Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][O:17][C:18]2=[O:23].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[N:13]/[C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][O:17][C:18]4=[O:23])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc2c1COC2=O
Reactant: O=Cc1ccc2ncccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: O=C1OCc2c(/N=C/c3ccc4ncccc4c3)cccc21
Yield: 93.5 %

Procedure:
A solution of quinoline-6-carbaldehyde (786 mg, 5.0 mmol), 4-aminoisobenzofuran-1(3H)-one (745 mg, 5.0 mmol) and anhydrous magnesium sulfate (6.0 g, 50.0 mmol) in acetonitrile (100 ml) was heated at reflux for two days. The solution was filtered and removed in vacuum. The crude product was re-crystallized from isopropanol to give the title compound (1.348 g, yield 93%) LC-MS (ESI) m/z: 289 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 5.57 (s, 2H), 7.63-7.77 (m, 4H), 8.14-8.16 (d, J=8.8 Hz, 1H), 8.39-8.42 (m, 1H), 8.53-8.56 (m, 2H), 8.99-9.01 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[CH2:5][N:6]([CH2:18][C@@H:19](O)[CH3:20])[C:7](=[O:17])[C@@H:8]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH3:9].C1(OP(OC2C=CC=CC=2)(OC2C=CC=CC=2)=O)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[CH2:5][N:6]1[CH2:18][C@@H:19]([CH3:20])[N:10]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[C@@H:8]([CH3:9])[C:7]1=[O:17]
Reactant: COc1ccc(CN(C[C@H](C)O)C(=O)[C@H](C)NC(=O)C(F)(F)F)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=P(Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C[C@@H](C)N(C(=O)C(F)(F)F)[C@@H](C)C2=O)c(OC)c1
Reaction time: 8 h
Yield: 43.1 %

Procedure:
(2S, 2S)-N-(2,4-Dimethoxy-benzyl)-N-(2-hydroxypropyl)-2-(2,2,2-trifluoroacetylamino)-propionamide (3.64 g, 9.29 mmol) is dissolved in 25 mL of tetrahydrofuran. Triphenylphosphate (3.65 g, 14.0 mmol) is added, and the resulting mixture is cooled to 0° C. before diethyl azodicarboxylate (2.2 mL, 14 mmol) is added slowly. The resulting mixture is left to stir overnight. The reaction mixture is condensed, and the residue is purified by column chromatography (SiO2, 25% ethyl acetate/hexane). The desired product, (3S, 5R)-1-(2,4-dimethoxy-benzyl)-3,5-dimethyl-4-trifluoroacetyl-piperazin-2-one (1.5 g, 43% yield), is isolated as a clear oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[CH:15])[CH:5]=[CH:4][C:3]1=2.Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21

Procedure:
A mixture of 4 g (19 millimoles) of (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethyne, 2.8 g (12.5 millimoles) of 4-bromobenzonitrile, 50 mg of palladium (II) acetate, 100 mg of triphenylphosphine and 25 ml of degased anhydrous triethylamine was refluxed for 4 hours under nitrogen Thereafter, solid material was filtered off and the filtrate was evaporated down.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[CH3:28][C:29]([CH3:31])=O.P([O-])(O)(O)=O.[Na+].C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[N:8]([CH:29]([CH3:31])[CH3:28])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)=O
Agent: O=P([O-])(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCN(C(C)C)C2Cc1ccc(OCc2ccccc2)cc1
Reaction time: 48 h
Yield: 80 %

Procedure:
To a mixture of 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.36 g, 1 mmol), acetone (3 mL), and sodium dihydrogenphosphate (0.4 g) in methanol (5 mL) was added sodium cyanoborohydride (0.5 g, 8 mmol). After 48 hours, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated to give the title compound (0.321 g, 80% yield): ES-MS (m/z) 402 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([S:11]([NH:14][C:15]3[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=3)[C:18]([NH:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)=[O:19])(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[N:2]1.O1C=[CH:36][C:35](C2SC(S(Cl)(=O)=O)=CC=2)=N1>>[CH2:35]([O:26][C:25](=[O:27])[C:24]1[CH:28]=[CH:29][C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:30]=[CH:31][CH:32]=[C:15]([NH:14][S:11]([C:9]3[S:10][C:6]([C:3]4[CH:4]=[CH:5][O:1][N:2]=4)=[CH:7][CH:8]=3)(=[O:13])=[O:12])[CH:16]=2)=[CH:22][CH:23]=1)[CH3:36]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccon2)s1
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(-c4ccon4)s3)c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(-c4ccon4)s3)c2)cc1

