Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.C(N[C:12]1[CH:20]=[C:19](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH:18]=[CH:17][C:13]=1C(O)=O)(=O)C1C=CC=CC=1.[C:30]([O:33]CC)(=[O:32])C>[C].[Pd]>[OH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]1[C:13]([CH2:12][CH3:20])=[C:17]([CH:18]=[CH:19][CH:21]=1)[C:30]([OH:33])=[O:32]
Reactant: O=C(Nc1cc(/C=C/c2ccccc2O)ccc1C(=O)O)c1ccccc1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CO
Product: CCc1c(C(=O)O)cccc1-c1ccccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
12 mg of 5% palladium-carbon was added to a mixed solution of 1.5 mL of methanol and 1.5 mL of ethyl acetate containing 60 mg of 2-(benzamido)-4-((E)-2-(2-hydroxyphenyl)vinyl)benzoic acid and stirred under hydrogen atmosphere at room temperature for 3 hours and minutes. 6.0 mg of 5% palladium-carbon was added to the reaction mixture and stirred under hydrogen atmosphere at room temperature for 3 hours and 20 minutes. 6.0 mg of 5% palladium-carbon was added to the reaction mixture and stirred under hydrogen atmosphere at room temperature for 2 hours and 40 minutes. Insoluble were removed by filtration and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 47 mg of 2-(benzamido)-4-(2-(2-hydroxyphenyl(ethyl)benzoic acid as white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](=[O:38])(=[O:37])[NH:23][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:18][CH:17]=1)(C)(C)C>ClCCl>[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:23][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=[O:37])=[O:38])=[CH:18][CH:17]=1
Reactant: CCCCCCCCCCCC(=O)NS(=O)(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCC(=O)NS(=O)(=O)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 128.9 %

Procedure:
Trifluoroacetic acid (25 ml) was at room temperature added to a solution of (4-(dodecanoylsulfamoyl)benzyl)carbamic acid tert-butyl ester (170 mg, 0.40 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 1 h at room temperature. The solvents were removed in vacuo. The residue was dissolved in dichloromethane (40 ml) and the solvent was removed in vacuo. The latter procedure was repeated once to give 0.19 g of the trifluoroacetic salt of 4-aminomethyl-N-(dodecanoyl)benzenesulfonamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:5][Mg]Cl.[Mg].CC1C=C(C=C(C)C=1)CCl.[CH2:23]([C:25]([CH3:27])=[O:26])[CH3:24]>C(OCC)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:5][C:25]([OH:26])([CH2:23][CH3:24])[CH3:27]
Reactant: CCC(C)=O
Reactant: Cc1cc(C)cc(C[Mg]Cl)c1
Agent: Cc1cc(C)cc(CCl)c1
Agent: [Mg]
Solvent: CCOCC
Product: CCC(C)(O)Cc1cc(C)cc(C)c1
Reaction time: 2 h

Procedure:
3,5-dimethylbenzylmagnesium chloride was manufactured from 2.6 g of magnesium powder and 15.5 g of 3,5-dimethylbenzyl chloride dissolved in 200 ml of diethyl ether and reacted with 7.5 g of methyl ethyl ketone in a temperature range of from 20° C. to 25° C. After 2 hours, the whole was poured onto ice and acidified, and the organic phase was separated off and extracted by shaking with water and sodium bicarbonate solution. After drying the organic phase with solid potassium carbonate, fractional distillation was carried out. 13 g of end product were obtained in a temperature range of from 63° C. to 65° C. at 0.12 mbar.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][C@@H:8]([C:10]([OH:12])=O)[NH2:9])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:15]([N:19]=[C:20]=[O:21])[CH2:16][CH2:17][CH3:18]>>[CH2:15]([N:19]1[C:10](=[O:12])[CH:8]([CH2:7][C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[NH:9][C:20]1=[O:21])[CH2:16][CH2:17][CH3:18]
Reactant: Cc1ccc(C[C@H](N)C(=O)O)s1
Reactant: CCCCN=C=O
Agent: [Na+]
Agent: [OH-]
Product: CCCCN1C(=O)NC(Cc2ccc(C)s2)C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
DL-β-(5-Methylthiophen-2-yl)alanine (4.1 g; 0.022 mole) was dissolved in 2 N sodium hydroxide solution (11 ml; 0.022 mole), cooled to 0° C. and n-butyl-isocyanate (3.75 ml; 0.033 mole) added gradually maintaining the temperature at 0° C. for 2 hours. The mixture was allowed to come to room temperature and stirred overnight. The mixture was filtered (solid discarded) and the filtrate washed with ether. The washed filtrate was acidified with concentrated hydrochloric acid (11 ml) and heated on a steam bath for 1 hour. After cooling to room temperature the resultant solid was separated by filtration, water washed and dried. Recrystallisation from ethyl acetate gave the title compound. Yield 4.2 g (72%), m.p. 107° C.
Reaction SMILES: B(Br)(Br)Br.ClCCl.C[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][C:18]3[C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][CH:11]=1>CO>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([NH2:27])=[O:26])[C:18]=3[N:17]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2nc3cccc(C(N)=O)c3[nH]2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cccc2[nH]c(-c3ccc(O)cc3)nc12

