Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:56]([O:60][C:61]([N:63]1[CH2:68][CH:67]=[C:66](B2OC(C)(C)C(C)(C)O2)[CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]>CN(C=O)C.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd]>[C:56]([O:60][C:61]([N:63]1[CH2:64][CH:65]=[C:66]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH:10]=[C:9]([C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=2)[N:18]=4)[CH2:67][CH2:68]1)=[O:62])([CH3:59])([CH3:57])[CH3:58]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OS(=O)(=O)C(F)(F)F)cc1OCC2
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Temperature: 90 °C
Yield: 45.2 %

Procedure:
To a mixture of trifluoro-methanesulfonic acid 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl ester (83 mg, 0.19 mmol) and 2N aqueous sodium carbonate (600 L) in DMF (1.2 mL) was added palladium bis(dibenzylideneacetone) (6 mg, 0.01 mmol), triphenylphosphine (4 mg, 0.015 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (75 mg, 0.24 mmol). The reaction mixture was degassed and then heated at 90° C. under an atmosphere of argon for 2 h before being concentrated in vacuo. The resultant residue was partitioned between ethyl acetate and water, the aqueous extracted with ethyl acetate (×3) and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in ethyl acetate) to give 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a white solid (41 mg, 45%). LCMS (*) RT=3.24 min, [M+H]+=478. 1H NMR 400 MHz (CDCl3) δ: 9.65 (1 H, s), 7.94 (1 H, s), 7.89 (1 H, s), 7.00 (1 H, s), 6.84 (1 H, s), 4.60 (2 H, s), 4.50 (2 H, s), 4.18 (2 H, s), 3.67 (2 H, s), 2.62 (2 H, s), 1.59 (6 H, d, J=6.62 Hz), 1.50 (9 H, s)
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([CH2:11][C:12]([O:14]CC)=[O:13])#[N:10].N1CCCCC1.C(O)(=O)C>CCCCC>[C:9]([C:11](=[CH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:12]([OH:14])=[O:13])#[N:10]
Reactant: CCOC(=O)CC#N
Reactant: O=CC1CCCCC1
Solvent: CCCCC
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: N#CC(=CC1CCCCC1)C(=O)O

Procedure:
A mixture of 56 g of cyclohexanecarboxaldehyde, 56.5 g of ethyl cyanoacetate, 1 g of piperidine and 100 ml of acetic acid was heated on a steam bath for 30 minutes. The acetic acid was stripped under reduced pressure. The residue was dissolved in 500 ml of pentane. The solution was extracted, successively, with water, sodium bicarbonate solution, and water. The pentane was evaporated under reduced pressure and the residue was distilled to give the ethyl ester of 2-cyano-3-cyclohexyl-2-propenoic acid (4A), bp: 120°-121° C. at 0.01 Torr.
Reaction SMILES: C1C2C=CC3C=CC=CC=3C(=O)C=2C=CC=1C(C)C#N.Cl.[CH:22]1[C:32]2[CH:31]=[CH:30][C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[C:27](=[O:37])[C:26]=2[CH:25]=[CH:24][C:23]=1[CH:38](C)[C:39]([OH:41])=[O:40].C1C2C=CC3C=CC=CC=3C(=O)C=2C=CC=1CC#N>CC(C)=O.CCCCCC.C(Cl)(Cl)Cl.CCCCCC.O.CCOCC.C(O)(=O)C>[CH:22]1[C:32]2[CH:31]=[CH:30][C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[C:27](=[O:37])[C:26]=2[CH:25]=[CH:24][C:23]=1[CH2:38][C:39]([OH:41])=[O:40]
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: CC(C#N)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: Cl
Agent: N#CCc1ccc2c(=O)c3ccccc3ccc2c1
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
3.4 Gm. of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionitrile is refluxed for 90 minutes in a mixture of 210 ml. of acetic acid and 300 ml. of concentrated hydrochloric acid. The mixture is cooled and ether and water are added. The organic layer is washed, dried and evaporated to give 3.4 gm., 93%, of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139°C.; m.p. (acetone-hexane) 113°-115°C. Use of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetonitrile gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10](I)=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([CH3:19])[N:7]=1)=[O:5])[CH3:2].[CH2:20]([Li])CCC.CI.C(OCC)(=O)C>C1COCC1.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:20])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([CH3:19])[N:7]=1)=[O:5])[CH3:2]
Reactant: [Li]CCCC
Reactant: CCOC(=O)c1nn(C)c(-c2ccc(F)cc2)c1I
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1nn(C)c(-c2ccc(F)cc2)c1C
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of 4.06 g of 5-(4-Fluoro-phenyl)-4-iodo-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester in 80 mL of dry THF were added dropwise 8.13 ml of a 1.6 M solution of n-Butyllithium in THF maintaining the temperature below −70° C. The solution was stirred for 15 min at −75° C. and 1.4 ml of Methyl iodide was added. The reaction mixture was stirred for 30 min at −75° C. and allowed to warm up to room temperature. The mixture was worked up with Ethyl acetate and brine. The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product (3.15 g) was purified by chromatography on silica gel (Heptane/Ethyl acetate 2:1). The desired product was obtained as a yellow oil (1.00 g, 35%), which solidified on standing. MS: m/e=263.1 ([M+1]+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=3)=[O:13])[CH:9]=2)[NH:4][N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)=[O:13])[CH:9]=2)[NH:4][N:3]=1
Reactant: COc1cccc(CNC(=O)Nc2ccc3[nH]nc(N)c3c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1n[nH]c2ccc(NC(=O)NCc3cccc(O)c3)cc12
Reaction time: 48 h
Yield: 83.8 %

