Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:15][CH2:16][CH2:17][OH:18]>O1CCOCC1>[N:1]1([CH2:15][CH2:16][CH2:17][OH:18])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: c1c[nH]nn1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Product: OCCCn1ccnn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
1,2,3-triazole (2 g, 28.96 mmol) was dissolved in 1,4-dioxane (40 mL), and potassium carbonate (8 g, 57.92 mmol), potassium iodide (962 mg, 5.79 mmol) and 3-bromopropanol (3.3 mL, 43.43 mmol) were added thereto, followed by stirring at 100° C. for 3 hours. After the reaction was completed, the reactants were cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the title compound (2.5 g, 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([C:27]1[CH:28]=[C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=3)[C:10]([F:11])([F:12])[F:13])=[C:4]([Cl:24])[CH:3]=2)[CH:30]=[CH:31][C:26]=1[F:25])=[O:36])[CH3:39]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 165, step 3) was reacted with 4-fluoro-3-ethoxycarbonylphenylboronic acid to give the title compound as a colorless foam. MS (m/e)=512.4 [M+H+].
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1>CS(C)=O.ClCCl>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Temperature: 95 °C

Procedure:
5-Fluoro-2-nitrobenzotrifluoride (400 mg, 1.91 mmol) and trans-4-aminocyclohexanol (220 mg, 1.91 mmol) were dissolved in dimethylsulfoxide (10 mL). The resulting mixture was heated at 95° C. for 3.5 hr. After cooling at room temperature, the mixture was diluted with dichloromethane (15 mL) and washed with water (3×10 mL). The organic phase was collected and dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was re-crystallized from petrol ether. The desired product was then isolated as a yellow solid (490 mg, 84% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]2[C:4]=1[CH:5]=[C:6]1[C:11](=[CH:12]2)[CH:10]2[O:19][CH:7]1[C:8](=[CH2:21])[C:9]2=[CH2:20].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>>[CH3:27][O:26][C:22]([CH:23]1[CH2:24][CH2:20][C:9]2[CH:10]3[O:19][CH:7]([C:6]4[C:11]3=[CH:12][C:13]3[C:4](=[C:3]([O:2][CH3:1])[CH:16]=[CH:15][C:14]=3[O:17][CH3:18])[CH:5]=4)[C:8]=2[CH2:21]1)=[O:25]
Reactant: C=CC(=O)OC
Reactant: C=C1C(=C)C2OC1c1cc3c(OC)ccc(OC)c3cc12
Product: COC(=O)C1CCC2=C(C1)C1OC2c2cc3c(OC)ccc(OC)c3cc21

Procedure:
In a manner analogous to that described in Example 1, a mixture of 1,2,3,4-tetrahydro-5,8-dimethoxy-2,3-dimethylene-1,4-epoxyanthracene and methyl acrylate was reacted to give 1,2,3,4,5,12-hexahydro-7,10-dimethoxy-5,12-epoxynaphthacene-2-carboxylic acid methyl ester which was converted via 5,12-diacetoxy-1,2,3,4-tetrahydro-7,10-dimethoxy-2-naphthacenecarboxylic acid methyl ester into 5,12-diacetoxy-1,2,3,4,6,11-hexahydro-7,10-dimethoxy-6,11-dioxo-2-naphthacenecarboxylic acid methyl ester.
Reaction SMILES: [NH2:1][OH:2].[C:3]([O:12][CH2:13][CH3:14])(=[O:11])/[CH:4]=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(O)C>[OH:2][NH:1][C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][C:3]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: NO
Solvent: CCO
Product: CCOC(=O)C[C@H](NO)C(=O)OCC
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Hydroxylamine Free base (50% aq. soln., 45.0 g, 0.68 mol) was added dropwise to a solution of diethyl maleate (100.0 g, 0.56 mol) in ethanol (100 mL) in a 3-neck flask blanketed with nitrogen. The reaction temperature was maintained below 55° C. with an ice bath. The mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure to give crude diethyl N-hydroxyaspartate (103 g, 89% yield). The product was analyzed by nuclear magnetic resonance spectroscopy (NMR) and shown to be at least 95% pure. NMR (acetone-d6) 1.20 (m, 6H), 2.59 (dd, J 6.8, 16.1 Hz, 1H), 2.76 (dd, J 6.8, 16.1 Hz, 1H), 3.89 (t, J 6.8 Hz, 1H), and 4.11 (m, 4H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].Cl.Cl.[CH3:11][O:12][C:13](=[O:41])[CH2:14][CH:15]([NH2:40])[CH:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=[C:31]([CH3:39])[CH:30]=3)=[CH:23][CH:22]=2)[CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:41])[CH2:14][CH:15]([NH:40][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:7])[CH:16]1[O:20][N:19]=[C:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=[C:31]([CH3:39])[CH:30]=3)=[CH:25][CH:26]=2)[CH2:17]1
Reactant: O=C(Cl)c1ccco1
Reactant: COC(=O)CC(N)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CC(NC(=O)c1ccco1)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Reaction time: 2 h
Yield: 100 %

