Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.OC1C=CC=CC=1>CC(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: BrCCCCCCBr
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: Cc1ccc(N=Nc2ccc(OCCCCCCBr)cc2)cc1
Reaction time: 20 h

Procedure:
A 2 l three-neck flask equipped with a mechanical stirrer was charged with 42.4 g (0.2 mol) of 4-hydroxy-4′-methylazobenzene synthesized in the same manner as in the Example, 448 g (2 mol) of 1,6-dibromohexane and 212 g (1.5 mol) of potassium carbonate anhydride. To the mixture was added 800 ml of acetone and the resulting mixture was suspended by stirring. The reaction system was heated until acetone was refluxed to react hydroxybenzene with bromoalkane. After the reaction was continued for 20 hours, insoluble salts were separated by filtration and removed. The system was concentrated to a volume of about ⅓ by using a rotary evaporator. When the system was cooled in a freezing chamber, 4-(6-bromohexyloxy)-4′-methylazobenzene was produced as a crystal. After the generated product was subjected to filtration, it was washed with a small amount of cool acetone, cool ether and n-hexane in this order and then dried under reduced pressure to obtain 38.1 g of crude 4-(6-bromohexyloxy)-4′-methylazobenzene (yield: 50.8%). The resulting product was recrystallized from ethanol to obtain 32 g (yield: 42%) of 4-(6-bromohexyloxy)-4′-methylazobenzene. It was found from an analysis using high performance liquid chromatography that the purity of the product was 98.6% or more.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)[CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)[CH2:16][CH2:17]2)[N:1]=[C:28]([CH3:35])[C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: N#Cc1c(N)cccc1OCC1CCN(C(=O)c2cccc(O)c2)CC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCN(C(=O)c4cccc(O)c4)CC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-((1-(3-hydroxybenzoyl)piperidin-4-yl)methoxy)benzonitrile (Example 34b) and ethyl 3-oxobutanoate as a yellow solid (49%). 1H NMR (400 MHz, DMSO-d6) δ 1.24 (m, 2H), 1.31 (t, J=4.0 Hz, 3H), 1.77-1.89 (m, 2H), 2.22 (brs, 1H), 2.55 (s, 3H), 2.79 (brs, 1H), 3.04 (brs, 1H), 3.64 (brs, 1H), 4.10 (m, 2H), 4.32 (q, J=8.0 Hz, 2H), 4.49 (brs, 1H), 6.71-6.82 (m, 3H), 6.93 (d, J=8.0 Hz, 1H), 7.19-7.25 (m, 2H), 7.52 (t, J=8.0 Hz, 1H), 8.06 (brs, 2H), 9.64 (s, 1H). MS 464 (MH+).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccc(O)cc1
Reactant: BrCc1ccccc1
Product: Oc1ccc(OCc2ccccc2)cc1