Procedure:
500 mg of 1-(3-amino-1H-indazol-5-yl)-3-(3-methoxybenzyl)urea are suspended in 10 ml of DCM, and 916 μl of BBr3 are added. After two days at RT, the mixture is carefully quenched using 1 ml of methanol and evaporated to dryness. Purification by silica-gel chromatography (eluent: DCM/MeOH 4:1) gives 400 mg of 1-(3-amino-1H-indazol-5-yl)-3-(3-hydroxybenzyl)urea (“A2) as a virtually colourless solid (84%); MS-FAB (M+H+)=298.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[CH3:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[N:25][C:24]([NH2:27])=[N:23]2)=[CH:19][CH:18]=1>>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([NH:27][C:24]2[N:25]=[CH:26][N:22]([CH2:21][C:20]3[CH:28]=[CH:29][C:17]([CH3:16])=[CH:18][CH:19]=3)[N:23]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: Cc1ccc(Cn2cnc(N)n2)cc1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2ncn(Cc3ccc(C)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 43 starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole and 1-(4-methyl-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a light yellow solid (Yield=60%). MS ISP (m/e): 375.4 (100) [(M+H)+].
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH:14]12[O:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19]2>O>[OH:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCC2OC2C1
Reactant: C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OC1CCCCC1N1CCCCC1
Temperature: 90 °C
Yield: 102.3 %