Procedure:
4-[3-(5-Isoxazol-3-yl-thiophene-2-sulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=468.1 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 5-isoxazol-3-yl-thiophene-2-sulfonyl chloride and yielded 4-[3-(5-isoxazol-3-yl-thiophene-2-sulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:3]([CH3:5])[CH3:4].[Li]CCCC.[C:30]([N:37]1[C@@H:42]([CH:43]=O)[CH2:41][CH2:40][CH2:39][C@@H:38]1[CH3:45])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].CCOC(C)=O.CCCCCC>C1COCC1.O>[C:30]([N:37]1[C@@H:42]([CH:43]=[CH:2][CH:3]([CH3:5])[CH3:4])[CH2:41][CH2:40][CH2:39][C@@H:38]1[CH3:45])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: C[C@H]1CCC[C@H](C=O)N1C(=O)OC(C)(C)C
Reactant: CC(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)C=C[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
A suspension of isobutyltriphenylphosphonium bromide (10.58 g, 26.5 mmol) in 42 mL of THF was cooled to −30° C. and treated with n-BuLi (12.2 mL, 26.88 mmol) dropwise. The deep red solution was slowly warmed to 0° C., stirred for 30 min, and then cooled to −78° C. The ylide was treated with a solution of trans-N-Boc-2-Methyl-6-Piperidinecarboxaldehyde (4.00 g, 18.93 mmol) in 6 mL of THF, and the mixture was slowly warmed to room temperature. The mixture was diluted with water, and the organic layer was separated. The aqueous layer was extracted with ether and the combined extracts were dried over K2CO3 and then concentrated to give a crude product as an oil. Chromatography on silica with 5% EtOAc/hexane afforded 3.2 g (63%) of the product which was homogeneous by TLC analysis. 1H NMR (250 MHz) δ 5.41-5.14 (m, 2H), 4.62-4.58 (m, 1H), 4.05-4.01 (m, 1H), 2.69-2.68 (m, 1H), 1.90-1.38 (m, 15H), 1.23-1.20 (d, 3H), 0.93-0.87 (t, 6H); 13C NMR (62.7 MHz) 156.1 (s), 136.8 (s), 129.8 (s), 79.0 (s), 49.1 (s), 47.5 (s), 28.7 (s), 28.5 (s), 27.9 (s), 26.6 (s), 23.3 (s), 23.0 (s), 20.2 (s), 15.1 (s) ppm.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1c(F)cccc1Cl
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1c(F)cccc1Cl
Yield: 2.5 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted 2-chloro-6-fluorophenylboronic acid (available from Combi-Blocks Inc.; 87 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-6′-fluoro-biphenyl-2-carboxylic acid (3 mg, 3%). 1H NMR (300 MHz, DMSO-d6) δ 13.18 (br s, 1H), 8.61 (d, J=1.9 Hz, 1H), 8.50 (s, 1H), 8.28-8.38 (m, 2H), 8.10 (dd, J=8.4, 2.0 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.39-7.57 (m, 3H), 7.33 (d, J=9.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1)[C:5](Cl)=[O:6].O[NH:17][C:18](=[NH:38])[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][N:23]=[C:24]2[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][N:17]=[C:18]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:38]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: O=C(Cl)c1ccc(OCC2CC2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OCC5CC5)c(Cl)c4)n3)cccc12
Reaction time: 1.5 h
Yield: 16.1 %

