Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]4[N:15]=[CH:16][S:17][C:13]=4[CH:12]=3)[S:8][C:7]=2[CH:20]=1.[N:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[Al+3].[Cl-].[Cl-].[Cl-].C(S)C>C(Cl)Cl>[S:17]1[C:13]2[CH:12]=[C:11]([C:9]3[S:8][C:7]4[CH:20]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=4[C:10]=3[C:34]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH2:28][CH2:27][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:38][CH:37]=3)=[O:35])[CH:19]=[CH:18][C:14]=2[N:15]=[CH:16]1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc2cc(-c3ccc4ncsc4c3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc3ncsc3c2)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product from Example 18, Step 2 (63 mg, 0.21 mmol) and 4-(2-Piperidin-1-yl-ethoxy)-benzoyl chloride (1.38 mL, 0.25 mmol) in 1 mL of methylene chloride was added AlCl3 (212 mg, 1.6 mmol) and the reaction was stirred at room temperature for 3 hrs. When acylation was complete, to demethylate, ethanethiol (0.069 mL, 0.93 mmol) was added dropwise and the reaction stirred for a further 1.5 hrs. The reaction was cooled to 0° C. and quenched with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with 10% MeOH/methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel using 2% MeOH/methylene chloride to 4% MeOH/methylene chloride as the gradient eluant to obtain the title product.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:33]4C(=O)C5=CC=CC=C5C4=O)[CH:27]=3)[C:15](=[O:25])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:33][CH2:32][C:28]1[CH:27]=[C:26]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[C:15]2=[O:25])[CH:31]=[CH:30][CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Yield: 2.7 %

Procedure:
A solution of 230 mg of 7-anilino-3-(2-bromophenyl)-3,4-dihydro-1-[3-(phthalimidomethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 10 ml of ethanol was treated with 0.5 ml of hydrazine hydrate. After 18 hours the mixture was evaporated and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 5 mg (2.8%) of 1-[3-(aminomethyl)phenyl]-7-anilino-3-(2-bromophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 121° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7](/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11])[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=1.[Mg].[CH3:16]I.[Cl-].[NH4+]>CCOCC>[CH3:16][CH:5]1[C:6]([CH3:14])([CH3:13])[CH:7](/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11])[C:2]([CH3:1])=[CH:3][CH2:4]1
Reactant: CI
Reactant: CC(=O)/C=C/C1C(C)=CCCC1(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)/C=C/C1C(C)=CCC(C)C1(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 50.0 g (0.26 mol) of α-ionone in 150 ml of ether were allowed to drop over a period of 20 minutes into a Grignard solution, which was cooled to 0° C. and which had been prepared from 7.5 g (0.31 mol) of magnesium shavings in 75 ml of ether and 46.9 (0.33 mol) of methyl iodide in 180 ml of ether, in such a manner that the temperature lay between 10° C. and 20° C. Subsequently, the mixture was stirred at the reflux temperature of the ether for a further 1 hour, cooled down to 0° C. and then cautiously treated with concentrated ammonium chloride solution and an additional 500 ml of ether. The ether phase was washed with water until neutral, dried and concentrated. There were obtained 60.0 g of crude product which contained above 95% 9-methyl-α-ionol (GC) and which was accordingly further processed directly in this form. In a manner analogous to the epoxidation of α-irone (Example 4), from 58.1 g (~0.26 mol) of 9-methyl-α-ionol there was obtained 68.0 g of crude 9-methyl-α-ionol epoxide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:16][CH:15]([C:5]2=1)[CH2:14][CH2:13]3.[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1)#[CH:18]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:18]=[CH:17]\[C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:6]1[CH2:11][C@@H:12]3[NH:16][C@H:15]([C:5]2=1)[CH2:14][CH2:13]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCC(C3)N1
Reactant: C#Cc1ccc(C)nc1
Product: Cc1ccc2c(c1)c1c(n2/C=C\c2ccc(C)nc2)C[C@H]2CC[C@@H]1N2

Procedure:
The coupling of 2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (212 mg, 1.00 mmol; Example 4A) and 5-ethynyl-2-methylpyridine (586 mg, 5.00 mmol; International Publication No. WO2005090333) was performed as described in Example 20 to afford the racemate of the title compound. The individual enantiomers were separated by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine) to afford the title compound as the first-eluting peak: 1H NMR (300 MHz, methanol-d4) δ ppm 1.37-1.53 (m, 1H), 1.99-2.13 (m, 3H), 2.29-2.36 (m, 1H), 2.38 (s, 3H), 2.41 (s, 3H), 3.01 (dd, J=16, 5 Hz, 1H), 3.90 (t, J=6 Hz, 1H), 4.55 (d, J=4 Hz, 1H), 6.58 (d, J=8 Hz, 1H), 6.80-6.88 (m, 2H), 6.90 (d, J=9 Hz, 1H), 7.01-7.14 (m, 2H), 7.28 (s, 1H), 7.93 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 330 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C(O)C>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])=[CH:20][CH:19]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1ccc(Br)cc1
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Br)cc1
Yield: 44.4 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 4.42 g (25.8 mmol) p-bromoaniline was heated to reflux under N2 for 3 hours. Removed heat and added saturated sodium bicarbonate until basic. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solids, and air dried. Washed with water and dried in vacuo. Boiled in 1.4 liters ethyl acetate, and without completely dissolving all solids, stirred with Darco, and filtered. Stripped solvent and dried in vacuo, giving 3.524 g of yellow solid: mass spectrum (electrospray m/e): M+H=369, 370.9.