Procedure:
Furan-2-carbonyl chloride ((0.07 g, 0.54 mmol) was added to a mixture of 3-amino-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester di-hydrochloride salt (0.22 g, 0.45 mmol) from step 10e, methylene chloride (10 mL) and aqueous sodium carbonate (5 mL) under a nitrogen atmosphere at room temperature. The reaction was stirred vigorously for 2 h, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 3-[(furan-2-carbonyl)-amino]-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester (0.23 g, 100%) as an oil. MS found: (M+H)+=514.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12]>N1C=CC=CC=1>[F:1][C:2]1[N:7]=[C:6]([NH:8][C:11](=[O:12])[C:10]([CH3:15])([CH3:14])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(F)n1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cccc(F)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
6-fluoropyridin-2-amine (13.1 g, 117 mmol) was dissolved in anhydrous pyridine (100 mL), and cooled to 0° C. followed by fast dropwise addition of trimethylacetyl chloride (15.9 mL, 129 mmol) over 2 min. 5 min later, the resulting slurry was stirred over night at room temperature. Partial of the solvent was removed on rotary vacuum. The residue was partitioned between saturated ammonium chloride (200 mL) and EtOAc (200 mL). After separation, the organic layer was washed with brine (50 mL), dried over MgSO4, concentrated on rotary vacuum, and purified on flash chromatography eluting with 25˜75% EtOAc/Hexanes (1400 mL) to afford the expected product as a white solid (21.4 g, 93% yield); 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 9 H), 6.63 (dd, J=8.06, 2.01 Hz, 1 H), 7.76 (q, J=8.14 Hz, 1 H), 7.85 (s, 1 H), 8.09 (dd, J=8.06, 1.76 Hz, 1 H); Mass spec. 197.15 (MH+), Calc. for C10H13FN2O196.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].Cl[N:14]1C(=O)CC[C:15]1=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:6]2[C:5]([CH2:12][N:14]([CH3:15])[C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Br)ccc1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Product: CN1Cc2ccc(Br)cc2C1=O
Yield: 10.1 %

Procedure:
Methyl 5-bromo-2-methylbenzoate (3 g) in ethyl acetate (100 mL) was treated with N-chlorosuccinimide (1.749 g). The mixture was stirred and heated under reflux whilst being irradiated with a halogen lamp for 5 h. The reaction mixture was cooled and washed with 10% aqueous sodium metabisufite (100 mL) and water. The organic phase was dried over magnesium sulfate and concentrated to an oil. The crude product was treated with 8M methylamine in ethanol (20 mL) and the resulting mixture heated under reflux for 30 min. After cooling, the solution was concentrated to an oil, and the mixture purified on silica gel eluting with ethyl acetate to afford the sub-titled compound (0.300 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]4[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=4)[C:20]([NH:22][CH3:23])=[O:21])=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:23][NH:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][CH:26]=[C:17]([C:15]2[CH:14]=[N:13][N:12]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:7]=4)=[CH:9][N:10]=[C:11]3[CH:16]=2)[CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(Cl)c4)cnc3c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)c1