Procedure:
In analogy to the procedure described in Example 1a), the alkylation of hydroquinone with benzylbromide yielded the 4-benzyloxy-phenol as a colourless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:13]C)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]>Br>[N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: COc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Br
Product: O=[N+]([O-])c1cc(O)cc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
3,5-Dinitroanisole (1.36 g, 6.9 mmol) and concentrated aqueous HBr (50 ml) was heated to reflux temperature for 16 h. After cooling to ambient temperature, the solid precipitate was filtered off, washed with water and dried. Yield: 325 mg (26%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:26])(=O)=O)=CC=1>O1CCCC1>[F:26][C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: c1csc(-c2cccs2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2cccs2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
2,2′-Bithiophene (7.40 g) in tetrahydrofuran (90 ml) was cooled to −78° C. under argon atmosphere, and thereto were added dropwise n-butyl lithium (1.59 M hexane solution, 28.0 ml). The mixture was stirred at 0° C. for one 30 minutes, and cooled again to −78° C. Added thereto was N-fluorobenzenesulfonimide (15.5 g), and the mixture was gradually warmed, and stirred at room temperature for 17 hours. The reaction mixture was poured into ice-cold water, and the solution was extracted with hexane twice, and the extract was washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane) to give 2-(5-fluoro-2-thienyl)thiophene (5.89 g) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:26]=[CH:25][C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[C:4]([F:27])[CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:26]=[CH:25][C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[C:4]([F:27])[CH:3]=1)(=[O:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc(N)cc3F)cc2CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1,1-dimethylethyl 7-[(4-amino-2-fluorophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (E274, Step 2) (250 mg, 0.67 mmol) in dichloromethane (10 ml) was added triethylamine (0.19 ml, 1.34 mmol) and acetyl chloride (50 μL, 0.74 ml) and the reaction stirred at room temperature for 16 hours. The reaction was then diluted with dichloromethane and washed with a 3N aqueous solution of citric acid, then saturated sodium bicarbonate then water and the dichloromethane dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate:pentane (1:1) to afford the title compound. MS (ES+) m/e 413 [M−H]−.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[CH2:15]([O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:12][CH3:13])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: COc1cc(C#N)ccc1O
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(C#N)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
To a suspension of sodium hydride, 60% dispersion in oil,(4.8 g; 0.11 mol) in 40 mL of DMF, a solution of 4-hydroxy-3-methoxy-benzonitrile (14.9 g; 0.1 mol) in DMF (40 mL) was added dropwise over 10 minutes. After addition, the reaction mixture was stirred at ambient temperature for 30 minutes, then bromohexane (16.5 g; 0.1 mol) in DMF (20 mL) was added. The reaction mixture was stirred at ambient temperature for 18 hours. The DMF containing reaction mixture was concentrated to a residue, and H2O (100 mL) was added to the residue. The solid was collected by filtration to obtain 8.2 g (35% yield) of the tide compound as white solid. 1H-NMR (DMSO-d6; 200 MHz) δ7.45 (s, 1H), 7.42 (s, 1H), 7.1 (d, 1H), 4.0 (t, 2H), 3.8 (s, 3H), 1.6-1.8 (m, 2H), 1.2-1.5 (m, 8H), and 0.9 ppm (t, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([NH:14][C:15]([CH3:26])([CH3:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]([CH3:27])=[N:9]2)(=[O:3])[CH3:2].FC(F)(F)S(O[Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])(=O)=O>C(Cl)Cl>[Si:34]([O:3][C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([NH:14][C:15]([CH3:26])([CH3:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:10]([CH3:27])=[N:9]2)=[CH2:2])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1cccc2nc(C)c(NC(C)(C)CNC(=O)OC(C)(C)C)nc12
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2nc(C)c(NC(C)(C)CNC(=O)OC(C)(C)C)nc12

Procedure:
A solution of tert-butyl (2-((8-acetyl-3-methylquinoxalin-2-yl)amino)-2-methylpropyl)carbamate (339a, 0.78 g, 2.094 mmol), tert-butyldimethylsilyl trifluoromethanesulfonate (0.72 mL, 3.14 mmol), and TEA (0.88 mL, 6.28 mmol) in DCM (21 mL) was stirred at 0° C. for 20 min when the silyl enol ether was observed via lcms. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (100 mL) before the organic layer was separated, dried over Na2SO4, and concentrated to give tert-butyl (2-((8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methylquinoxalin-2-yl)amino)-2-methylpropyl)carbamate (339b) as a yellow oil. MS (ESI, pos. ion) m/z: 487.3 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C@@H:5]1[CH2:9][S:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:6]1.O1CCCC1.[BH4-].[Li+].O>O1CCCC1>[Cl:19][C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([NH:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:14]=1)[NH:11][C:10]([C:7]1[S:8][CH2:9][C@@H:5]([CH2:4][CH2:3][OH:2])[N:6]=1)=[CH:18]2
Reactant: COC(=O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
The compound (550 mg, 1.4 mmol) prepared in Example 26 was dissolved in tetrahydrofuran (50 ml). 1 M lithium borohydride tetrahydrofuran solution (2.11 ml, 2.11 mmol) was added thereto, and the mixture was stirred for 1 h while raising the reaction temperature from −60° C. to 0° C. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and separated by column chromatography to give the title compound (510 mg, Yield 100%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].Br[CH2:28][CH2:29][CH2:30][CH:31](Br)[CH3:32]>>[CH3:25][O:24][C:11]1[CH:12]=[C:13]([C:20]([F:21])([F:22])[F:23])[CH:14]=[C:15]([C:16]([F:19])([F:18])[F:17])[C:10]=1[C:9]([NH:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[N:1]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH3:28])=[O:26]
Reactant: CC(Br)CCCBr
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N1CCCC1C