Reaction SMILES: C1(C)C=CC=CC=1.CS(OC[C@H:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[O:15][CH:16]1CCCCO1)(=O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C@@H:14]1[O:15][CH2:16]1
Reactant: CS(=O)(=O)OC[C@@H](OC1CCCCO1)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: Clc1cccc([C@H]2CO2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Into toluene (10 ml) were added (S)-2-(3-chlorophenyl)-2-(3,4,5,6-tetrahydro-[2H]-pyran-2-yloxy)ethyl methanesulfonate (3.0 g), p-toluenesulfonic acid monohydrate (1.7 g) and methanol (0.5 g), and the resulting mixture was:stirred at 50° C. for 1 hour. The reaction mixture was Washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated aqueous sodium chloride solution. To the organic layer was added 20% NaOH (10 ml) and the resulting mixture was stirred vigorously at room temperature for 1 hour. The reaction mixture was subjected to layer separation, and the organic layer was washed with water, then with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off, then the solvent was distilled off, and the resulting oily substance was distilled under reduced pressure to obtain a colorless oily compound mentioned above (1.27 g, 91.7%). The optical purity of the product obtained was 99.9% e.e. as determined by HPLC.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][O:15][CH3:16])[CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11]C)=[O:10].[Li+].[OH-]>C1COCC1.O>[CH3:16][O:15][CH2:14][CH2:13][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6]/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10]
Reactant: COCCN(C/C=C/C(=O)OC)CCOC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCN(C/C=C/C(=O)O)CCOC

Procedure:
(E)-Methyl 4-(bis(2-methoxyethyl)amino)but-2-enoate (77) (10.0 g, 43 mmol) was hydrolyzed with LiOH (5.4 g, 130 mmol) in THF (100 mL) and H2O (50 mL) to give (E)-4-(bis(2-methoxyethyl)amino)but-2-enoic acid (78) (quantative yield) as a yellow oil. LC-MS (ESI): m/z (M+1) 218.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=2)=[CH:4][CH:3]=1.ClC1C=C(C(=[N:35][OH:36])C(C2C=CC(F)=CC=2)=O)C=CN=1>>[F:16][C:12]1[CH:11]=[C:10]([C:9](=[N:35][OH:36])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:17])[CH:15]=[CH:14][N:13]=1
Reactant: O=C(C(=NO)c1ccnc(Cl)c1)c1ccc(F)cc1
Reactant: O=C(Cc1ccnc(F)c1)c1ccc(F)cc1
Product: O=C(C(=NO)c1ccnc(F)c1)c1ccc(F)cc1

Procedure:
22b was prepared from 21b (10.0 g; 43 mmol) using the method described in the synthesis of 22a.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]([CH3:13])[CH2:8][C:9](OC)=[O:10].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]([CH3:13])[CH2:8][CH:9]=[O:10]
Reactant: COC(=O)CC(C)c1cnccn1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(CC=O)c1cnccn1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of ester 12e (0.29 g, 1.493 mmol) in 5.3 mL dry CH2Cl2 was cooled to -78° C. and treated with DIBAL (1.0M solution in dry CH2Cl2, 1.5 mL, 1.493 mmol, 1.0 equiv), then an additional 0.7 mL DIBAL (0.5 equiv) solution was added and the reaction was quenched immediately upon completion by tlc with 2.0 mL dry CH3OH. The reaction mixture was diluted with 5 mL saturated aqueous sodium potassium tartrate and warmed gradually to room temperature, partitioned, and extracted with CH2Cl2 (3×5 mL). The combined extracts were washed with saturated aqueous sodium potassium tartrate (3×5 mL), dried (MgSO4), filtered and concentrated in vacuo. SGC chromatotron (SiO2, 4 mm, 0-10% CH3OH/CHCl3) afforded 13e (0.213 g, 0.224 g theoretical, 95%). For 13e: 1H NMR (CDCl3, 250 MHz) d 9.75 (s, 1H, CHO), 8.52 (br d, 1H, J=1.5 Hz, Pyr C3-H), 8.44 (dd, 1H, J=1.5, 2.5 Hz, Pyr C5-H), 8.38 (d, 1H, J=2.5 Hz, Pyr C6-H), 3.55 (ddq, 1H, J=6.0, 7.0, 7.9 Hz, CHCH3), 3.08 (ddd, 1H, J=1.2, 7.9, 17.8 Hz, CHH), 2.73 (ddd, 1H, J=1.2, 6.0, 17.8 Hz, CHH), 1.33 (d, 3H, J=7.0 Hz, CH3); 13C NMR (CDCl3 , 125 MHz) d 200.8, 158.2, 144.1, 143.8, 142.6, 49.3, 33.2, 20.8; IR (neat) nmax 3054, 2966, 1722, 1668, 1525, 1471, 1406, 1294, 1147, 1117, 1016, 848, 769 cm-1. See FIG. 19a.