Procedure:
Under an argon atmosphere 1M boron tribromide in dichloromethane (3.8 ml, 3.79 mmol) was transferred to a flask containing 2-(4′-methoxyphenyl)benzimidazole-4-carboxamide (NU 1076 from Example 5) (202.4 mg, 0.758 mmol). The resulting solution was refluxed for 24 hours using an air condenser. The solvent was removed by distillation to complete dryness. The solid residue was treated with 10% NaOH (10 ml), followed by dropwise addition of concentrated hydrochloric acid to neutralise (pH 7). The white precipitate was collected by filtration and dissolved in ethyl acetate (0 ml). The organic solvent was washed with water (2×3 ml), dried over MgSO4, and the product was obtained by removal of the solvent under reduced pressure. (109.5 mg, 57%). mp 266-267° C.; Found C 63.27, H 4.37, N 15.67 C14H11N3O2.0.75 MeOH requires C 63.04 H 4.69 N 15.76; vmax(cm−1) 3424.01, 3384.16, 3309.20, 3249.55, 3155.62, 1642.35, 1618.02, 1594.50, 1577.74; δH 7.03-7.07 (2H, d, J=8.5), 7.34-7.42 (1H, t), 7.75-7.79 (1H, d), 7.85 (1H, br s), 7.90-7.94 (1H, d), 8.15-8.19 (2H, d, J=8.5), 9.4-9.6 (1H, br s), 10.0-10.4 (1H, br s), 13.0-13.4 (1H, br s); m/z (EI) 253 (M+), 236, 208, 93.
Reaction SMILES: [CH2:1]([C:6]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:21])[C:8]=2[CH:7]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].C(C1C=CC=CC=1)C(C)(C)C.C1(=O)OC(=[O:37])C2=CC=CC=C12>>[CH2:1]([C:6]1[CH:19]=[CH:18][C:17]([C:16]([C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]([OH:21])=[O:37])=[O:20])=[CH:8][CH:7]=1)[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: CC(C)(C)Cc1ccccc1
Product: CC(C)(C)Cc1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
A process for the preparation of 2-neopentylanthraquinone, wherein neopentylbenzene is acylated with phthalic anhydride by a Friedel-Crafts reaction to give 2-(4-neopentylbenzoyl)-benzoic acid and the latter is cyclized in the presence of a strong anhydrous acid to give a composition consisting essentially of 2-neopentylanthraquinone without isomerization or degradation of the neopentyl group taking place.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[NH:17])[NH:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[H][H]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[NH:15])[NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(C(=N)N)CC1
Yield: 114.6 %

Procedure:
Dissolve 4-(N-Hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester (9.7 g 1.00 equiv; 39.9 mmoles) in methanol (300 mL) and add acetic acid (2 equiv, 79.73 mmoles; 4.6 mL), and methanol washed Raney Nickel (2.7 g). Heat the reaction to 50° C., then hydrogenate with 1 ATM hydrogen gas for 4.5 hours. Filter the reaction mixture through Celite and concentrate under reduced pressure. Suspend the solid in diethyl ether, filter and dry under reduced pressure to give 10.39 g of 4-carbamimidoyl-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: COC(=O)C[S:5][C:6](=S)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:15][NH2:16]>C(O)C>[C:6]([NH:15][NH2:16])(=[S:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)CSC(=S)c1ccccc1
Reactant: NN
Solvent: CCO
Product: NNC(=S)c1ccccc1
Reaction time: 2 h
Yield: 94 %