Procedure:
Piperidine hydrochloride (3.648 g, 30 mmol) was stirred in a mixture of 4.0 mL of water and 4.146 g of ground potassium carbonate. This mixture was heated to 90° C. and cyclohexene oxide (1.01 mL, 10 mmol) was added. The resulting mixture was heated at 100° C. for 18 hours. The reaction was cooled then filtered to remove carbonate salts. The filter cake was washed with 25 mL of diethyl ether and 50 mL of ethyl acetate. The filtrate and washings were combined and washed with brine (2×20 mL), dried over magnesium sulfate, filtered, and evaporated to give 1.875 g (>100%) of the title compound which was used without further purification. 1H NMR consistent with desired product.
Reaction SMILES: C([C@@H]1COC(=O)N1C(=O)[C@H]([CH2:19][S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1)(=[O:22])=[O:21])C(C)C)C1C=CC=CC=1.Cl.Cl.FC1C=CC(C2C=NC(N3CCNCC3)=NC=2)=CC=1.[CH3:64][O:65][C:66]([C:68]1(CS(Cl)(=O)=O)[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]1)=[O:67]>>[CH3:64][O:65][C:66]([C:68]1([CH2:19][S:20]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[N:34]=[CH:33][C:32]([C:35]4[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=4)=[CH:31][N:30]=3)[CH2:27][CH2:28]2)(=[O:22])=[O:21])[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]1)=[O:67]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COC(=O)C1(CS(=O)(=O)Cl)CCCCC1
Agent: Cl
Agent: Fc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Product: COC(=O)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCCCC1
Yield: 48 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 5-(4-fluorophenyl)-2-piperazine-1-ylpyrimidine, dihydrochloride (0.599 g) and 1-chlorosulfonylmethylcyclohexanecarboxylic acid methyl ester (0.575 g), to yield the title compound as a white solid (0.417 g, 48%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].[OH-].[Li+].C(O)(=O)C>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of methyl 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (for a preparation see Intermediate 6) (580 mg, 1.273 mmol) in ethanol (10 mL) was treated with a aqueous lithium hydroxide solution (1N, 2.55 mL, 2.55 mmol) and the resulting mixture was stirred for 2 h. The bulk of ethanol was evaporated in vacuo and the residue was diluted with water (ca. 5 mL). The cloudy mixture was treated with acetic acid (0.146 mL, 2.55 mmol) and the precipitate formed was isolated by filtration, washed with Et2O and dried at 60° C. for 16 h to give 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (410 mg, 0.959 mmol, 75% yield) as a pale yellow solid which was used in the next step without further purification. LCMS (HpH, 2 min), Rt=0.63 min, MH+=428.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([CH3:19])(O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[I:25]I>C(#N)C.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:19])[C:9]=2[I:25])=[CH:4][CH:3]=1
Reactant: II
Reactant: CC(O)(C#Cc1ccc(Cl)cc1)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1I
Reaction time: 1.5 h
Yield: 75.8 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-methyl-1-phenylbut-3-yn-2-ol (3D) (1.77 g, 6.53 mmol) in acetonitrile (50 mL) was added sodium bicarbonate (1.097 g, 13.06 mmol), followed by iodine (4.974 g, 19.60 mmol). The reaction mixture was stirred for 1.5 h, then diluted with diethyl ether. The organic layer was washed with 1 M sodium thiosulfate solution (50 mL). The aqueous layer was back-extracted with diethyl ether and the combined organic layer was dried (MgSO4), filtered, concentrated, adsorbed onto silica gel and purified by flash column chromatography (silica gel, hexanes) to give 3E as an off-white solid (1.8733 g). 1H-NMR: 300 MHz, (CDCl3) δ 7.74 (d, J=6.6 Hz, 1H), 7.73 (s, 1H), 7.48-7.40 (m, 3H), 7.24-7.20 (m, 2H), 7.13 (d, J=8.1 Hz, 2H), 2.64 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>O1CCCC1>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[C:14]([B:22]([OH:27])[OH:23])=[CH:13][C:12]([Cl:15])=[N:11][CH:10]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cnc(Cl)cc1B(O)O
Temperature: -78 °C
Yield: 100.3 %

Procedure:
Tert-butyl[(6-chloropyridin-3-yl)methyl]carbamate (1.00 g, 0.004 mol) was dissolved in anhydrous tetrahydrofuran (20 mL) in an oven-dried 50-mL round-bottomed flask. The solution was stirred under an atmosphere of nitrogen and cooled to at −78° C. Tert-butyllithium (1.7 M in pentane, 5.1 mL, 0.009 mol) was slowly added via syringe. The reaction solution turned yellow, then dark orange during the addition. The resulting solution was stirred at −77° C. for 10 min, then was slowly warmed to −20° C. Triisopropyl borate (3.79 mL, 0.017 mol) was added quickly via syringe and the mixture was allowed to warm to room temperature with stirring. The reaction was cooled to 0° C. and quenched by the slow addition of 1.00 M of hydrochloric acid in water (8.65 mL) with good stirring. The reaction mixture was then added to water (100 mL) in a separatory funnel and was extracted with ethyl acetate (3×75 mL). The extracts were combined, dried over sodium sulfate, filtered, concentrated and dried under vacuum to leave 1.15 g (97% yield) (5-{[(tert-butoxy-carbonyl)amino]methyl}-2-chloropyridin-4yl)boronic acid as an orange foam. The product structure was confirmed by NMR and MS and used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.[NH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[C:24]([Cl:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2>>[Cl:36][C:24]1[CH:23]=[C:22]([NH:21][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[CH:20][C:11]=3[O:10][CH2:9][CH2:8][NH:7][C:4](=[O:6])[CH2:3][O:2][CH3:1])[N:16]=[CH:15][N:14]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: COCC(=O)O
Reactant: NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: COCC(=O)NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 50 %