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[O:9]=[C:10]1[C:23]2[CH:22]=[C:21]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:19][C:18]=2[C:17](=[O:28])[C:16]2[C:11]1=[CH:12][C:13]([S:29](Cl)(=[O:31])=[O:30])=[CH:14][CH:15]=2>N1C=CC=CC=1.C(Cl)Cl>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][S:29]([C:13]2[CH:14]=[CH:15][C:16]3[C:17](=[O:28])[C:18]4[C:23](=[CH:22][C:21]([S:24]([NH:1][C:2]5[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=5)(=[O:26])=[O:25])=[CH:20][CH:19]=4)[C:10](=[O:9])[C:11]=3[CH:12]=2)(=[O:31])=[O:30])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C1c2ccc(S(=O)(=O)Cl)cc2C(=O)c2cc(S(=O)(=O)Cl)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1c2ccc(S(=O)(=O)Nc3cccc(O)c3)cc2C(=O)c2cc(S(=O)(=O)Nc3cccc(O)c3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
3-aminophenol (0.76 g, 7 mmol) in pyridine (10 ml) was treated with the product from Example 10A in methylene chloride. The mixture was stirred at room temperature for 18 hours and the solvents removed under reduced pressure. The residue was taken up in ethyl acetate, washed three times with 1N hydrochloric acid, dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was filtered through a pad of silica gel with 5% methanol in methylene chloride. The filtrate was concentrated under reduced pressure and the residue was taken up in a mixture of ethyl acetate:hexanes (1:1). The mixture was washed three times with water, dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was titurated with methylene chloride and the orange solid collected by filtration to provide the title compound (0.47 g, 28% yield for 2 steps). 1H NMR (CD3OD) δ 7.16 (d, 2H, J=1.5 Hz), 6.86 (d, 2H, J=6 Hz), 6.69 (dd, 2H, J1=6 Hz, J2=1.5 Hz), 5.55-5.47 (m, 2H), 5.20-4.95 (m, 6H); MS (ESI−) 549 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:12]=[C:11]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]>C1(C)C=CC=CC=1>[C:4]([O:25][C:24](=[O:26])[CH2:23][CH2:22][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[N:12]=1)([CH3:9])([CH3:5])[CH3:3]
Reactant: O=C(O)CCc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(Cl)cc2Cl)n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(Cl)cc2Cl)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 196.7 %

Procedure:
To a 3-neck round bottom flask fitted with an air condenser was added 3-[5-(3,4-dichloro-phenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]-propionic acid (1.0 g, 2.3 mmol, 1.0 equiv) and toluene (23 mL) under nitrogen. The mixture was heated to 80° C. then N,N-dimethyl-di-tert-butylacetal (2.36 g, 11.6 mmol, 5.0 equiv) was added dropwise (neat). The reaction mixture was heated at 80° C. for 1 h then additional N,N-dimethyl-di-tert-butylacetal (2.36 g, 11.6 mmol, 5.0 equiv) was added. This mixture was stirred at 80° C. for 2 h then cooled to room temperature and partitioned between water (100 mL) and ether (100 mL). The organic layer was washed with 1 M sodium hydroxide (50 mL), water (50 mL) then brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude material was then purified by flash chromatography (20% ethyl acetate/hexanes) to afford the desired ester (1.1 g, >99%). HPLC: Rt=3.59 (Method A). MS (ESI): mass calculated for C22H20Cl4N2O2, 484.03; m/z found, 485.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 7.81 (d, J=2.2 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.61-7.59 (m, 2H), 7.48 (d, J=2.2 Hz, 1H), 7.05 (dd, J=8.2, 1.9 Hz, 1H), 6.71 (s, 1H), 2.87 (t, J=7.4 Hz, 2H), 2.61 (t, J=7.4 Hz, 2H), 1.38 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)(=[O:14])=[O:13].[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28].CCN(C(C)C)C(C)C>>[N:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[NH:15][S:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:7][C:2]=2[NH:1][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])(=[O:13])=[O:14])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Reactant: CC(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 41.6 %