Procedure:
Add a solution of thiobenzoylsulfanylacetic acid methyl ester (1.9 g, 8.4 mmol) in ethanol (30 mL) to a solution of anhydrous hydrazine (1 mL) at room temperature under nitrogen and stir for 2 hours. Then add water (20 mL) and remove the solvent under reduced pressure. Dissolve the residue in ethyl acetate (300 mL), wash with water (200 mL) and brine (200 mL), and dry over magnesium sulfate. Remove the solvent under reduced pressure to provide thiobenzoic acid hydrazide (1.2 g, 94%).
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=2)=[CH:19][CH:18]=1.Cl>ClCCl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]23[CH2:1][CH:24]2[CH2:25][NH:26][CH2:27][CH2:28]3)=[CH:19][CH:18]=1
Reactant: CC[Zn]CC
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: Cl
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(C23CCNCC2C3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Diethylzinc (1M in hexane, 19 ml) in dichloromethane (100 ml) was mixed with trifluoroacetic acid (3 ml) at 0C. After 20 minutes, diiodomethane (3 ml) in dichloromethane (10 ml) was added. Then 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (3.0 g) in dichloromethane (10 ml) was added, and the mixture was stirred at room temperature overnight. After addition of hydrochloric acid (1N), the phases were separated and the organic phase was washed with water, dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 191.25 (C12H14FN); MS (ESI): 192 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[C:4]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3cc(OC)c(OC)cc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-methoxy-phenylboronic acid to give [1-(3-Methoxy-phenyl)-6,7-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 391(MH+).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=1[CH3:18]>C(O)C.[H][H].[C].[Pd]>[C:1]1([CH3:19])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:10]([CH3:18])=[C:11]([CH:12]=[CH:13][CH:14]=1)[NH2:15]
Reactant: Cc1cc(C)c(-c2cccc([N+](=O)[O-])c2C)c(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(-c2cccc(N)c2C)c(C)c1
Yield: 84.6 %

Procedure:
Palladium-carbon (10%, 1.1 g) was added to a solution of 1-mesityl-2-methyl-3-nitrobenzene (11.0 g, 43 mmol) in ethanol (220 mL) at room temperature, followed by stirring for one day in hydrogen atmosphere. The mixture was filtered through Celite and evaporated. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (8.2 g) as white crystals.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[CH3:6][N:7]([CH3:29])[CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[N:23][CH:22]=3)=[CH:15][CH:14]=2)[CH2:9]1>>[CH:5]1([CH2:4][O:27][C:24]2[CH:25]=[CH:26][C:21]([C:20]([NH:19][C:16]3[CH:15]=[CH:14][C:13]([N:10]4[CH2:11][CH2:12][CH:8]([N:7]([CH3:29])[CH3:6])[CH2:9]4)=[CH:18][CH:17]=3)=[O:28])=[CH:22][N:23]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(O)nc3)cc2)C1
Reactant: BrCC1CC1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(OCC4CC4)nc3)cc2)C1

Procedure:
(Bromomethyl)cyclopropane was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide by method H-a. This resulted in the product with the molecular weight of 380.22 (C22H28N4O2); MS (ESI): 381 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:21]>O1CCOCC1.O.[Cu]Br>[Br:21][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: N#Cc1ccccc1-c1cc(N)ccc1F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccccc1-c1cc(Br)ccc1F
Temperature: 3 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of 5′-amino-2′-fluorobiphenyl-2-carbonitrile (7.85 g, 37 mmol) in 1,4-dioxane (25 ml) was treated with 48% hydrobromic acid (125 ml) and the resulting suspension stirred and cooled to 3° C. (internal temperature). A solution of sodium nitrite in water (5 ml) was then added dropwise over 20 min keeping the internal temperature <5° C. Stirring at <5° C. was continued for 2 h before pouring the reaction into a cooled (5° C.) solution of freshly purified copper(I) bromide (6.37 g, 44 mmol) in 48% hydrobromic acid (50 ml). The resulting purple reaction mixture was stirred at 5° C. for 10 min then warmed to 50° C. for 20 min. The reaction was diluted with ice-cold water (500 ml) and extracted with ethyl acetate (2×250 ml). The organics were combined, washed with 5% aqueous sodium sulfite, saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica eluting with isohexane (containing 1% methanol) on a gradient of ethyl acetate (2-10%) afforded a colourless oil which crystallised on standing to give 5′-bromo-2′-fluorobiphenyl-2-carbonitrile as a white solid (6.5 g, 64%): δH (400 MHz, CDCl3) 7.09-7.14 (1H, m), 7.45-7.57 (4H, m), 7.66 (1H, td, J 8 and 2), 7.77 (1H, dd, J 8 and 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[O:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:25]3[O:26][C:22]([CH3:21])=[CH:23][CH:24]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1ccc(C(=O)O)o1
Product: Cc1ccc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)o1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 5-methyl-2-furancarboxylic acid (CAN 1917-15-3) as starting materials; LC-MS (UV peak area/ESI) 98.0%, 409.574 (M−H)−.
Reaction SMILES: NN1CCCC1.[F:7][C:8]([F:23])([F:22])[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:19](N)=[O:20])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[OH-:24].[Na+].Cl>CO>[F:7][C:8]([F:23])([F:22])[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:19]([OH:24])=[O:20])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: [OH-]
Reactant: NC(=O)C1(c2ccc(OC(F)(F)F)cc2)CC1
Agent: Cl
Agent: NN1CCCC1
Agent: [Na+]
Solvent: CO
Product: O=C(O)C1(c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 78 °C