Procedure:
3-[3-(2-Chloro-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-N-methyl-benzamide (1 eq, 0.110 mmol, 40 mg) and phenyl boronic acid (1.2 eq, 0.132 mmol, 16.1 mg) are dissolved in DME (1.5 ml) and water (0.5 ml) and Na2CO3 (2 eq, 0.22 mmol, 27.3 mg) is added. PdCl2(PPh3)2 (0.1 eq, 0.011 mmol, 7.7 mg) is then added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield N-Methyl-3-[3-(2-phenyl-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-benzamide as a yellow solid; [M+H]+=406
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]([C:14]([O:16][CH3:17])=[O:15])=[N:6]1.[N-:18]=[N+:19]=[N-:20].[Na+]>CS(C)=O.O>[N:18]([CH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]([C:14]([O:16][CH3:17])=[O:15])=[N:6]1)=[N+:19]=[N-:20]
Reactant: COC(=O)c1cc(C(=O)OC)n(CCCBr)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(C(=O)OC)n(CCCN=[N+]=[N-])n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 5-1 (1.0 g, 3.45 mmol) in 10 ml DMSO was treated with NaN3 (0.883 g, 13.8 mmol) and mixture stirred at 25° C. for 5 h. Next, the reaction mixture was diluted with 100 ml of H2O and then extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (2×100 ml) and brine (1×100 ml), dried over Na2SO4 and evaporated to give 5-2 as a colorless oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)([CH3:3])[CH3:2].[CH:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.[BH4-].[Na+].C(O)(=O)C>CO>[CH:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][NH:26][C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:19][C:16]1[CH:15]=[CH:14][CH:13]=[CH:18][CH:17]=1)([CH3:3])[CH3:2]
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: CC(C)Oc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Oc1ccccc1CNc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a solution of 1.64 g of 2-isopropoxybenzaldehyde in 10 ml of methanol was added 1.85 g of 2-aminodiphenyl ether, and then the mixture was stirred at room temperature for 30 minutes and cooled on ice-water. To the cooled reaction solution was gradually added 1.50 g of sodium borohydride, followed by stirring under ice-cooling for 30 minutes and then at room temperature for 30 minutes. An aqueous acetic acid solution (1.5 ml of acetic acid—30 ml of water) was added dropwise to the reaction solution, followed by stirring at room temperature for 10 minutes. After extraction with ethyl acetate, the extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:25) to give 2.65 g of N-(2-isopropoxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[C:5]=1[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([O:23][CH3:24])[CH:17]=1.[CH3:26][O:27]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[C:5]=1[O:15][C:16]1[CH:17]=[C:18]([O:23][CH3:24])[CH:19]=[C:20]([CH3:22])[C:21]=1[CH:26]=[O:27]
Reactant: COC(=O)c1cc(OC)c(C)c(OC)c1Oc1cc(C)cc(OC)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c(C)c(OC)c1Oc1cc(OC)cc(C)c1C=O
Temperature: -78 °C
Yield: 60 %