Procedure:
The title compound, MS: m/e=453.2 [(M+H)+], was prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 1,4-dibromopentane. The two diastereomers were not separated.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C:20]([C:23]1[N:27]([CH3:28])[C:26](=[O:29])[O:25][N:24]=1)([CH3:22])[CH3:21]>>[CH3:22][C:20]([NH:19][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:23]1[N:27]([CH3:28])[C:26](=[O:29])[O:25][N:24]=1)[CH3:21]
Reactant: Cn1c(C(C)(C)N)noc1=O
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: Cn1c(C(C)(C)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)noc1=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 3-(1-amino-1-methyl-ethyl)-4-methyl-4H-[1,2,4]oxadiazol-5-one hydrochloride (1:1) (Example 338c) as starting materials; LC-MS (UV peak area/ESI) 99%, 373.1870 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:42]([O:49][C:50]1[CH:77]=[CH:76][C:75](O)=[CH:74][C:51]=1[C:52]([NH:54][C:55]1[CH:67]=[C:66]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH:65]=[CH:64][C:56]=1[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[O:53])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1>[CH2:42]([O:49][C:50]1[CH:77]=[CH:76][C:75]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)=[CH:74][C:51]=1[C:52]([NH:54][C:55]1[CH:67]=[C:66]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH:65]=[CH:64][C:56]=1[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[O:53])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(O)ccc1OCc1ccccc1
Reactant: OCCN1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
1-(2-Hydroxyethyl)pyrrolidine (0.016 mL), triphenylphosphine (0.038 g), and diisopropyl azodicarboxylate (0.029 mL) were added to a tetrahydrofuran (1.2 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-hydroxybenzamido)-4-phenylbenzoate (0.060 g), followed by stirring at room temperature for 25 minutes. To the reaction mixture, 1-(2-hydroxyethyl)pyrrolidine (0.016 mL), triphenylphosphine (0.038 g), and diisopropyl azodicarboxylate (0.029 mL) were added, followed by stirring at room temperature for 20 minutes. To the reaction mixture, 1-(2-hydroxyethyl)pyrrolidine (0.016 mL), triphenylphosphine (0.038 g), and diisopropyl azodicarboxylate (0.029 mL) were added, followed by stirring at room temperature for 30 minutes. To the reaction mixture, 1-(2-hydroxyethyl)pyrrolidine (0.016 mL), triphenylphosphine (0.038 g), and diisopropyl azodicarboxylate (0.029 mL) were added, followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: 80-0% hexane/ethyl acetate] to obtain 0.071 g of tert-butyl 2-(2-(benzyloxy)-5-(2-(pyrrolidin-1-yl)ethoxy)benzamido)-4-phenylbenzoate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]2=[O:19])[CH:7]=1.[CH3:21][C:22]1[N:23]=[CH:24][S:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Ag+2].O.C(#N)C>[CH3:20][C:5]1[CH:4]=[CH:3][C:2]([C:24]2[S:25][CH:26]=[C:22]([CH3:21])[N:23]=2)=[CH:7][C:6]=1[CH:8]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]1=[O:19]
Reactant: Cc1cscn1
Reactant: Cc1ccc(Br)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: Cc1csc(-c2ccc(C)c(C3C(=O)C(C)(C)OC(C)(C)C3=O)c2)n1
Temperature: 65 °C
Yield: 17.1 %