Procedure:
The procedure described in Example 1 was repeated using methoxyacetic acid and 5-(2-aminoethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 2.6, preparation of starting materials) to give the title compound in 50% yield; NMR spectrum (DMSO-d6) 3.20 (s, 3H), 3.68 (m, 2H), 3.73 (s, 2H), 4.38 (t, 2H), 5.29 (s, 2H), 7.14 (d, 1H), 7.21 (d, 1H), 7.34 (m, 2H), 7.55 (t, 1H), 7.71 (t, 1H), 7.86 (t, 1H), 7.97 (d, 1H), 8.17 (m, 1H), 8.44 (s, 1H), 8.58 (d, 1H), 9.81 (s, 1H); Mass Spectrum MH+ 494.
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][S:9](Cl)(=[O:11])=[O:10]>>[CH3:8][S:9]([O:7][CH:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH3:1])(=[O:11])=[O:10]
Reactant: CCCCC(C)O
Reactant: CS(=O)(=O)Cl
Product: CCCCC(C)OS(C)(=O)=O

Procedure:
The title compound was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (408 mg, 68%) from 2-hexanol (312 mg, 2.90 mmol) and methanesulfonyl chloride (500 mg, 4.40 mmol). 1H NMR (CDCl3, 300 MHz) δ0.89-0.94 (m, 3H), 1.31-1.43 (m, 5H), 1.57-1.71 (m, 4H), 2.99 (s, 3H), 4.76-4.82 (m, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1.[CH2:11]([N:13]([CH2:29][CH3:30])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])(=[O:16])=[O:15])[CH3:12].C1N2CCN(CC2)C1>C(#N)C>[CH2:29]([N:13]([CH2:11][CH3:12])[S:14]([C:17]1[C:18]([S:23]([NH:26][C:27]([NH:1][C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=2)=[O:28])(=[O:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])[CH3:30]
Reactant: CCN(CC)S(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1nc(N)nc(C)c1C
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CCN(CC)S(=O)(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c(C)c(C)n1

Procedure:
A mixture of 0.8 g of 2-amino-4,5,6-trimethylpyrimidine, 2.8 g of the crude sulfonyl isocyanate from Example 9 and a few crystals of DABCO in 25 ml of acetonitrile is stirred at room temperature for 16 hours. A small amount of unreacted aminopyrimidine is filtered off and the filtrate concentrated in-vacuo to give a hard glass. Crystallization from methanol gives N,N-diethyl-N'[4,5,6-trimethylpyrimidin-2-yl]aminocarbonyl-1,2-benzenedisulfonamide as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH4+:23].[OH-]>CN(C=O)C.C(Cl)Cl>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:23])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Cc2ccccc2)c1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1cccc(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the product from Step A (0.0119 moles) was added 150 mL of CH2Cl2, one drop of DMF, 10 mL of oxalyl chloride, and the mixture was stirred at room temperature for 3 hours. After cooling to 10° C., 30 mL of NH4OH (exothermic) was added and the mixture was stirred for 30 min. The reaction mixture was then concentrated and the resulting residue diluted with ethyl acetate. The organic layer was washed with 1N NaOH, brine, dried over Na2SO4, and concentrated to give the 3-(benzyl)benzamide as a white solid, which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]([OH:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:21]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][CH:13]3[CH3:20])=[O:23])=[CH:27][CH:26]=1
Reactant: CC1OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1
Product: CC1OCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 16, 3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid and 4-fluorobenzylamine. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.67 (3H, d, J=6.6 Hz, CH3), 3.91 (2H, m, CH2), 4.12-4.35 (2H, m, CH2), 4.52 (2H, d, J=5.9 Hz, NCH2), 4.70 (1H, q, J=6.6 Hz, OCH), 5.33 (2H, s, OCH2), 7.02 (2H, m, aromatics), 7.25 (2H, m, aromatics), 7.35 (3H, m, aromatics), 7.47 (2H, m, aromatics), 7.71 (1H, broad t, NH).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH:13][C:14]([CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=O)=[N:9]2)=[CH:4][CH:3]=1>CC(O)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[N:13][N:12]=3)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NNc2cnc3ccc(Br)cc3n2)CC1
Solvent: CC(=O)O
Product: Brc1ccc2ncc3nnc(C4CCNCC4)n3c2c1
Yield: 82.8 %