Procedure:
A mixture of 1 mmol of 3,5-dimethoxy-2-(5-methyl-3-methoxy-phenoxy)-4-methyl-benzoic acid methyl ester and 6 mmol of dichloromethyl methyl ether was taken in 8 mL of dichloromethane. The mixture was cooled to −78° C. under stirring, and then titanium tetrachloride (6 mmol) in dichloromethane (4 ml) was added dropwise over 0.5 h. Upon completion, the reaction mixture was poured into ice-cold water and partitioned. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over MgSO4, and the solvent was evaporated by a rotary evaporator. The residue was purified by column chromatography to afford 2-(3-methyl-2-Formyl-5-methoxy-phenoxy)-3,5-dimethoxy-4-methyl-benzoic acid methyl ester (60%).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[C:10]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)=[CH:11][C:12]([F:25])=[C:13]([CH:24]=1)[C:14](OC1C=CC(C)=CC=1)=[O:15].O>CC1CCCO1>[Cl:8][C:9]1[C:10]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:35])[F:36])[CH:28]=2)=[CH:11][C:12]([F:25])=[C:13]([CH:24]=1)[C:14]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:15]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 65 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To a suspension of sodium hydride (7.39 g, 184.66 mmol) in 2-methyltetrahydrofuran (400 mL) at 0-5° C. was added methanesulphonamide (16.47 g, 173.12 mmol) and the mixture stirred for 1 hour and allowed to reach room temperature. 4-Methylphenyl 5-chloro-4-[4-chloro-3-(trifluoromethyl)phenoxy]-2-fluorobenzoate (Preparation 163, 53 g, 115.41 mmol) in 2-methyltetrahydrofuran (100 mL) was added and the reaction mixture heated at 65° C. for 6 hours and cooled. Water (250 mL) was charged to the stirred reaction mixture and the layers separated. The organic layer was further washed with 1M citric acid solution (200 mL) and concentrated under reduced pressure at 45° C. The resulting solid was stirred in tert butyl methyl ether (250 mL) at 50° C. for 1 hour, cooled to 0-5° C., filtered and dried to give the title compound as an off-white solid (27.5 g, 53%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.O>N1C=CC=CC=1>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[CH:16][CH:15]=1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a solution of 4-ethylbenzenesulfonyl chloride (90%, 4.25 g (20.8 mmol)) in pyridine (10 ml), 4-chloroaniline (2.55 g (20.0 mmol)) was added with stirring at room temperature. After 18 hours' stirring at room temperature, water (100.0 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid, water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 5.26 g (89%) of 4′-chloro-4-ethylbenzenesulfonanilide as white crystals.
Reaction SMILES: S([O-])(=O)(=O)C.[CH3:6][C:7]1[O:11][N:10]=[C:9]([CH2:12]OS(C)(=O)=O)[CH:8]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[N:38]=[C:26]2[N:27]=[C:28]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:29]=[C:30]([NH2:31])[N:25]2[N:24]=1.CCN(CC)CC>CC#N>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[N:38]=[C:26]2[N:27]=[C:28]([N:32]3[CH2:37][CH2:36][N:35]([CH2:12][C:9]4[CH:8]=[C:7]([CH3:6])[O:11][N:10]=4)[CH2:34][CH2:33]3)[N:29]=[C:30]([NH2:31])[N:25]2[N:24]=1
Reactant: Nc1nc(N2CCNCC2)nc2nc(-c3ccco3)nn12
Reactant: Cc1cc(COS(C)(=O)=O)no1
Agent: CS(=O)(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(CN2CCN(c3nc(N)n4nc(-c5ccco5)nc4n3)CC2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The mesylate derivative from subpart (a) above (0.28 mmol) was added to a solution of 2-furan-2-yl-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.14 mmol; see Example 1(a) above) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temperature for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[S:3])[NH2:2].C(=O)(O)[O-].[Na+].Br[CH:22]1[C:27](=O)[CH2:26][CH2:25][O:24][CH2:23]1>C(O)C>[N:2]1[C:27]2[CH2:26][CH2:25][O:24][CH2:23][C:22]=2[S:3][C:1]=1[C:4]1[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(C(N)=S)c(C)cc1C
Reactant: O=C1CCOCC1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc(-c2nc3c(s2)COCC3)c(C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.8 %

Procedure:
To a solution of methyl 5-carbamothioyl-2,4-dimethylbenzoate (compound 130.1, 500 mg, 2.24 mmol, 1.00 equiv) in ethanol (5 mL) was added sodium bicarbonate (396 mg, 4.71 mmol, 1.00 equiv) and 3-bromodihydro-2H-pyran-4(3H)-one (compound 1.10.1, 186 mg, 1.04 mmol, 1.00 equiv). The resulting solution was stiffed overnight at 80° C. under nitrogen. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was taken up 10 mL of water and ethyl acetate. The aqueous phase was extracted with 2×20 mL of ethyl acetate and the combined organic layers were dried (MgSO4), and concentrated under reduced pressure to yield 400 mg (56%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.Cl[C:26]([O:28][CH2:29][CH2:30][Cl:31])=[O:27]>O>[CH3:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[NH:8][C:26](=[O:27])[O:28][CH2:29][CH2:30][Cl:31]
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1N
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(N)c([N+](=O)[O-])cc1NC(=O)OCCCl
Temperature: 90 °C

