CCOCC2)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-3-(1-methyl-1H-imidazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 4-(2-chloroethyl)morpholine using potassium carbonate as a base. Mass: 565.17 (M+H).