Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15](Cl)=[O:16])[CH3:13].C(Cl)Cl.O>N1C=CC=CC=1>[CH2:12]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11])=[O:16])[CH3:13]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCCCC(CC)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCC(CC)C(=O)Nc1cc([N+](=O)[O-])ccc1O
Reaction time: 1 h

Procedure:
77 g 2-amino-4-nitrophenol were dissolved in 1600 ml pyridine. 81 g 2-ethylhexanoic acid chloride were added at 15 C. over 1 hour and the batch was subsequently heated at 35 C. for 5 hours. 250 ml methylene chloride and 700 ml water were added thereto, and the organic phase was washed with water and dilute hydrochloric acid and dried over Na2SO4, and the solvent was distilled off. The crude product was purified by means of column chromatography (silica gel 60, mobile phase toluene/ethyl acetate (4:1)) and was recrystallised from aqueous ethanol: 39 g of yellow solid with a melting point of 151 to 152 C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:20][N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:22]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[C:11]2[N:10]=1.COCCOC.[S:44](N)([NH2:47])(=[O:46])=[O:45]>O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:20][N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:22]([NH:23][CH:24]3[CH2:25][CH2:26][N:27]([S:44]([NH2:47])(=[O:46])=[O:45])[CH2:28][CH2:29]3)=[C:11]2[N:10]=1
Reactant: NS(N)(=O)=O
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(F)ccc32)c1NC1CCNCC1
Solvent: COCCOC
Solvent: O
Product: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(F)ccc32)c1NC1CCN(S(N)(=O)=O)CC1
Temperature: 150 °C
Yield: 88.4 %

Procedure:
180 mg of 5-(2,6-difluorophenyl)-7-fluoro-N-(piperidin-4-yl)-2-([2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-amine, 2 ml of DME and 41 mg of sulphamide are mixed and microwave-heated at 150° C. for 1 h. The mixture is poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol/aqueous ammonia mixture (95/05/0.5 by vol.), to give 183 mg of 4-{[5-(2,6-difluorophenyl)-7-fluoro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-sulphonamide (yellow solid). LC-MS-DAD-ELSD: 607=(M+H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH2:16][CH2:17][CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)C>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([NH:20][NH2:21])[CH:12]=[C:11]([CH2:16][CH2:17][CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCCc1cc(Cl)nc(SCc2ccccc2)n1
Solvent: CCO
Solvent: O
Product: CCCc1cc(NN)nc(SCc2ccccc2)n1

Procedure:
A mixture of 40 g (0.014 mole) of 2-benzylthio-4-chloro-6-n-propylpyrimidine (from Part B) and 15 g (0.3 mole) of hydrazine hydrate in 300 ml of ethanol was heated at reflux for 2 hours, cooled and evaporated. Water was added to the residue. The white solid was collected by filtration and dried to provide 2-benzylthio-4-hydrazino-6-n-propylpyrimidine. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1.C(N(CC)CC)C.[I-].[Na+]>C(O)C>[C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]3[CH:29]=[CH:28][C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c2ccc(CCBr)cc2o1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc(CCN3CCN(c4cccc5ccccc45)CC3)cc2o1
Yield: 23 %

Procedure:
To a 100 ml round-bottomed flask equipped with magnetic stirrer, condenser, and nitrogen inlet were added 0.618 g (2.10 mmol) of N-(1-naphthyl)piperazine 0.472 g (1.95 mmol) of 6-(2-bromoethyl)-benzoxazolone, 0.411 ml (2.92 mmol) of triethylamine, 50 ml ethanol, and a catalytic amount of sodium iodide. The reaction was refluxed for 3 days, cooled, and evaporated to a brown gum. The gum was partitioned between 50 ml water and 75 ml methylene chloride, the pH adjusted with aqueous 1 N sodium hydroxide solution, and a little methanol added to facilitate phase separation. The methylene chloride layer was dried over sodium sulfate and evaporated, then chromatographed on silica gel. Fractions containing the product were combined and evaporated, the residue taken up in ethyl acetate, treated with hydrochloride gas, and the resulting hydrochloride salt of the product filtered off to give the while solid title compound, m.p. 282°-285° C., 213 mg (23% yield).
Reaction SMILES: [CH:1]1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][N:13]1[C:17]([C:18]2[S:28][C:21]3[N:22]=[CH:23][N:24]=[C:25](SC)[C:20]=3[CH:19]=2)=[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:15]=[CH:14]1.[O-:35][S:36]([O-:39])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH3:12][N:13]1[C:17]([C:18]2[S:28][C:21]3[N:22]=[CH:23][N:24]=[C:25]([S:36]([CH3:1])(=[O:39])=[O:35])[C:20]=3[CH:19]=2)=[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:15]=[CH:14]1
Reactant: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3C)cc12
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reaction time: 6 h
Yield: 56 %