Procedure:
In a similar fashion using route 15 general procedure 30, 2-amino-N-(quinolin-8-yl)-4-trifluoromethyl-benzenesulfonamide (Example Compound 35) (40 mg, 0.11 mmol), isobutyryl chloride (11 μl, 0.11 mmol) and DIPEA (47 μl, 0.27 mmol) gave the title compound (20 mg, 43%) after purification by column chromatography with DCM/n-hexane (4:1) as the eluent.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9]([N+:15]([O-])=O)=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].[Sn]>C(O)C>[ClH:2].[NH2:15][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:4]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:3]=2[Cl:2])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: Nc1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)O
Yield: 74.5 %

Procedure:
Concentrated hydrochloric acid (100 ml) was added dropwise to a mixture of 5-(2,4-dichlorophenoxy)-2-nitrobenzoic acid (10 g) and granulated tin (20 g) cooled to 10°-15° C. The mixture was then heated to 60°-70° C. for 1 hour. Ethanol (100 ml) was added and the mixture heated for a further 2 hours at 60°-70° C. The precipitate was collected and recrystallised from ethanol to give the hydrochloride (3.8 g) with a melting point of 166°-168° C. with decomposition.
Reaction SMILES: [N:1]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)=[N:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C([O:20][CH2:21][CH3:22])(=O)C>ClCCl>[C:21]([NH:14][C:13]1[CH:15]=[CH:16][C:10]([N:1]=[N:2][C:3]2[CH:4]=[CH:5][C:6]([NH2:7])=[CH:8][CH:9]=2)=[CH:11][CH:12]=1)(=[O:20])[C:22]1[CH:8]=[CH:9][CH:3]=[CH:4][CH:5]=1
Reactant: CCOC(C)=O
Reactant: Nc1ccc(N=Nc2ccc(N)cc2)cc1
Solvent: ClCCl
Product: Nc1ccc(N=Nc2ccc(NC(=O)c3ccccc3)cc2)cc1
Yield: 54 %

Procedure:
Following the general monoacylation procedure, 4,4′-azodianiline (50 mg, 240 μmol) was treated with benzoyl choloride (26 μl, 240 μmol). Silica gel chromatography through a wide column (10% ethyl acetate in dichloromethane) provided S5 as an orange solid (44 mg, 130 μmol, 54% yield): 1H (DMSO, 400 MHz): 6.04 (s, 2H); 6.66 (d, 2H, J=8.4); 7.52-7.65 (m, 5H); 7.76 (d, 2H, J=8.8); 7.88-7.98 (m, 4H); 10.46 (s, 1H). 13C (DMSO, 100 MHz): 113.4, 120.5, 122.3, 124.9, 127.7, 128.4, 131.7, 134.8, 140.4, 142.9, 148.4, 152.5, 165.7. HRMS (ESI+): calc'd for C19H17N4O+—317.1397, found—317.1403 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)=[O:4].O.[ClH:23]>C(OCC)(=O)C>[ClH:23].[ClH:23].[N:9]1([CH2:8][CH2:7][O:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: COC(=O)COCCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)COCCN1CCNCC1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
2 g (0.0066 mol) of tert-butyl 4-(2-methoxycarbonylmethoxyethyl)piperazine-1-carboxylate prepared in Example I.4.3. are dissolved in 5 ml of ethyl acetate in a 50 ml three-necked round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. 20 ml of a 3M solution of hydrochloric acid in ethyl acetate are added in a single portion with stirring. The mixture is stirred at room temperature for 30 minutes. 5 ml of a 3M solution of hydrochloric acid in ethyl acetate are then added and stirring is continued for 30 minutes. The precipitate is filtered off and is washed with 2×5 ml of ethyl acetate. 1.68 g (93%) of methyl 2-(1-piperazinyl)ethoxyacetate dihydrochloride are obtained in the form of a beige-colored solid. NMR: δ: 3.4 (2H, t, 4.8 Hz), 3.47-3.65 (8H, m); 3.67 (3H, s); 3.92 (2H, t, 4.8 Hz); 4.21 (2H, s); 10.1 (2H, bs). Mass spectrum: 202 (M+·).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH:7]=[N:8][OH:9])([O-:3])=[O:2].ClN1C(=O)CCC1=O.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]([F:33])([F:32])[F:31])=[CH2:29])[CH:25]=[C:24]([Cl:34])[CH:23]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[Cl:21][C:22]1[CH:27]=[C:26]([C:28]2([C:30]([F:33])([F:31])[F:32])[O:9][N:8]=[C:7]([C:6]3[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:29]2)[CH:25]=[C:24]([Cl:34])[CH:23]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: O=[N+]([O-])c1cccc(C=NO)c1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