Procedure:
A mixture of 1-(4-trifluoromethoxyphenyl)cyclopropanecarbonitrile (4.0 g), 25% aqueous sodium hydroxide (0.46 mL), 30% aqueous hydrogen peroxide (25 mL), and methanol (100 mL) was heated at 55° C. for 1 h with stirring. The reaction mixture was concentrated under reduced pressure, the precipitated crystals were collected by filtration, to obtain white solid 1-(4-(trifluoromethoxy)phenyl)cyclopropanecarbamide (4.5 g). (3) A mixture of 1-(4-trifluoromethoxyphenyl)cyclopropanecarbamide (4.5 g), 15% aqueous sodium hydroxide (150 mL), and methanol (60 mL) was heated at 78° C. for 18 h with stirring. The reaction mixture was left stand for cooling, then the reaction solution was adjusted to pH 2 using 15% hydrochloric acid and concentrated under reduced pressure. The precipitated crystals were collected by filtration to obtain white solid 1-(4-(trifluoromethoxy)phenyl)cyclopropanecarboxylic acid (4.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[N:15]=[C:16](C3C=CC(F)=CC=3)[C:3]=12.[F:33][C:34]1[CH:35]=[C:36]([CH:42]=[CH:43][CH:44]=1)C(CC#N)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][C:25]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[O:26])[N:15]=[C:16]([C:43]3[CH:42]=[CH:36][CH:35]=[C:34]([F:33])[CH:44]=3)[C:3]=12
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCOCC1
Reactant: N#CCC(=O)c1cccc(F)c1
Product: O=C(Cn1nc(-c2cccc(F)c2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCOCC1

Procedure:
Example 69 (Compound 76) was synthesised following a similar procedure outlined in Example 68 (Compound 75), using 3-fluorobenzoylacetonitrile instead of 4-fluorobenzoylacetonitrile in step 1. Compound 76 was obtained as a yellow solid (4.8 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:26][N:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4]1.[OH-].[Na+]>CO>[CH3:1][O:2][CH:3]1[CH2:26][N:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[CH2:4]1
Reactant: CCOC(=O)CCCCCCN1CC(OC)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC1Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N(CCCCCCC(=O)O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
rac-Ethyl 7-(7-methoxy-2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) (139 mg, 0.277 mmol) in MeOH (3 ml) at RT was treated with 2M NaOH (416 μL, 0.831 mmol) and the mixture was stirred at RT for 4 hours. A further portion of 2M NaOH (416 μL, 0.831 mmol) was added the reaction mixture was stirred at RT overnight. The organic solvent was removed in vacuo and the resulting aqueous portion was diluted with water (20 ml). The pH was adjusted to pH1 using 2M HCl and the mixture was extracted with DCM (×3). The combined organic extracts were isolated using a phase separating cartridge and the solvent was removed in vacuo. Purification of the crude product by chromatography on silica eluting with 0-30% EtOAc/iso-hexane followed by 10% MeOH in EtOAc afforded the title compound;
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.[CH3:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[C:15]1([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:27]4[CH:28]=[CH:29][C:24]([C:22](=[O:23])[CH3:21])=[CH:25][CH:26]=4)[CH:5]=3)=[C:10]([C:11]([F:14])([F:12])[F:13])[O:9][N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Temperature: 120 °C
Yield: 25.2 %