Procedure:
m-CPBA (70-75%, 105 mg) was added to a stirred solution of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (example 7) (72 mg) in DCM (5 mL), stirred for 6 hours then 2M Na2S2O3 (2.5 mL) was added. The organic layer was separated and the aqueous layer extracted with DCM (2×15 mL). The combined organics were washed with saturated aqueous NaHCO3 (10 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with hexane:EtOAc (1:4) afforded the title compound as a yellow solid (44 mg, 56%);
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[N:12]=[C:13]([C:17]([O:19]CC)=[O:18])[NH:14][C:15](=[O:16])[C:6]1=[CH:5]2.[OH:22][C:23]1C=C2C(=CC=1)N=C1N=C(C(O)=O)NC(=O)C1=C2>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:22][CH3:23])[N:8]=[C:7]1[N:12]=[C:13]([C:17]([OH:19])=[O:18])[NH:14][C:15](=[O:16])[C:6]1=[CH:5]2
Reactant: CCOC(=O)c1nc2nc3ccc(O)cc3cc2c(=O)[nH]1
Reactant: O=C(O)c1nc2nc3ccc(O)cc3cc2c(=O)[nH]1
Product: COc1cc2nc3nc(C(=O)O)[nH]c(=O)c3cc2cc1O

Procedure:
In like manner, ethyl 7-hydroxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylate hemitrifluoroacetate (210 mg.) is converted to 7-hydroxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylic acid. Yield - 191 mg., 91%; m.p. 340° C. (dec.)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[CH2:16]([NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:17]>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:18]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][CH3:17]
Reactant: COc1ccc(N)c(CO)c1
Reactant: CCNC1CCCCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(Cc1cc(OC)ccc1N)C1CCCCC1

Procedure:
2-Amino-N-cyclohexyl-N-ethyl-5-methoxy-benzylamine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and N-ethyl-cyclohexylamine analogous to Example 1. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][C:17]1[C:18]([NH:25][C:26](=[O:28])[CH3:27])=[N:19][CH:20]=[C:21]([CH:23]=[CH2:24])[CH:22]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:24][CH2:23][C:21]3[CH:22]=[C:17]([CH3:16])[C:18]([NH:25][C:26](=[O:28])[CH3:27])=[N:19][CH:20]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc(NC(C)=O)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ncc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1C

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, N-(3-methyl-5-vinylpyridin-2-yl)acetamide and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH2:17]([O:4][C:3](=[O:5])[C@H:2]([OH:1])[CH2:6][CH:7]([CH3:9])[CH3:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)C[C@@H](O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)C[C@@H](O)C(=O)OCc1ccccc1