Procedure:
To a mixture of 4-(5-bromo-2-methylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (200 mg, 0.589 mmol), 4-methylthiazole (70 mg, 0.707 mmol), silver carbonate (814 mg, 2.94 mmol), triphenylphosphine (15 mg, 0.0589 mmol) and [1,1-bis(diphenylphosphino)-ferrocene]palladium(II)chloride (24 mg, 0.0294 mmol) is added a degassed solvent mixture of water/acetonitrile (1.5 ml, 1:1 ratio), followed by subsequent purging with nitrogen then heating at 65° C. for 65 hours with shaking. After cooling to room temperature the reaction mixture is then partitioned between 2M aqueous hydrochloric acid and dichloromethane, and the organic phase is separated. The aqueous layer is washed with a further aliquot of dichloromethane, and the combined organic layers are evaporated under reduced pressure to give a brown solid which is purified by preparative reverse phase HPLC to give 4-[2-methyl-5-(4-methylthiazol-2-yl)phenyl]-2,2,6,6-tetramethylpyran-3,5-dione as a pale yellow solid (36 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:15]1>C1CCCCC1.CCOC(C)=O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]#[C:6][CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[CH:16]=[C:17]2[C:22]([CH:21]=[CH:20][CH:19]=[CH:18]2)=[N:14]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: BrCCCCC#Cc1ccccn1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C(#Cc1ccccn1)CCCCn1cc2ccccc2n1
Yield: 9 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 109(D), from 2-(6-bromo-hex-1-ynyl)-pyridine (250 mg, 1.05 mmol, Example 124(B)) and indazole (124 mg, 1.05 mmol). The crude product was purified by flash chromatography (cyclohexane/AcOEt 75:25) to yield 2-(6-(pyridin-2-yl)hex-5-ynyl)-2H-indazole (26 mg, 94 μmol, 9%) as a brown oil and (cyclohexane/AcOEt 1:1) to yield 1-(6-(pyridin-2-yl)hex-5-ynyl)-1H-indazole (15 mg, 54 μmol, 5%) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[C:11]=[O:12]>C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]([NH:10][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)=[O:12])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (3.0 g, 15.8 mmol) in THF (15 mL) was added 1-isocyanato-3-(trifluoromethyl)benzene (3.55 g, 18.9 mmol). The reaction was stirred at room temperature overnight. Solid product was present in the reaction vessel. Product was further precipitated by the addition of 1:2 ether/hexanes. The solids were collected by filtration, dried under hi vacuum and found to be clean title compound in 60% yield. 1H-NMR (DMSO-d6) δ 9.44 (s, 1H), 8.76 (d, J=1.2 Hz, 1H), 8.12 (t, J=8.7, 1H), 8.05 (s, 1H), 7.64-7.37 (m, 5H); MS [M+H]+=378.9, LCMS RT=3.92 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:17][CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:18]4[N:22]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[F:30])[CH:21]=[N:20][N:19]=4)[S:11][C:10]=3[C:9]=2[CH:31]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.C(O)C>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[N:22]1[CH:21]=[N:20][N:19]=[C:18]1[C:12]1[S:11][C:10]2[C:9]3[CH:31]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1
Reactant: COC(=O)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2,4-difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid methyl ester (210 mg) in THF (4 mL) and ethanol (2 mL) was added sodium hydroxide solution (38 mg in 2 mL of water) and the reaction stirred at room temperature for 16 h. The reaction was then acidified with 2 M hydrochloric acid and the resulting solid was filtered and air-dried to give 2-[4-(2,4-difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][S:12]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[O:10])=[CH:4][C:3]=1[CH3:21].[C:22]1([CH2:28]C(O)=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>>[Cl:20][C:17]1[S:16][C:15]([S:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:3]([CH3:21])[CH:4]=2)=[O:10])(=[O:14])=[O:13])=[CH:19][CH:18]=1
Reactant: Cc1cc(NC(=O)NS(=O)(=O)c2ccc(Cl)s2)ccc1N
Reactant: O=C(O)Cc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Product: Cc1cc(NC(=O)NS(=O)(=O)c2ccc(Cl)s2)ccc1NCc1ccccc1