Procedure:
0.6 mol (100 g) of 4-methyl-2,5-diamino-nitrobenzene and 0.36 mol (50 g) of potassium carbonate are introduced into 500 ml of dioxane to which 145 ml of water have been added. The mixture is heated to 90° C., whilst stirring, and 0.6 mol (86 g) of chloroethyl chloroformate is then added gradually, in the course of 10 minutes. When the addition has ended, the heating is maintained for 10 minutes at 90° C. The reaction medium is cooled to 15° C. and the desired product is then filtered off. After washing with a small amount of dioxane and then with water and alcohol, the product is recrystallised from dioxane and then dried in vacuo. It melts at 192° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:21](O)=O.C=O>O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH3:21])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)=[O:20])[CH3:2]
Reactant: CCOC(=O)c1ccc(NCc2ccc(Cl)cc2)cc1
Reactant: O=CO
Agent: C=O
Solvent: O
Product: CCOC(=O)c1ccc(N(C)Cc2ccc(Cl)cc2)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
To ethyl-4-(4-chlorobenzylamino)-benzoate (5.8 g; 0.02 mole) was added 80% formic acid (30 ml) and 40% formaldehyde solution (10 ml) and the mixture was heated at 100° C. for 6 hours. The reaction mixture was cooled to room temperature, water (60 ml) added and the product filtered, dried under vacuum at 60° C. and was crystallised from ethanol to give N-(4-ethoxycarbonylphenyl)-N-(4-chlorobenzyl)-methylamine (4.86 g; 80%). M.p. 106°-7° C.
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:23])=[CH:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])=[CH:7][CH:6]=1>CO>[N:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:23])[CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: CC(=CC(=O)OCc1ccccc1)c1ccncc1
Solvent: CC(=O)O
Solvent: CO
Product: CC(CC(=O)O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
Next, methanol (31 ml) and acetic acid (0.71 ml, 12.4 mmol) were added to benzyl 3-(4-pyridyl)-2-butenate (1.75 g, 6.20 mmol), and a nitrogen gas was bubbled through the mixture at room temperature for 10 minutes. A catalytic amount of 10%-palladium on carbon was added to the mixture, and the whole was stirred under a hydrogen atmosphere at room temperature overnight. The resulting insoluble matter was filtered out, and the filtrate was concentrated under reduced pressure. The resulting crystals were filtered off with acetone to give 3-(4-pyridyl)butyric acid (0.61 g, 60%) as pale yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13](O)=[O:14])=[CH:9][CH:8]=2)[CH2:3]1.C1N=C[N:20](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+].O>CN(C=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13]([NH2:20])=[O:14])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)COc1ccc([C@@H]2CCC(=O)C2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)COc1ccc([C@@H]2CCC(=O)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.9 %

Procedure:
(R)-[4-(3-Oxo-cyclopentyl)-phenoxy]-acetic acid (preparation 31) (1.6 mmol, 375 mg) was dissolved in DMF (3 mL), then CDI (1.84 mmol, 299 mg) was added and the reaction mixture stirred at r.t. for 90 min. Ammonium hydroxide (25% aq, 7 mL) was added and a precipitate formed. Water (7 mL) was added and the precipitate filtered off and dried in vacuo to yield the title compound (302 mg, 81%). 1H NMR (300 MHz, CDCl3) δ 7.25-7.14 (m, 2H), 6.97-6.83 (m, 2H), 6.78 (bs, 1H), 5.91 (bs, 1H), 4.49 (s, 2H), 3.52-3.28 (m, 1H), 2.77-2.57 (m, 1H), 2.57-2.11 (m, 5H), 2.09-1.79 (m, 1H).