Procedure:
264.0 g of (R)-2-hydroxy-isocaproic acid were dissolved in 1.8 liters of absolute dioxan in a three-necked flask fitted with a stirrer, thermometer and reflux condenser with a calcium chloride tube. The solution was treated successively with 285 ml. of triethylamine and 236 ml. of benzyl chloride and heated at an internal temperature of 100° for 20 hours with stirring in an oil-bath. After cooling, the resulting triethylamine hydrochloride was filtered off and washed with 500 ml. of ethyl acetate. The filtrate was evaporated under reduced pressure at 50°. The residual oil was dissolved in 800 ml. of ethyl acetate and washed twice with 150 ml. portions of 3-N hydrochloric acid, twice with 100 ml. portions of 5% sodium chloride solution, twice with 150 ml. portions of 10% potassium bicarbonate solution and twice with 100 ml. portions of 5% sodium chloride solution. After each of these washings, the oil was rinsed with 200 ml. of ethyl acetate. The ethyl acetate solutions were dried over magnesium sulphate and evaporated under reduced pressure at 50°. The crude product which was thus-obtained was distilled at 0.3 Torr (112°-115°). There was obtained benzyl-(R)-2-hydroxyisocaproate; [α]D25 =+18.0° (c = 1 in methanol); nD23 = 1.498.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[NH2:28][C:26]([C:25]1[CH:29]=[CH:30][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=2)=[O:13])=[CH:23][CH:24]=1)=[O:27]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC(=O)c1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(C(N)=O)cc2)cc1
Yield: 8.9 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (4.00 g, 11.7 mmol) in 100 mL of dichloromethane and 4-aminobenzamide (3.20 g, 23.5 mmol) in 26 mL of pyridine. The crude product was triturated with a hot mixture of acetonitrile and DMF, filtered, recrystallized from ethanol-water-DMF, triturated with a hot mixture of methanol and DMF, and filtered to yield 0.563 g of the title compound, mp >270° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]([OH:28])([C:26]#[CH:27])[CH3:25].C(N(CC)CC)C>CS(C)=O.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:27]#[C:26][C:24]([CH3:25])([OH:28])[CH3:23])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(C)O
Reactant: COCCNc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COCCNc1nc2ccc(C#CC(C)(C)O)cc2n1-c1ccnc(N)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
A mixture of 1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine (120 mg, 0.33 mmol), 2-methylbut-3-yn-2-ol (277.2 mg, 3.30 mmol), bis(triphenylphosphine)palladium(II) dichloride (231.67 mg) and triethylamine (2.4 mL) in dimethylsulfoxide (1 mL) was stirred under nitrogen for 1 hr at 70° C. The reaction mixture was cooled to room temperature and the solid material was removed by filtration. The filtrate was diluted with 5 mL of water then extracted with 3×30 mL of ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC to give 5.0 mg (4%) of 4-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]-2-methylbut-3-yn-2-ol as a white solid: 1H NMR (300 MHz, DMSO) delta 8.43 (d, J=5.4 Hz, 1H), 8.21 (d, J=5.4 Hz, 1H), 7.47 (s, 1H), 7.25 (s, 1H), 7.16-7.12 (m, 3H), 6.91 (d, 1H), 5.40 (s, 1H), 3.63-3.57 (m, 4H), 3.35 (s, 3H), 1.47 (s, 6H); LC-MS: m/z=+367 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.C([Li])CCC.[CH3:14]SSC.[S:18](S([O-])=O)([O-:21])(=O)=[O:19].[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([S:18]([CH3:14])(=[O:21])=[O:19])[CH:7]=1
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CSSC
Reactant: Brc1cncc(Br)c1
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CS(=O)(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3,5-dibromopyridine (2.96 g, 12.5 mmol) in diethyl ether (70 ml) at −78° C. was added n-butyllithium 1.6M in hexanes (8.6 ml, 13.7 mmol) and the resulting mixture was stirred in the cold for 3 hours. Dimethyl disulfide (1.12 ml, 12.5 mmol) was added and the mixture was warmed to room temperature, then partitioned between ether and water. To the crude product from evaporation of the organic phase was added tetrahydrofuran (80 ml), methanol (20 ml), oxone (17 g) and enough saturated aqueous sodium bicarbonate to afford a slightly basic medium. After stirring for 4 hours at room temperature, an excess of 1M aqueous sodium metabisulfite was added, the organic solvents were evaporated, and the residue was partitioned between ethyl acetate and water. The crude product from the organic phase was stirred in a small volume of ethyl acetate and filtered to afford the 3-Bromo-5-methylsulfonylpyridine compound as a solid.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:21][CH2:22][C:23](Cl)=[O:24].C([O-])(O)=O.[Na+]>ClCCl.O>[C:10]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:23](=[O:24])[CH2:22][Cl:21]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)Nc1ccccc1-c1ccccc1
Temperature: -18 °C
Reaction time: 15 h
Yield: 14.3 %