Procedure:
To a solution of 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (70 mg, 0.25 mmol) in DMF (2.5 mL) was added 4-fluoroacetophenone (35 mg, 0.25 mmol) and potassium carbonate (69.1 mg, 0.5 mmol) and the resulting mixture heated at 120° C. overnight. The resulting mixture was then poured into HCl (1 N, 200 mL) and extracted with ethyl acetate which was then washed with brine, dried over sodium sulphate and evaporated. Purification by preparative HPLC on reversed phase eluting with an acetonitrile/water [0.1% aq NH3 (25%)] gradient afforded the title compound (25 mg, 25%) which was obtained as a white solid. MS: m/e=398.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][C:13](=[O:16])[NH:12][C:11]2[N:17]([CH3:26])[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:10]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][C:13](=[O:16])[N:12]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:11]2[N:17]([CH3:26])[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:10]1=2
Reactant: Cn1nc(-c2ccccn2)c2c1NC(=O)CSC2c1ccc(Cl)cc1Cl
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CSC(c2ccc(Cl)cc2Cl)c2c(-c3ccccn3)nn(C)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.3 %

Procedure:
To a solution of 4-(2,4-dichloro-phenyl)-1-methyl-3-(pyridine-2-yl)-6,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-(4H)-one (0.50 g, 1.2 mmol, prepared using C from Example 2 step B with thioglycolic acid and 2,4-dichloro-benzaldehyde) in anhydrous DMF was added cesium carbonate (0.804 g, 2.5 mmol), sodium iodide (0.370 g, 2.5 mmol) and methyl bromoacetate (0.128 mL, 1.4 mmol). The resulting mixture was stirred at rt for about 3 h, and then partitioned between ethyl acetate (50 mL) and water (25 mL). The layers were separated and the organic layer was washed with 5% aqueous sodium bicarbonate (2×25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM/ethyl acetate 9:1) to give methyl 2-(4-(2,4-dichlorophenyl)-1-methyl-7-oxo-3-(pyridin-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-8(4H)-yl)acetate (0.16 g, 0.34 mmol, 28%) as a white solid: 1H-NMR (CDCl3, Bruker 400 MHz) 3.34 (1 H, d, J=17 Hz), 3.46 (1 H, dd, J=17 Hz, 2 Hz), 3.83 (3 H, s), 3.88 (3 H, s), 4.72 (1 H, d, J=15 Hz), 4.87 (1 H, d, J=15 Hz), 6.63 (1 H, d, J=9 Hz), 6.78 (1 H, d, J=2 Hz), 6.96-7.05 (2 H, m), 7.43 (1 H, d, J=2 Hz), 7.57 (1 H, dt, J=8 Hz, 2 Hz), 7.82-7.88 (1 H, m), 8.35 (1 H, m)
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7]([C:9]2[C:17](=[O:18])[N:16]3[C:12]([S:13][C:14]4[CH:22]=[C:21]([CH2:23][CH2:24]C)[C:20]([CH2:26][CH2:27]C)=[CH:19][C:15]=43)=[N:11][CH:10]=2)=[O:8])=[N:4][N:3]=[N:2]1.N1C(NC(C2C(=O)N3C(SC4C=C(C(C)C)C(C(C)C)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(CCC)C(C)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(C)C(CCC)=CC=43)=NC=2)=O)=NN=N1>>[NH:1]1[C:5]([NH:6][C:7]([C:9]2[C:17](=[O:18])[N:16]3[C:12]([S:13][C:14]4[CH:22]=[C:21]([CH2:23][CH3:24])[C:20]([CH2:26][CH3:27])=[CH:19][C:15]=43)=[N:11][CH:10]=2)=[O:8])=[N:4][N:3]=[N:2]1
Reactant: CCCc1cc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2cc1CCC
Agent: CC(C)c1cc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2cc1C(C)C
Agent: CCCc1cc2c(cc1C)sc1ncc(C(=O)Nc3nnn[nH]3)c(=O)n12
Agent: CCCc1cc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2cc1C
Product: CCc1cc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2cc1CC

Procedure:
N-(5-tetrazolyl)-7,8-di-n-propyl-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7,8-di-i-propyl-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-methyl-8-n-propyl-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; and N-(5-tetrazolyl)-7-n-propyl-8-methyl-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide.