Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[N:16][CH:17]=[C:18]([C:20](O)=[O:21])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:30](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.N=[C:61]1[CH2:66][CH:65]([CH2:67][CH2:68][OH:69])[CH2:64][CH2:63][NH:62]1>CN(C=O)C.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:15]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[N:16][CH:17]=[C:18]([C:20](=[O:21])[NH:30][N:62]3[CH2:63][CH2:64][CH:65]([CH2:67][CH2:68][OH:69])[CH2:66][CH2:61]3)[CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C1CC(CCO)CCN1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)O)cnc2OCC(F)(F)F)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)NN3CCC(CCO)CC3)cnc2OCC(F)(F)F)CC1
Reaction time: 8 h

Procedure:
In a 10 mL round-bottomed flask, the above prepared 2-(2,2,2-trifluoro-ethoxy)-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-5,1′-dicarboxylic acid 1′-tert-butyl ester (100 mg, 247 mmol, Eq: 1.00) was combined with tetrahydrofuran (3 mL) and DMF (1 mL) to give a colorless solution. TBTU (119 mg, 371 μmol, Eq: 1.5) and N,N-diisopropylethylamine (160 mg, 216 μl, 1.24 mmol, Eq: 5) were added and the reaction mixture was stirred for 10 min at rt before 2-(1-aminopiperidin-4-yl)ethanol (61.1 mg, 297 μmol, Eq: 1.2, preparation see Example 38) was added and the reaction mixture kept overnight at rt. The reaction mixture was then quenched with sat NH4Cl sol. 10 mL and extracted with EtOAc (2×20 mL). The organic layers were washed with 1 M NaOH, then with H2O/NaCl sol., combined, dried over Na2SO4, and concentrated in vacuo. Purification by flash chromatography (silica gel, 20 g, 2% to 5% MeOH in DCM) delivered eventually 101 mg of the title compound as white foam; MS (EI) 531.6 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.Cl[C:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17](=[O:25])(=[O:24])[N:16]=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17](=[O:24])(=[O:25])[N:16]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)cnc1CCCCNC1=NS(=O)(=O)c2ccccc21
Reaction time: 0.25 h

Procedure:
To a refluxing solution of 4-(5-bromo-3-methyl-2-pyridinyl)butylamine (1.87 g, 7.69 mmol) in chloroform (80 ml, freed of EtOH by passage through Woelm Grade I neutral alumina) was added over 50 minutes a solution of 3-chloro-1,2-benzisothiazole-1,1-dioxide (U.S. Pat. No. 4,490,527) (1.55 g, 7.69 mmol) in chloroform (50 ml, purified as above) while maintaining reflux. After the addition was complete, reflux was continued for another 15 minutes. Evaporation in vacuo gave a yellow orange foam. Crystallization from 2-propanol and recrystallization from methanol/methylene chloride/2-propanol (Norite) gave 2.07 g of the title compound as a tan solid hydrochloride: m.p. 232°-244° C., IR(KBr) 3070, 1610, 1578, 1508, 1280, 1140 cm-1. 1H NMR (Me2SO d6) 9.85 (1H, t), 8.70 (1H, s), 8.33 (1H, m), 8.27 (1H, s), 7.88 (3H, m) 3.40 (2H, m), 2.90 (2H, m), 2.37 (3H, s), 1.70 (4H, m).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]([CH3:22])[NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].[H-].[Na+].[Cl-].ClC[C:40]1[CH:41]=[NH+:42][CH:43]=[CH:44][CH:45]=1.O.[CH3:47]N(C)C=O>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14]([CH3:47])([CH3:22])[N:13]([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: ClCc1ccc[nH+]c1
Reactant: CN(C)C=O
Reactant: CC1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC1(C)N(c2cccnc2)C(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
(rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-2-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (200 mg, 0.41 mmol) was dissolved in dimethyl formamide (10 mL) and sodium hydride (40 mg, 60% in mineral oil, 1 mmol) and 3-chloromethyl pyridinium chloride (82 mg, 0.5 mmol) were added and stirred at room temperature overnight. Water (30 mL) was added and the reaction mixture extacted with ethyl actetate. The organic phases were pooled, dried with MgSO4 and the solvent was evaporated. The residue was purified by chromatography on silica gel (ethyl acetate) to yield the desired product (219 mg, 93%), MS: m/e=577.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11](Br)=[CH:12][CH:13]=1)=[O:8].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)=[CH:12][CH:13]=1)=[O:8]
Reactant: CS(=O)(=O)Nc1c(F)cc(CNC(=O)c2ccc(Br)s2)cc1F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1c(F)cc(CNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F
Temperature: 110 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
To a suspension of 5-bromo-thiophene-2-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide (100 mg, 0.235 mmol), Pd(PPh3)4 (4.1 mg, 0.0035 mmol), and 4-trifluoromethyl phenyl boronic acid (53.5 mg, 0.282 mmol) in toluene (1 mL) was added 2N—Na2CO3 (0.5 mL)/EtOH (0.5 mL). The mixture was stirred 3 hours at 110° C. and was diluted with EtOAc. The mixture was washed with 1N HCl, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in n-hexane) to give title compound (90 mg, 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:49]=[CH:48][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([C:37](=O)[C:38]6[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=6)=[CH:33][CH:32]=5)=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([SiH](CC)CC)C.ClC(Cl)C.C(Cl)(Cl)Cl>ClCCl>[N+:1]([C:4]1[CH:49]=[CH:48][C:7]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([CH2:37][C:38]6[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=6)=[CH:33][CH:32]=5)=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccc(Cc2ccc(Cc3ccc(Cc4ccc(C(=O)c5ccc([N+](=O)[O-])cc5)cc4)cc3)cc2)cc1)c1ccc([N+](=O)[O-])cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1ccc(Cc2ccc(Cc3ccc(Cc4ccc(Cc5ccc(Cc6ccc([N+](=O)[O-])cc6)cc5)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.8 %

Procedure:
In a 1-liter four-necked flask equipped with a stirring device, a thermometer, a condenser and a nitrogen substituting device, 17.7 g of 1,1-bis(4-(4-(4-nitrobenzoyl)phenylmethyl) phenyl)methane was dissolved in 150 milliliters of dichloromethane, 14.5 g of triethylsilane and 20.7 g of boron trifluoride ethyl ether complex were added, and they were stirred for 20 hours at reflux of dichloroethane. After the end of the reaction was confirmed by a liquid chromatography, the reaction solution was cooled to room temperature, poured in 100 milliliters of ice water, and then 150 milliliters of chloroform was added for extraction. Thereafter, the solution was washed with a 6N-HCl aqueous solution of from 50° to 55° C., an aqueous solution of sodium hydrogencarbonate, brine and water, removed off chloroform and dichloroethane by a rotary evaporator, and then recrystallized from a chloroform solvent, to obtain 16.4 g of 1,1-bis(4-(4-(4-nitrophenylmethyl)phenylmethyl)phenyl)methane as crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:14])[CH:4]=1)=O.[CH:15](C1C=CC(C(O)=O)=C(C)C=1)=O.OS(O)(=O)=O>CCO>[CH3:14][C:5]1[CH:4]=[C:3]([CH:1]=[CH2:15])[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(C=O)cc1C
Reactant: Cc1cc(C=O)ccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: C=Cc1ccc(C(=O)OCC)c(C)c1
Temperature: 80 °C
Yield: 80 %

Procedure:
Ethyl 4-formyl-2-methylbenzoate (AI16). To a stirred solution of 4-formyl-2-methylbenzoic acid (3 g, 18.2 mmol) in EtOH (30 mL) was added conc. H2SO4 (2 mL) and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water. The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a solid (2.8 g, 80%): 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.04 (m, 1H), 7.75 (m, 2H), 4.43 (m, 2H), 2.65 (s, 3H), 1.42 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][NH:25][CH2:26][CH3:27])[CH:7]=1)[CH3:2].C(N(CC)CC)C.Cl[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][N:25]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH2:26][CH3:27])[CH:7]=1)[CH3:2]
Reactant: CCNCc1cc([N+](=O)[O-])ccc1Oc1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CN(CC)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To [3-(2-ethylaminomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.5 g, 1.29 mmol) in CH2Cl2 (20 mL) was added triethylamine (1 mL, 7.17 mmol), followed by benzyl chloroformate (0.25 g, 1.5 mmol), and the reaction was stirred at room temperature for 30 minutes. After work-up, the crude material was purified by silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5]CC)=O.[C:12]([NH2:20])(=[NH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na]>C(O)C>[C:13]1([C:12]2[NH:20][C:3](=[O:5])[CH2:2][C:1](=[O:9])[N:19]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)c1ccccc1
Agent: [Na]
Solvent: CCO
Product: O=C1CC(=O)NC(c2ccccc2)=N1

Procedure:
Wherein R1, R2 and R3 are defined as above. The cyclization reaction between the commercially available diethyl malonate and an appropriate benzamidine is effected by refluxing a substantially equimolar mixture of these reactants in a reaction-inert solvent, such as ethanol, in the presence of sodium metal for a period of about two to about five hours. After the reaction is complete, the reaction mixture is filtered, the filter cake dissolved in water and precipitated by acidification to afford a 2-phenyl-4,6-(1H,5H)-pyrimidinedione (I).
Reaction SMILES: [IH:1].[CH:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1>C(O)C>[I-:1].[CH:2]1[C:15]2[C:6](=[NH+:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2nc3ccccc3cc2c1
Reactant: I
Solvent: CCO
Product: [I-]
Product: c1ccc2[nH+]c3ccccc3cc2c1
Temperature: 55 °C
Yield: 96 %