Procedure:
Triethylamine (26.7 g) was added to a solution of 2-aminobiphenyl (41.4 g) in dichloromethane (248 mL) at room temperature. The solution obtained was cooled to −18° C. and chloracetylchloride (28.8 g) was slowly added. The suspension obtained was further stirred for 1 hour at 0° C. and for 15 hours at room temperature. Dichloromethane (150 mL), ice-water (500 mL), water (500 mL) and saturated aqueous NaHCO3 (150 mL) were added. After stirring, the phases were separated, the organic phase was washed with half-saturated aqueous NaCl (1000 mL) and the aqueous phases were extracted with dichloromethane (250 mL). The combined organic layers were dried (MgSO4) and concentrated under vacuum to a weight of ca. 100 g. After 40 minutes stirring at room temperature, the precipitate was filtered off, washed with dichloromethane (80 mL) and dried under high vacuum to afford N-biphenyl-2-yl-2-chloro-acetamide (8.6 g, 14.5%) as white crystals. The filtrate was further concentrated under reduced pressure to a weight of ca. 115 g and hexane (100 mL) was added dropwise. After 1 hour of stirring at room temperature, the precipitate was filtered off, washed with 3 portions of hexane/dichloromethane 4:1 (22 mL) and dried under high vacuum affording N-biphenyl-2-yl-2-chloro-acetamide (31.2 g, 53.0%) as a grey powder. The filtrate was concentrated under reduced pressure to a weight of ca. 90 g and stirred for 1 hour at room temperature. The precipitate was filtered off, washed with 2 portions of hexane/dichloromethane 4:1 (17 mL) and dried under high vacuum affording N-biphenyl-2-yl-2-chloro-acetamide (10.8 g, 18.3%) as a grey powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:10][C:11]1([CH3:19])[O:18][C:16](=[O:17])[CH2:15][C:13](=[O:14])[O:12]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1CCC[C@H]1C(O)=O.C(#N)C>[CH3:10][C:11]1([CH3:19])[O:18][C:16](=[O:17])[CH:15]([CH:20]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13](=[O:14])[O:12]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC#N
Product: CC1(C)OC(=O)C(C(c2ccccc2)c2c[nH]c3ccccc23)C(=O)O1
Reaction time: 2 h
Yield: 67.3 %

Procedure:
Indole (10 g, 85 mmol), Meldrum's acid (12.3 g, 85 mmol), benzaldehyde (18.11 g, 171 mmol) and proline (0.05 g) were combined with 50 ml of acetonitrile and stirred in an oil bath at approximately 35°-40° C. for two hours [Y. Oikawa, H. Hirasawa, and O. Honemitsu, Tetrahedron Letters, 1759 (1978)]. The reaction mixture was concentrated in vacuo to dryness. The residue was slurried with methanol and filtered to provide 19.99 grams of 3-[α-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)benzyl]indole. A portion of the product was recrystallized from ethyl acetate to provide a white crystalline product: mp 147°-150° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.C(OC([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=O)(C)(C)C.O>C(OCC)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:24]2[CH2:25][CH2:26][NH:21][CH2:22][CH:23]=2)=[N:8][CH:9]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Clc1ccc(C2=CCNCC2)nc1
Reaction time: 0.5 h