Procedure:
A solution of 3-chloro-4-[(cyclopropylmethyl)oxy]benzoyl chloride (D16; 73.5 mg, 0.3 mmol) in dry DMF (1.5 ml) was added to a stirred solution of 1,1-dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36; 85 mg, 0.270 mmol) and triethylamine (0.063 ml, 0.450 mmol) in dry DMF (1.5 ml) at 0° and the mixture was stirred at 0° for 1.5 h. The mixture was then heated at 100° with stirring under nitrogen for 16 h. The cooled mixture was partitioned between saturated aqueous sodium bicarbonate (30 ml) and ethyl acetate (3×20 ml), and the organic layer was washed with 50:50 brine:water and brine, dried (MgSO4) and evaporated in vacuo to give a brown oil. The crude product was purified by flash chromatography on silica gel, eluting with 0-30% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (22 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[C:12]([CH3:13])=[N:11][NH:10][C:9]1=[O:14].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18]>C(#N)C>[CH3:13][C:12]1[N:8]([CH3:7])[C:9](=[O:14])[N:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[N:11]=1
Reactant: COC(=O)CBr
Reactant: Cc1n[nH]c(=O)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1nc(C)n(C)c1=O
Temperature: 50 °C

Procedure:
1222 mg of potassium carbonate are added to a solution of 500 mg of 4,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one in 15 ml of acetonitrile, and the mixture is warmed to 50° C. After addition of 879 mg of methyl bromoacetate, the mixture is heated at reflux for 16 hours. The mixture is concentrated under reduced pressure, the residue is taken up in dichloromethane, washed with diluted hydrochloric acid (pH 2) and dried over sodium sulphate, and the solvent is removed under reduced pressure. This gives 593 mg of methyl (3,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)acetate (Va-6) in a purity of 93% (LCMS).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[Br:18]Br.O.S(=O)(O)[O-].[Na+]>C(O)(=O)C.C1(C)C=CC=CC=1.O>[Br:18][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:3]=1[N:2]([CH3:17])[CH3:1])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CN(C)c1ccc(C(=O)c2ccccc2)cc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(C(=O)c2ccccc2)cc1Br
Reaction time: 1 h

