Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][C:32]=1[Cl:33])[O:19][CH:20]([C:22]1[S:26][C:25]([N:27]=[C:28]=[O:29])=[N:24][N:23]=1)[CH3:21]>CCCCCC>[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][C:32]=1[Cl:33])[O:19][CH:20]([C:22]1[S:26][C:25]([NH:27][C:28](=[O:29])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:24][N:23]=1)[CH3:21]
Reactant: CNCC(OC)OC
Reactant: CC(Oc1ccc(Cl)c(Cl)c1)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2ccc(Cl)c(Cl)c2)s1)OC
Yield: 68.1 %

Procedure:
3.3 grams (0.028 mole) of methylaminoacetaldehyde dimethylacetal was slowly added to a 50 milliliter benzene solution containing 9.0 grams (0.028 mole) of the 5-[1-(3,4-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting solution was heated to reflux and hexane was added, crystals formed on cooling. The crystals were filtered off, and dried in a vacuum oven at 80° C. to give 8.3 grams of fluffy white crystals at 3-[5-[1-(3,4-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-1-yl]-1-methyl-1-(2,2-dimethoxyethyl)urea. (Melting point 124°-127° C.).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Br-].[C:9]([CH2:12][CH2:13][N+:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=[CH:25][CH:26]=[CH:27]NC2C=CC=CC=2)=[CH:16][CH:15]=1)([OH:11])=[O:10].[CH3:35][CH:36]1[N:40]([CH2:41][CH2:42][CH2:43][S:44]([O-:47])(=[O:46])=[O:45])[C:39]2[C:48]3[C:53]([CH:54]=[CH:55][C:38]=2[S:37]1)=[CH:52][CH:51]=[CH:50][CH:49]=3.C(OCC)C>CS(C)=O.C(O)C>[C:9]([CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[CH:24][CH:25]=[CH:26][CH:27]=[CH:35][CH:36]2[N:40]([CH2:41][CH2:42][CH2:43][S:44]([O-:47])(=[O:45])=[O:46])[C:39]3[C:48]4[C:53]([CH:54]=[CH:55][C:38]=3[S:37]2)=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH:16]=[CH:15]1)([OH:11])=[O:10].[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: O=C(O)CC[n+]1ccc(C=CC=CNc2ccccc2)c2ccccc21
Reactant: CC1Sc2ccc3ccccc3c2N1CCCS(=O)(=O)[O-]
Agent: [Br-]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CCO
Product: CC[NH+](CC)CC
Product: O=C(O)CCN1C=CC(=CC=CC=CC2Sc3ccc4ccccc4c3N2CCCS(=O)(=O)[O-])c2ccccc21

Procedure:
A solution of 3 ml of triethylamine in 100 ml of dimethylsulfoxide was added to 4 g of 1-(2-carboxyethyl)-4-(4-anilino-1,3-butadien-1-yl)-quinolinium bromide and 3 g of 3-(2-methylnaphtho[1,2-d]thiazolin-1-yl)-propane-1-sulfonate and the resulting mixture was subjected to reaction at 100° C. for 2 hours. After completion of the reaction, the reaction product was cooled, and diethyl ether was added, after which the resulting precipitate was collected by filtration to obtain a crude dye. It was boiled together with ethanol to obtain crystals, and the crystals were recrystallized from methanol containing a small quantity of triethylamine to obtain 0.9 g of the objective compound (melting point 219° C.) which was dark green. Its maximum absorption wavelength as measured in triethylamine-containing methanol was 760 nm.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CS([Cl:37])(=O)=O>C(Cl)Cl>[Cl:37][CH2:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(CO)n2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(CCl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl 4-(6-hydroxymethylpyridine-2-carbonyl)-piperazine-1-carboxylate (1.26 g) and diisopropylethylamine (1.0 g) were dissolved in 20 mL of methylene chloride, 0.1 mL of methanesulfonyl chloride was added dropwise into the above solution at ice temperature, and the mixture was stirred at room temperature overnight. After the solvent was removed under reduced pressure from the reaction mixture, the residue was purified by chromatography on silica gel (methylene chloride-ethanol=40:1) to give 1.07 g of t-butyl 4-(6-chloromethylpyridine-2-carbonyl)piperazine-1-carboxylate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]21.[CH:25](=O)[CH3:26].[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:29].[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:24]([CH2:25][CH3:26])[CH2:28][CH3:29])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(Cl)cc1Cl
Reactant: CC=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 24 %