Procedure:
1.0 equivalent of N-(4-amino-3-methylphenyl){[(5-chloro(2-thienyl))sulfonyl]amino}-carboxamide was treated with 1.0 equivalent of PhCH2COOH/PyBOP to give X═CH2, {[(5-chloro(2-thienyl))sulfonyl]amino}-N-{3-methyl-4-[benzylamino]phenyl}carboxamide. ES-MS (M+H)+=464, 466 (Cl).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1.I[CH3:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:10]([CH3:15])[C:11](=[O:13])[CH3:12])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(=O)NC(C)c1ccc(Br)cc1
Reactant: CI
Product: CC(=O)N(C)C(C)c1ccc(Br)cc1

Procedure:
The title compound was prepared from N-[1-(4-bromophenyl)ethyl]acetamide and iodomethane in a manner similar to that described for description 24.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[CH3:8][O:9][CH2:10][CH:11]=O.C1CCCCC1>O>[CH3:8][O:9][CH2:10][CH:11]1[O:6][CH2:5][C:2]([CH3:7])([CH3:1])[CH2:3][O:4]1
Reactant: CC(C)(CO)CO
Reactant: COCC=O
Solvent: O
Solvent: C1CCCCC1
Product: COCC1OCC(C)(C)CO1
Yield: 79 %

Procedure:
A mixture of 520 g (5 moles) of 2,2-dimethyl-1,3-propanediol, 479 g (5.5 moles) of 85% strength methoxy-acetaldehyde and 250 ml of cyclohexane was heated with 5 g of the ion exchanger Lewasorb AC 10 under a water separator until water no longer separated off. The ion exchanger was filtered off, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 632 g (79% yield) of 2-methoxymethyl-5,5-dimethyl-1,3-dioxane of boiling point 96° C./60 mbar were obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])[CH2:3][CH2:2]1.[BrH:14]>O>[BrH:14].[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:5][CH2:6]1
Reactant: COC(=O)CCCN1CCOCC1
Agent: Br
Solvent: O
Product: O=C(O)CCCN1CCOCC1

Procedure:
15 g. (0.052 mole) of methyl γ-morpholinobutyrate [Cruickshank and Sheehan, J. Am. Chem. Soc. 83 2891 (1961)] was dissolved in a mixture of 45 ml. of 47% hydrobromic acid and 45 ml. of water and heated for 16 hours at reflux. The solution was taken to dryness under reduced pressure, and the solid which formed was triturated with acetone. The material was filtered and crystallized from 60 ml. of acetic acid to give 12.4 g. (95%) of product as colorless crystals, m.p. 151° - 152.5°. The infrared and nmr spectra are consistent with the proposed structure.
Reaction SMILES: O[C:2]1[C:11]([NH:12][C:13]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[NH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[C:15]1[C:13]1[O:14][C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=2[N:12]=1
Reactant: COC(=O)c1cccc(NC(=O)c2cc3ccccc3[nH]2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)c1cccc2nc(-c3cc4ccccc4[nH]3)oc12
Yield: 47.9 %

Procedure:
Methyl 2-hydroxy-3-(1H-indole-2-carboxamido)benzoate (170 mg, 0.5 mmol) and 4-methylbenzenesulfonic acid monohydrate (400 mg, 4.0 mmol) were added to xylene (10 mL) and the mixture was stirred at reflux for 10 hr. The resulting mixture was extracted with dichloromethane (100 mL×4) and concentrated. Then the crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20:1) to obtain methyl 2-(1H-indol-2-yl)benzo[d]oxazole-7-carboxylate as a solid (70 mg, yield 43%). LC-MS (ESI) m/z 293 [M+1]+.