Procedure:
22.5 g (0.1 mol) of 4-dimethylaminobenzophenone were dissolved in 60 ml of acetic acid, and then a solution of 5.3 ml (0.105 mol) of bromine in 20 ml of acetic acid was added dropwise thereto over a period of one hour, while stirring. The mixture was then stirred for 30 minutes more, and some water and some sodium bisulfite for decolorization were added. The greasy substance thus obtained was shaken with toluene/water, the toluene phase was washed twice more with water and dried, and the toluene was distilled off in vacuo. Yield: 24.4 g (80% of theory); viscous oil.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4](I)[C:3]=1[F:11].[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].CN(C=O)C>C(N(CC)CC)C.[Cu](I)I.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>[Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[F:11]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1cc(F)c(Br)c(F)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1c(N)cc(F)c(Br)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
A solution of 4-bromo-3,5-difluoro-2-iodoaniline (3.0 g, 9.0 mmol) in triethylamine (50 mL) was degassed with nitrogen for 10 minutes, then treated with copper iodide (209 mg, 1.10 mmol), Dichlorobis(triphenylphosphine)palladium(II), (769 mg 1.10 mmol), and ethynyl(trimethyl)silane (1.42 mL, 10.1 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture turned dark and formed a precipitate. After two hours, the reaction mixture was treated with DMF (8 mL) and stirred for an additional 72 hours at room temperature. The reaction mixture was heated to 50° C. for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo, azeotroping with heptanes (3×100 mL). The black oil was partitioned between diethyl ether (300 mL) and water (300 mL), and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a dark solid. The crude product was purified by flash chromatography to give the title compound (1.75 g). MS (ES+) 306.0 ((M+2)+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cccc(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(OCc2ccccc2)c1Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A mixture of 5.37 g (30.9 mmol) of 2-chloro-3-nitrophenol and 12.6 g (38.7 mmol) of cesium carbonate in 60 mL of dimethylformamide (DMF) was cooled to 0° C. and 4.04 mL (34.0 mmol) of benzyl bromide was added. The mixture was warmed to 22° C. and stirred for 16 hours. Water was added and the resulting mixture was extracted with ether. The organic extract was dried (Na2SO4) and evaporated. The residue was crystallized from ethyl acetate and hexane to give 1-(benzyloxy)-2-chloro-3-nitrobenzene.
Reaction SMILES: [H-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:18])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:6][C:5]=1[OH:19].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([O:19][C:5]1[CH:6]=[C:7]([C:10]([CH3:18])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])[CH:8]=[CH:9][C:4]=1[Br:3])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCCC(C)(C)c1ccc(Br)c(O)c1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a -18° C. slurry of 23.0 g. (0.575 mole) of potassium hydride in 400 ml. of N,N-dimethylformamide is added over a 45 minute period a solution of 150 g. (0.5 mole) of 2-(4-bromo-3-hydroxyphenyl)-2-methyloctane in 400 ml. of N,N-dimethylformamide (reaction temperature ≤-15° C.). The reaction mixture is stirred 15 minutes longer after which a solution of 98.3 g. (0.575 mole) of benzyl bromide in 200 ml. of N,N-dimethylformamide is added. The mixture is then warmed to room temperature and stirred 30 minutes longer. It is quenched by addition to 6 liters of ice water. The quenched mixture is extracted six times with 500 ml. of ether. The combined extract is washed twice with one liter portions of water and once with one liter of saturated sodium chloride, dried over magnesium sulfate and evaporated to a quantitative yield of the title product.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12](O)([CH3:14])[CH3:13]>[Pd].Cl.CCO>[F:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH:12]([CH3:14])[CH3:13]
Reactant: COc1ccc(C(C)(C)O)c(F)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(C(C)C)c(F)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 10% palladium on carbon (69.8 mg) in a solution of 2-(2-fluoro-3,4-dimethoxyphenyl)propan-2-ol (698 mg, 3.26 mmol) in 5N HCl (0.7 mL) and EtOH (5.6 mL) was stirred at room temperature under H2 (15 psi) overnight. The mixture was filtered through a plug of Celite and washed with EtOAc (˜75 mL). The filtrate was washed with 50% saturated brine (10 mL), dried (MgSO4) and concentrated in vacuo to afford 2-fluoro-1-isopropyl-3,4-dimethoxybenzene. 1H NMR (500 MHz, CDCl3) δ 6.86 (t, J=8.3 Hz, 1H), 6.63 (dd, J=8.7, 1.5 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.19-3.11 (m, 1H), 1.22 (d, J=6.8 Hz, 6H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+:5].[Cs+].[C:7]1([C:13]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[Cs+:5].[C:7]1([C:13]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O-:32])=[O:31])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)CCCCCCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C([O-])CCCCCCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Aqueous cesium carbonate (1M, 0.16 ml) was added dropwise to a solution of 16-triphenylmethoxyhexadecanoic acid (0.16 g, 0.31 mmol) from Example 1b(i) above in tetrahydrofuran (10 ml) until the pH reached approximately 8, whereupon the solvent was removed under reduced pressure and the residue dried under vacuum for 2 hours. The oily semicrystalline residue was dispersed in dry dimethylformamide (10 ml) and evaporated to dryness in vacuo.
Reaction SMILES: Br[CH:2]([CH2:19][CH3:20])[C:3]([N:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:4].[N:21]1[C:33]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[NH:26][C:25]=2[N:24]=[C:23]([SH:34])[N:22]=1.CCN(CC)CC.C(OCC)(=O)C>CN(C=O)C>[N:21]1[C:33]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[NH:26][C:25]=2[N:24]=[C:23]([S:34][CH:2]([CH2:19][CH3:20])[C:3]([N:5]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:12][C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:4])[N:22]=1
Reactant: CCC(Br)C(=O)N1c2ccccc2Sc2ccccc21
Reactant: Sc1nnc2c(n1)[nH]c1ccccc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(Sc1nnc2c(n1)[nH]c1ccccc12)C(=O)N1c2ccccc2Sc2ccccc21
Temperature: 0 °C