Procedure:
To a solution of 10-chloro-1-(2,4-dichlorophenyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-7-amine (29 mg, 0.075 mmol) in methanol (5.0 mL) and acetic acid (1.0 mL) was added acetaldehyde (0.05 mL, 0.84 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (173 mg, 0.84 mmol) at 0° C. After stirring at room temperature for 5 h, the mixture was con concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on a silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (8 mg, 0.018 mmol, 24%) as a white amorphous.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:10])[CH3:9])=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.[OH-].[Na+].C(OCC)C>O>[C:1]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][C:4]([CH:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[C:8](=[O:10])[CH3:9])=[CH:5][CH:6]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(=O)Cc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(=O)C(Cc1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
9.93 g of 1-(4-biphenylyl)-2-propanone, 8.4 g of 4-chlorobenzyl chloride and 2.1 g of sodium hydroxide were mixed and heated for 5 hours with stirring on an oil bath of 80° to 90° C. The reaction solution was left to cool to room temperature. Then, ethyl ether and water were added thereto. The organic layer was collected by separation and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane to obtain 8.42 g (yield: 53%) of the above-identified compound as colorless needles having a melting point of from 107° to 108.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])/[CH:5]=[C:6](\[CH3:30])/[CH:7]=[CH:8]/[CH:9]=[C:10](/[C:15]1[C:24]([OH:25])=[CH:23][C:22]2[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1)\[C:11]([F:14])([F:13])[F:12])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:38](I)[CH3:39].CC(C)=O>CCOC(C)=O.CCCCCC>[CH2:1]([O:3][C:4](=[O:31])/[CH:5]=[C:6](\[CH3:30])/[CH:7]=[CH:8]/[CH:9]=[C:10](/[C:15]1[C:24]([O:25][CH2:38][CH3:39])=[CH:23][C:22]2[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1)\[C:11]([F:13])([F:12])[F:14])[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/c1cc2c(cc1O)C(C)(C)CCC2(C)C)C(F)(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)/C=C(C)/C=C/C=C(/c1cc2c(cc1OCC)C(C)(C)CCC2(C)C)C(F)(F)F

Procedure:
Following General Procedure A and using (2E,4E,6Z)-8,8,8-trifluoro-7-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-methyl-octa-2,4,6-trienoic acid ethyl ester (Intermediate 5, 160 mg, 0.37 mmol), K2CO3 (253 mg, 1.83 mmol), EtI (0.15 mL, 1.83 mmol), and acetone (2 mL) followed by HPLC (2.5% EtOAc-hexane), the title compound was obtained as a clear syrup (81 mg, 48%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][NH:21][CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.CCN(C(C)C)C(C)C.[CH3:38][N:39]=[C:40]=[O:41].Cl>C(Cl)Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][N:21]([C:40]([NH:39][CH3:38])=[O:41])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2
Reactant: CN=C=O
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)N1Cc2ccccc2C2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
A vial was charged with N-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide (15 mg, 40 μmol), i-Pr2NEt (11 μL, 60 μmol) and CH2Cl2 (1 mL). Methyl isocyanate (3 μL, 43 μmol) was added and the mixture was stirred overnight at rt. A 10-mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL) and allowed to stand for 5 min. The reaction mixture was applied to the cartridge and eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford N1′(2-adamantyl)-N2-methyl-1H-spiro[isoquinoline-4,4′-piperidine]-1′,2(3H)-dicarboxamide (7.7 mg, 44%). LC-MS Method 1 tR=1.77 min, m/z=437; 1H NMR (CDCl3) δ=1.60-2.10 (18H), 2.80 (1H), 2.88 (s, 3H), 3.25 (m, 2H), 3.77 (s, 2H), 3.88 (d, 2H), 3.98 (s, 1H), 4.52 (s, 2H), 4.87 (1H), 7.05-7.40 (4H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].F[C:12]1[C:17]([F:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=1.Cl>CS(C)=O>[F:18][C:17]1[C:12]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[N:13][CH:14]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:16]=1
Reactant: Oc1ccc(O)cc1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A mixture of 16.5 g (0.15 mol) of hydroquinone, 19.1 g (0.3 mol) of potassium hydroxide (88%) in 600 ml of dimethylsulfoxide is stirred at room temperature under a nitrogen atmosphere until everything is dissolved. A solution of 13.7 g (0.075 mol) of 2,3-difluoro-5-trifluoromethyl-pyridine in 25 ml of dimethylsulfoxide is added dropwise at a temperature of 15°-20°. The reaction mixture is then stirred at room temperature for 24 hours. Then it is poured into ice/water and the mixture is acidified with hydrochloric acid, extracted with methylene chloride, washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. The residue crystallizes in hexane/ethyl acetate to yield 14.5 g (71%) of white crystals, melting at 97°.
Reaction SMILES: C(O[C:4](=[O:9])[CH2:5][N+:6]([O-:8])=[O:7])C.[H-].[Na+].[H][H].[CH3:14][N:15]1C(=O)O[C:18](=[O:19])[C:17]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:16]12.Cl>CC(N(C)C)=O>[OH:19][C:18]1[C:17]2[C:16](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:15]([CH3:14])[C:4](=[O:9])[C:5]=1[N+:6]([O-:8])=[O:7]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1c(=O)c([N+](=O)[O-])c(O)c2ccccc21
Temperature: 90 °C
Yield: 26.9 %