Procedure:
Butyllithium (15% in hexane; 7.6 ml) was added dropwise to a solution of 2-bromo-5-chloropyridine (2.0 g) in diethyl ether (50 ml) at −78° C. and, after one hour, a solution of N-tert-butoxycarbonyl-4-piperidinone (2.1 g) in diethyl ether (10 ml) was added dropwise. After 30 minutes, water was cautiously added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was treated with thionyl chloride (3 g) for 24 hours, and the concentrated reaction solution was purified by preparative HPLC. The product with the molecular weight of 194.67 (C10H11ClN2); MS (ESI): 195 (M+H+) was obtained in this way.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1.ClCCl.CO>CN(C)C=O>[C:26]([O:25][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:4]2[C:3](=[O:10])[C:2]([CH3:1])=[C:7]([Cl:8])[NH:6][C:5]2=[O:9])=[CH:31][CH:30]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: Cc1c(Cl)[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1c(Cl)[nH]c(=O)n(Cc2ccc(C(=O)OC(C)(C)C)cc2)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.3 %

Procedure:
5-Methyl-6-chloropyrimidine-2,4-dione (1.00 g, 6.22 mmol) was dissolved in dimethylformamide (15 mL).To the solution was added cesium carbonate (2.02 g, 6.22 mmol) and t-butyl 4-bromomethylbenzoate (1.69 g, 6.22 mmol). The mixture was stirred at room temperature for 20 hours. The solvent was evaporated under a vacuum at 60° C. The residue was mixed with tetrahydrofuran (50 mL) and methanol (10 mL) and filtered. The filtrate was evaporated in a vacuum to an amber oil. The oil was purified by flash chromatography on silica gel eluting first with dichloromethane then with dichloromethane:methanol (19:1) to give the desired product (0.88 g, 40% yield). 1H-NMR (DMSO-d6) δ 11.8 (s, 1H), 7.85 (d, 2H), 7.34 (d, 2H), 5.22 (s, 2H), 1.88 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.S(Cl)([Cl:13])=O>>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([Cl:13])=[O:10])[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC1CCOCC1
Product: O=C(Cl)CC1CCOCC1
Temperature: 25 °C

Procedure:
A solution of tetrahydropyran-4-yl acetic acid (Combi-Blocks, Inc., 0.18 g, 1.2 mmol) in thionyl chloride (7 mL, 96 mmol, excess) was refluxed for 1 h then was cooled to ambient temperature and concentrated under reduced pressure. The residue was azeotroped twice with 10 mL of benzene to remove any remaining thionyl chloride. The resulting acid chloride was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][N:38]([CH3:48])[C:39](=[O:47])[CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:44]3[CH2:43][CH2:42][N:41]([CH2:40][C:39]([N:38]([O:37][CH3:36])[CH3:48])=[O:47])[CH2:46][CH2:45]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CON(C)C(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)OC)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-methoxy-N-methyl-acetamide hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 16b) in an analogous manner as described in example 25. LR-MS: 680.5 [(M+H)+]
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:23]=[CH:22][C:7]2=[C:8]3[C:17](=[CH:18][CH:19]=[C:6]2[CH:5]=1)[C:16](=[O:20])[C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]3=[O:21].CCCC[O:28][N:29]=O>O.C(O)CCC>[OH:3][C:4]1[CH:23]=[CH:22][C:7]2=[C:8]3[C:17](=[CH:18][CH:19]=[C:6]2[C:5]=1[N:29]=[O:28])[C:16](=[O:20])[C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]3=[O:21]
Reactant: CCCCON=O
Reactant: O=C1c2ccccc2C(=O)c2c1ccc1cc(O)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: O=Nc1c(O)ccc2c3c(ccc12)C(=O)c1ccccc1C3=O
Temperature: 60 °C

Procedure:
A solution of sodium hydroxide (0.72 g) in water (0.72 g) is added under stirring at ambient temperature to a suspension of 3-hydroxy-benzo[a]anthracene-7,12-dione, prepared as described in Journal Organic Chemistry (1986) 51 page 3502, (5 g; 18 mmoles) in butanol (25 ml). N-butylnitrite (2 g; 19.4 mmoles) is added over a period of 1 hour to the mixture, which is maintained at 60° C. The reaction mixture is maintained at 60° C. for 4 hours, cooled to ambient temperature and filtered. The solid is washed with toluene (2×10 ml), dried under vacuum and suspended in water (25 ml). Acetic acid (2 ml) is added to the suspension over a period of 30 minutes, operating at ambient temperature under stirring.