Procedure:
A mixture of tert-butyl 4-(2-(7-bromoquinoxalin-2-yl)hydrazinecarbonyl)piperidine-1-carboxylate (900 mg, 2.0 mmol) in AcOH (10 mL) was refluxed overnight. Then the solvent was removed, and the residue was purified by ISCO (MeOH/H2O=20%-90%) to afford 8-bromo-1-(piperidin-4-yl)[1,2,4]triazolo[4,3-a]quinoxaline as a pale yellow solid (550 mg, yield 83.0%). MS (m/z): 332 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[C:29](=[O:32])([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[O:32]1[C:29]2[CH:5]=[CH:6][C:7]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:12]([CH2:13][C@@H:14]5[CH2:18][CH2:17][N:16]([C:19]([CH:21]6[CH2:22][CH2:23]6)=[O:20])[CH2:15]5)=[N:11][NH:10][C:9]4=[O:24])=[C:4]([C:25]([F:28])([F:26])[F:27])[CH:3]=3)=[CH:2][C:3]=2[CH:4]=[CH:25]1
Reactant: O=C([O-])[O-]
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2C(F)(F)F)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2C(F)(F)F)C1
Temperature: 100 °C
Yield: 83.9 %

Procedure:
To a microwave vial were added 4-[4-bromo-2-(trifluoromethyl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (55 mg, 0.072 mmol), 4-[4-bromo-2-(trifluoromethyl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (55 mg, 0.072 mmol), cesium carbonate (82 mg, 0.251 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (6.0 mg, 0.00735 mmol) and the mixture was purged with nitrogen. 1,4-Dioxane (1 mL) and water (0.5 mL) were added to the mixture which was heated overnight at 100° C. Analysis by LCMS indicated desired product formation and consumption of starting material. The mixture was filtered through a syringe filter and purified by reverse phase HPLC (10-90% acetonitrile/water with 0.1% TFA). The desired fractions were collected and added to a separatory funnel containing ethyl acetate. The aqueous phase was adjusted to pH˜6 with 1N aq HCl. The aqueous phase was extracted with ethyl acetate (3×), and the combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the title product as a tan solid (15 mg, 41%). MS(ES)+ m/e 497.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:21](Br)[C:22]1[CH:30]=[CH:29][C:28]2[O:27][CH2:26][O:25][C:24]=2[CH:23]=1.C(=O)(O)[O-].[Na+].N1C=CC=CC=1>CCOCC>[CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:30]=[CH:29][C:28]2[O:27][CH2:26][O:25][C:24]=2[CH:23]=1)[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: BrCc1ccc2c(c1)OCO2
Reactant: CC(C)CCOCCCCCCOCCCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)CCOCCCCCCOCCCCCCOCc1ccc2c(c1)OCO2
Reaction time: 18 h

Procedure:
2.88 g (0.010 mol) of 6-(6-Isopentyloxyhexyloxy)-hexanol are mixed with 2.15 g (0.010 mol) of piperonyl bromide and 1.26 g (0.015 mol) of sodium bicarbonate and the mixture is stirred at 80° for 18 hours and then at 120° C. for 6 hours. 1.0 cc of pyridine is added to the reaction mixture which is heated to 80° over the course of 2 hours. The reaction mixture is cooled, taken up in ether, washed with 2N sulphuric acid, water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated. After chromatography of the residue on silica gel with hexane/acetone (98:2) and (96:4), [6-(6-Isopentyloxyhexyloxy)-hexyl]-piperonyl ether is obtained as a colourless oil.