Procedure:
A solution of ethylnitroacetate (15.96 g, 120 mmol) was added slowly in a suspension of sodium hydride (60% in mineral oil, 5.28 g, 132 mmol) in dimethylacetamide under N2 atmosphere. The mixture was allowed to stir at room temperature until the evolution of hydrogen gas ceased, then heated to 90° C. for 30 min. and cooled to room temperature. A solution of N-methylisatoic anhydride (23.38 g, 132 mmol) in dimethylacetamide was added slowly and heated overnight at 120° C. The mixture was cooled to room temperature, poured into ice water, and acidified by cold 10% HCl. The solids formed were filtered and washed several times by water to yield 7.1 g (27%) of yellow solids. Mp 193° C. 1H NMR (DMSO-d6): δ3.60 (s, 3H), 7.37 (t, J=7.6 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.77 (t, J=7.5 Hz, 1H), 8.12 (d, J=7.9 Hz, 1H). EIMS m/z 221 (M+1), 243 (M+23). Anal. (C10H8N2O4) C, H, N.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][C:9]([OH:12])([CH3:11])[CH3:10])=[C:6](I)[C:5]([C:14]#[N:15])=[N:4]1)[CH3:2].[CH2:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])[C:17]#[CH:18].C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C.[Cu]I.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>[CH2:1]([N:3]1[C:7]([CH2:8][C:9]([OH:12])([CH3:11])[CH3:10])=[C:6]([C:18]#[C:17][CH2:16][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]([C:14]#[N:15])=[N:4]1)[CH3:2]
Reactant: C#CC[Si](C)(C)C
Reactant: CCn1nc(C#N)c(I)c1CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1nc(C#N)c(C#CC[Si](C)(C)C)c1CC(C)(C)O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 1-ethyl-5-(2-hydroxy-2-methylpropyl)-4-iodo-1H-pyrazole-3-carbonitrile (900 mg, 2.81 mmol), propargyltrimethylsilane (0.8 mL, 5.6 mmol), copper(I) iodide (107 mg, 0.562 mmol), dichlorobis(triphenylphosphine)palladium(II) (197 mg, 0.281 mmol), triethylamine (1.2 mL, 8.4 mmol) and acetonitrile (14 mL) were combined and then heated at reflux for five hours. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, and then filtered through a layer of silica gel. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a HORIZON HPFC system (40+M cartridge, eluting with a gradient of 0 to 80% ethyl acetate in hexanes) to provide 1-ethyl-5-(2-hydroxy-2-methylpropyl)-4-(3-trimethylsilylprop-1-ynyl)-1H-pyrazole-3-carbonitrile as a yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[OH-].[K+].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CS(C)=O>[CH3:11][C:4]1[CH:3]=[C:2]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: c1c[nH]cn1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 82.9 %