3-Nitro-benzaldehyde oxime (commercially available) (6.15 g, 37.0 mmol) and N-chlorosuccinimide (“NCS”) (4.94 g, 37.0 mmol) were dissolved in N,N-dimethylformamide (65 ml). This mixture was stirred at ambient temperature for 90 minutes. A solution of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (which was made as described, for example, in WO 05/085216) (8.53 mg, 37.0 mmol) and triethylamine (5.15 ml, 37.0 mmol) in N,N-dimethylformamide (70 ml) was added and the reaction mixture was stirred at ambient temperature for 18 hours. Water (300 ml) and ethyl acetate (300 ml) were added. The phases were separated and the organic phase was washed twice with water. The aqueous phases were extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) to give 5-(3,5-dichloro-phenyl)-3-(3-nitro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (14.5 g, 97% yield). The residue was used without further purification or analysis.
Reaction SMILES: [CH3:1][C:2]([CH3:46])([CH3:45])[CH2:3][O:4][C:5](=[O:44])[N:6]=[C:7]([NH2:43])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:29]2[N:33]=[C:32]([O:34][CH2:35]Cl)[N:31]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:30]=2)[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][OH:27])[C:17]=2[F:28])=[CH:10][CH:9]=1.C(=O)([O-])O.[K+].[CH2:52]([CH:54]([CH2:58][CH3:59])[C:55]([OH:57])=[O:56])[CH3:53].[I-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH2:43][C:7](=[N:6][C:5]([O:4][CH2:3][C:2]([CH3:46])([CH3:45])[CH3:1])=[O:44])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][OH:27])[C:17]=2[F:28])[C:29]2[N:33]=[C:32]([O:34][CH2:35][O:57][C:55](=[O:56])[CH:54]([CH2:58][CH3:59])[CH2:52][CH3:53])[N:31]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:30]=2)=[CH:10][CH:9]=1
Reactant: CCC(CC)C(=O)O
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCCl)n(-c3ncccn3)n2)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCC(CC)C(=O)OCOc1nc(C(Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2cc(OC)cc(OCCO)c2F)nn1-c1ncccn1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a mixture of [1-amino-1-[4-({(5-chloromethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)phenyl]methylidene]carbamic acid 2,2-dimethylpropyl ester (Example 2b, 100 mg), potassium hydrogen carbonate (109 mg), and DMF (13.3 mL), 2-ethylbutanoic acid (88.3 mg) and sodium iodide (117 mg) were added, and the resulting mixture was stirred at 45° C. overnight and then cooled to room temperature. To the reaction mixture, ice and saturated aqueous ammonium chloride solution were added, and the resulting mixture was extracted with a mixture of THF and ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate.
Reaction SMILES: [Cl:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[CH:8]=[O:9].[CH3:10][Mg]Br.CC(O)C>C1COCC1>[Cl:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[CH:8]([OH:9])[CH3:10]
Reactant: C[Mg]Br
Reactant: O=CC1=C(Cl)CCCC1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(O)C1=C(Cl)CCCC1
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-cyclohex-1-enecarbaldehyde (13.6 mmol) in THF at 0° C. was added methyl magnesium bromide (3M in THF; 5.4 mL, 16.32 mmol). The reaction was stirred under N2 for 1 hour, and then iPrOH (2 mL) was added. The mixture was concentrated, and the residue was diluted with 1N aqueous HCl and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NH4Cl, dried over MgSO4, filtered, and concentrated, and the crude material was purified by silica gel chromatography to give the title compound.