Procedure:
Dropwise addition takes place of 1.5 g (7.5 mmole) of 65% hydroiodic acid to a 1.35 g (7.5 mmole) solution of acridine in 20 ml of ethanol. Towards the end of the addition an orange precipitate appears. Ethanol is then added accompanied by heating to 50 to 60° C. until the said precipitate has completely dissolved (approximately 20 ml of ethanol). Cooling takes place in the refrigerator and the acridinium iodide is filtered. In this way 2.2 g of a redorange monocrystalline solid are recovered corresponding to a 96% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(CC(O)C(F)(F)F)c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(CC(O)C(F)(F)F)c2=O)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
An amount of 280 mg (0.61 mmol) of the compound from Example 24A was dissolved in 4 ml of a 1:1 mixture of methanol and THF and admixed with 0.61 ml of 2 N sodium hydroxide solution. It was stirred at 80° C. for 1 h. For working out, it was admixed with 5 ml of water and extracted with 5 ml of ethyl acetate. The aqueous phase was acidified to a pH of 1 using 1 N hydrochloric acid and extracted with twice 5 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. This gave 275 mg (100% of theory) of the target compound.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[C:17]1([C:27](Cl)=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:27]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[O:28])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Product: CC(C)NCC(=O)c1ccc(OC(=O)c2cccc3ccccc23)c(O)c1

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 1-naphthalenecarbonyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(1-naphthalenecarbonyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(1-naphthalenecarbonyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.[C:12](OCC)(=[O:14])C>>[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([O:14][CH3:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: OC/C=C/c1cccc(Br)c1
Reactant: CCOC(C)=O
Product: COC(=O)/C=C/c1cccc(Br)c1
Yield: 73 %

Procedure:
The title compound was prepared from trans-3-(3-bromophenyl)-2-propenol by a sequence analogous to that described above for compound (9a) but using D-(-)-diethyl tartrate. Column chromatography (ethyl acetate--light petroleum (b.p. 40-60° C.), 3:7) provided the title compound (73%) as a pale yellow oil. Distilled at 160-185° C. at 0.1 mmHg. using a Kugelrohr short path distillation apparatus as a colourless oil; [α]D25 +37.6 (c=0.020 gml-1, CHCl3).
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Cl[C:13]1[CH:18]=[C:17](Cl)[CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].[ClH:23].[OH-].[Na+]>CN1C(=O)CCC1>[CH3:8][O:7][C:5](=[O:6])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:23])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])[C:3]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: Cl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COC(=O)C(C(=O)OC)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a stirred slurry of NaH (36.0 g, 1500 mmol) in NMP (1.0 L) was added dimethyl malonate (137.4 mL, 1200 mmol) drop wise. The reaction was cooled as needed to keep the internal temperature below 30 degrees Celsius. After gas evolution ceased, 2,4-dichloronitrobenzene (192 g, 1000 mmol) was added to the reaction. It was carefully heated to 65 degrees Celsius until the reaction was complete as determined by HPLC. The reaction was cooled to room temperature, and then poured over 500 mL ice mixed with 150 mL conc. HCl. The pH of the aqueous layer was adjusted to neutral using 1 N NaOH. The solids were removed by filtering through a coarse fritted filter, and rinsed with water (3 L). The yellow solids were allowed to dry overnight. Yield 261.5 g, 91%.
Reaction SMILES: [CH:1]([C:4]1[C:9]2[C:10](=O)[NH:11][S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:16][CH3:17])[CH:5]=1)([CH3:3])[CH3:2].[CH2:18]=[O:19].[BrH:20]>C(O)(=O)C>[Br:20][CH2:10][N:11]1[C:18](=[O:19])[C:9]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]([O:16][CH3:17])=[CH:7][C:8]=2[S:12]1(=[O:13])=[O:14]
Reactant: C=O
Reactant: Br
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)NC2=O
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Temperature: 0 °C
Yield: 66 %

Procedure:
To a mixture of 4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide in acetic acid (20 ml) was added paraformaldehyde (0.7 g, 23.33 mmol), followed by 48% HBr in acetic acid (4.2 ml, 23.45 mmol). The mixture was heated at 50°-55° C. for 4 hours, cooled, poured over ice-water and filtered. The product was purified by column chromatography on silica gel eluting with 10-15% ethyl acetate/hexane to afford 1.88 g (66%) of 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, m.p. 157°-159° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[N:4][C:3]=1[C:19]([O:21]CC)=O.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>CCOCC>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:19]([C:3]2[N:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:8][CH:7]=3)=[O:21])=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1nnc2ccc(CN3CCOCC3)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOCC
Product: O=C(NCc1ccc(Cl)cc1)c1nnc2ccc(CN3CCOCC3)cc2c1O
Yield: 89 %