Procedure:
To a solution of 4-fluoro-2-methyl-1-nitro-benzene (300 mg, 1.84 mmol) in DMSO (2 mL) were added KOH (20 mg, 3.87 mmol) and imidazole (263 mg, 3.88 mmol). The reaction mixture was heated to 100° C. for 3.5 h, cooled to room temperature, and diluted with ice-cold water. The resulting precipitate was filtered, washed with ice-cold water, and dried under vacuum to give the title compound (310 mg, 80%) as a yellow powder. 1H NMR (300 MHz, DMSO-d6) δ 8.46 (1H, s), 8.16 (1H, d, J=8.9 Hz), 7.90-7.92 (2H, m), 7.78 (1H, dd, J=2.5, 8.9 Hz), 7.17 (1H, s), 2.61 (3H, s). LRMS (M+H)+ m/z 204.
Reaction SMILES: Cl[CH2:2]CCC(Cl)=O.[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24]N=[C:22]2[O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=1[F:39].C1(C)C=CC=CC=1>C(O)C>[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]([NH:36][C:35]1[CH:37]=[CH:38][C:32]([O:31][C:22]2[C:21]3[C:26](=[CH:27][C:28]([O:29][CH3:30])=[C:19]([O:18][CH3:17])[CH:20]=3)[N:25]=[CH:24][CH:2]=2)=[C:33]([F:39])[CH:34]=1)=[S:16])=[O:13]
Reactant: O=C(Cl)CCCCl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(CCCCl)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCCCl)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
4-Chlorobutanoyl isothiocyanate was prepared using commercially available 4-chlorobutanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-Chlorobutanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 54%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:19])[N:6]3[CH2:20][CH2:21][N:22]=[C:5]3[C:4]=2[CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:19])[N:6]3[CH2:20][CH2:21][N:22]=[C:5]3[C:4]=2[CH:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)C1=NCCN1C(=O)N2Cc1ccccc1
Product: CC(=O)Nc1ccc2c(c1)C1=NCCN1C(=O)N2Cc1ccccc1

Procedure:
Preparation analogously to Example 37 from 9-amino-5-oxo-6-benzyl-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline and acetic anhydride.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].Cl.[C:20]1([S:26]([C:29]2[S:33][C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:31][CH:30]=2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([S:26]([C:29]2[S:33][C:32]([N:34]3[CH2:39][CH2:38][N:37]([C:8]([C:7]4[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:6]=4[O:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[O:10])[CH2:36][CH2:35]3)=[N:31][CH:30]=2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(c1ccccc1)c1cnc(N2CCNCC2)s1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3ccccc3)s2)CC1
Yield: 45 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example A8) and 1-(5-benzenesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 4(d)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 45%). MS (m/e): 564.3 (M+H+, 100%), 581.3 (M+NH4+, 94%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[C:12]1[CH2:11][CH2:10][C@@H:9]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH2:8][C:7]2=1)(=[O:3])[CH3:2].CO[CH:33](OC)[N:34](C)C.Cl.NO>O1CCOCC1.O>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:13]1[C:12]2[CH2:11][CH2:10][C@@H:9]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH2:8][C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([C:1]1[O:3][N:34]=[CH:33][CH:2]=1)[CH:5]=2
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C(C)C)C1
Agent: Cl
Agent: NO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(-c4ccno4)ccc3n2Cc2cccc(F)c2)C1
Temperature: 40 °C