Procedure:
A solution of ethyl 4-hydroxy-6-(4-morpholinylmethyl)-3-cinnolinecarboxylate (Preparation 11, 0.382 g) and 4-chlorobenzylamine (1.46 mL) is heated to 80° C. for 30 min over which time a solid forms. The reaction is diluted with Et2O and the resulting solid is collected and dried to yield 0.443 g (89%) of the desired compound as an off-white solid. Physical characteristics are as follows: m.p. 277-280° C. (dec); 1H NMR (DMSO-d6) δ10.12, 8.09, 7.86, 7.74, 7.40, 4.56, 3.63, 3.58, 2.38; MS (ESI+) for C21H21ClN4O3 m/z 413.0 (M+H)+MS (ESI−), 410.9 (M−H)−.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH:10]([CH3:14])[CH2:11][CH:12]=[O:13])[CH2:5]1)([CH3:3])[CH3:2].C=O.[C:17](O)(=O)CC.N1CCCC1>C(O)(C)C.CC(OC)(C)C>[CH:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH:10]([CH3:14])[C:11](=[CH2:17])[CH:12]=[O:13])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1CCCC(C(C)CC=O)C1
Reactant: CCC(=O)O
Agent: C=O
Solvent: COC(C)(C)C
Solvent: C1CCNC1
Solvent: CC(C)O
Product: C=C(C=O)C(C)C1CCCC(C(C)C)C1
Temperature: 45 °C
Reaction time: 3 h
Yield: 800 %

Procedure:
A solution of 3-(3-isopropylcyclohexyl)butanal (6 g, 30.5 mmol) in isopropanol (3.5 mL) followed by formaldehyde (37% wt in water, 30.5 mmol, 1 eq) was charged into a 50 mL three-necked round-bottom flask equipped with a reflux condenser and a mechanical stirrer. Propionic acid (228 L, 3.0 mmol, 0.1 eq) and pyrrolidine (255 L, 3.0 mmol, 0.1 eq) were added at ambient temperature. The reaction mixture was then stirred at 45° C. for 3 h. The crude mixture was cooled to ambient temperature dissolved in MTBE (100 mL) and washed with saturated aqueous NaHCO3 (100 mL), brine (100 mL), dried over magnesium sulphate and concentrated. The crude product was chromatographed on a silica gel column with 3% EtOAc in hexane as elution agent giving 3-(3-isopropylcyclohexyl)-2-methylenebutanal (5 g, gc purity>99%; yield 78%).
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[CH:1]1([CH2:7][NH:8][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCCCC1
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 113.3 %

Procedure:
Cyclohexylmethylamine (2.86 mL, 2.49 g, 22.0 mmol) was added to a mixture of N-(4-fluoro-3-nitrophenyl)acetamide (3.96 g, 20.0 mmol) and sodium carbonate (4.66 g, 44 mmol) in EtOH (50 mL) at room temperature. The reaction mixture was heated for 48 h at 60° C., and diluted with H2O (800 mL). The orange solid was precipitated out and collected to give the desired title product (6.60 g, 100%). MS (ESI) (M+H)+: 292.32.
Reaction SMILES: [NH2:1][C:2]1[N:33]([CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:31][CH3:32])[N:9]=[CH:10][C:5]=2[C:4](=[O:39])[C:3]=1[C:40](=[O:42])[NH2:41].[ClH:43].CCOCC>ClCCl.O1CCOCC1>[ClH:43].[NH2:1][C:2]1[N:33]([CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]4)=[CH:14][C:13]=3[O:31][CH3:32])[N:9]=[CH:10][C:5]=2[C:4](=[O:39])[C:3]=1[C:40]([NH2:41])=[O:42]
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(=O)c(C(N)=O)c(N)n(CC(C)(C)O)c2n1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1cc(C2CCNCC2)ccc1Nc1ncc2c(=O)c(C(N)=O)c(N)n(CC(C)(C)O)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2.28 g (3.92 mmol) of the product prepared in step 19.1 in 70 mL of dichloromethane is cooled on an ice-water bath, and 9.8 mL (39.20 mmol) of a 4N solution of hydrogen chloride in dioxane are added slowly. The mixture is stirred at room temperature for 1 hour, and ether is added. The solid is drained by suction, rinsed with pentane and dried in an oven. 2.2 g of the expected product are obtained in the form of a beige-coloured solid, which is used as obtained in the following step. Yield (dihydrochloride)=quantitative.