Procedure:
Combine (R)-N-[6-Acetyl-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 191) (0.055 g, 0.14 mmol) and dimethylformamide dimethylacetal (0.81 g, 6.8 mmol) and heat at 100° C. for 82 h. Concentrate in vacuo and treat the resulting residue with hydroxylamine hydrochloride (0.012 g, 0.18 mmol) in dioxane at 23° C. for 1 h before warming to 40° C. briefly. Dilute with water and collect 0.029 g of a solid by filtration. Recrystallize from EtOAc/hexanes to yield a light yellow solid. mp: 238-241° C.; MS (ES): m/z 432 (M+1); HPLC: Rt=2.59 (85%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].Br[CH:13]([CH3:17])[C:14](Br)=[O:15].C(N(CC)CC)C>CC(C)=O>[CH3:17][CH:13]1[O:4][C:3](=[O:5])[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:1][C:14]1=[O:15]
Reactant: CCCCCCC(O)C(=O)O
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCCCC1OC(=O)C(C)OC1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
2.5 g 2-hydroxyoctanoic acid (15.6 mmol) and 1.75 mL 2-bromopropionyl bromide (16.3 mmol) were stirred at 80° C. under nitrogen for 12 h. 150 mL acetone and 4.35 mL anhydrous triethylamine (31 mmol) were added to the mixture and the solution was stirred for 3 h at 60° C. After filtration of the triethylammonium bromide salts, acetone was distilled off and the resulting mixture was dissolved in 250 mL ethyl acetate:hexane mixture (1:2). After filtration over silica gel the solvents were distilled off, and the remaining crude product was recrystallized from hexane. 1H NMR (500 MHz, CDCl3): δ 5.00 (q, 1H), 4.89 (dd, 1H), 1.9-2.15 (br m, 2H), 1.70 (d), 1.66 (d), (3H, of 2 diastereoisomers), 1.45-1.65 (br m, 2H), 1.25-1.40 (br m, 6H), 0.90 (t, 3H). 13C NMR (500 MHz, CDCl3): δ 167.53, 166.90. 166.26, 165.87, 75.80, 72.49, 72.25, 31.92, 31.45, 31.39, 30.00, 28.73, 28.50, 24.60, 24.29, 22.48, 22.44, 17.54, 15.83, 14.00. ELEM. ANAL. Calcd. for C11H18O4: C, 61.68; H, 8.41. Found: C, 61.63; H, 8.48. Yield: 45%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:5]=[CH:6][C:7]=1[F:8]>C(O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(F)c(F)c1
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(F)c1
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A mixture of 4.53 g (13.9 mmol) 4-[(3,4-difluorophenyl)amino]-6-nitro-quinoline-3-carbonitrile, 200 ml ethanol and 15.72 g (69.4 mmol) SnCl2 dihydrate was heated to reflux under N2. Removed heat at 1½ hours, added ice water and made basic with sodium bicarbonate. Stirred for 2 hours and extracted with chloroform. Stirred organic layer with Darco, dried with sodium sulfate and filtered. Stripped solvent and dried in vacuo, giving 3.660 g of yellow-green solid: mass spectrum (electrospray m/e): M+H=297.1.
Reaction SMILES: Br[CH2:2]C1C=CC(F)=CC=1.Br.Br[CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[O:19]=[C:20]1[NH:24][CH2:23][CH2:22][N:21]1[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28]([O-:30])=[O:29]>>[O:19]=[C:20]1[N:24]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:23][CH2:22][N:21]1[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28]([O:30][CH3:2])=[O:29]
Reactant: BrCc1ccncc1
Reactant: O=C([O-])c1ccnc(N2CCNC2=O)c1
Reactant: Fc1ccc(CBr)cc1
Agent: Br
Product: COC(=O)c1ccnc(N2CCN(Cc3ccncc3)C2=O)c1
Yield: 43 %

Procedure:
Following the procedure as described in Preparation 17, making variations as required to replace 1-(bromomethyl)-4-fluorobenzene with 4-(bromomethyl)pyridine hydrobromide to react with 2-(2-oxoimidazolidin-1-yl)isonicotinate, methyl 2-(2-oxo-3-(pyridin-4-ylmethyl)imidazolidin-1-yl)isonicotinate was obtained as a colorless solid in 43% yield: mp 111-113° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.51 (d, J=5.7 Hz, 2H), 8.45-8.44 (m, 1H), 7.40-7.38 (m, 1H), 7.30 (d, J=6.0 Hz, 2H), 4.44 (s, 2H), 3.99 (t, J=7.9 Hz, 2H), 3.86 (s, 3H), 3.42 (t, J=7.9 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 165.7, 156.9, 153.7, 150.3, 149.1, 146.6, 138.5, 123.0, 116.4, 111.5, 53.2, 46.4, 41.7, 39.1; MS (ES+) m/z 312.9 (M+1).