Procedure:
2-bromo-1-(10H-phenothiazin-10-yl)butan-1-one (3.675 g, 25 mmol) and 5H-[1,2,4]triazino[5,6-b]indole-3-thiol (2.125 g, 25 mmol) were dissolved in 50 ml anhydrous DMF and cooled to 0° C. 11.1 ml Et3N (250 mmol) was dropped to the above mixture. After stirring for 1.5h, TLC indicated that the reaction was completed and stopped. 300 ml ethyl acetate was added to the reaction mixture. The organic phase was washed by saturated NH4Cl for five times. It was dried by anhydrous Na2SO4 and filtered. The organic phase was concentrated to about 15 ml and the pale solid was formed. The amorphous solid was collected and washed by a few ethyl acetate. 1H NMR (500 MHz, DMSO-d6) δ; 12.63 (br, 1H), 8.34 (d, J=7.5?, 1H), 7.89-7.96 (m, 1H), 7.56-7.73 (m, 4H), 7.37-7.47 (m, 5H), 7.29-7.22 (m, 1H), 5.27 (t, J=7.0, 1H), 1.86 (br, 1H), 1.74 (br, 1H), 0.85 (br, 3H). 13C NMR (125 MHz, DMSO-d6) δ 170.0, 146.8, 141.7, 140.9, 138.5, 138.3, 131.4, 128.6, 128.2, 128.0, 127.7, 127.4, 123.0, 122.0, 118.0, 113.2, 31.1, 25.9, 11.8. HRMS was calculated for C25H19N5OS2 469.1031 and found 469.1047.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[N+:12]([CH3:15])([O-:14])=[O:13]>>[CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:15][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)o1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C=C[N+](=O)[O-])o1
Temperature: 0 °C
Yield: 57.5 %

Procedure:
5-Methyl-2-furaldehyde (2.75 g) was gradually added by dropping, with stirring under ice cooling, to a solution prepared by dropping 3.05 g of nitromethane into 50 mL of an ice-cooled 20% aqueous solution of sodium hydroxide. After completion of the addition, the mixture was vigorously stirred for 10 minutes more to finish the reaction and the reaction solution was slowly poured over 60 mL of an ice-cooled 6N hydrochloric acid. The mixed solution was stirred for 10 minutes and the resulting separated crystals were filtered, washed with water and dried to give 2.20 g of the objective compound as yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[O:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](O)=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:20]([C@@H:16]2[CH2:17][CH2:18][CH2:19][O:15]2)=[O:21])[CH2:3]1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Reactant: O=C(O)[C@@H]1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CN(C(=O)[C@@H]2CCCO2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,3-dimethyl-6-nitroindoline (385 mg, 2 mmol), (S)-tetrahydrofuran-2-carboxylic acid (250 mg, 2.2 mmol), HOBt (266 mg, 2 mmol), EDAC (700 mg, 3.5 mmol), and DIEA (2 mL) in DCM (50 ml) was stirred at RT for overnight. The reaction mixture was washed in turn with aqueous NaHCO3 (sat., 50 mL), aqueous HCl (0.5N, 50 mL), H2O (50 mL), and brine (50 mL). The DCM layer was concentrated in vacuum to give the desired compound. MS: (ES+) 291(M+H). Calc'd. for C15H18N2O4—290.31.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13]Cl)[C:4]=2[O:3]1.[CH2:16]([O:18][P:19]([O:23]CC)[O:20][CH2:21][CH3:22])[CH3:17]>>[CH2:16]([O:18][P:19]([CH2:13][CH2:12][O:11][C:10]1[C:4]2[O:3][C:2]([CH3:15])([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)(=[O:23])[O:20][CH2:21][CH3:22])[CH3:17]
Reactant: CC1(C)Cc2cccc(OCCCl)c2O1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCOc1cccc2c1OC(C)(C)C2)OCC

Procedure:
68.2 g. (0.3 mole) 2,3-dihydro-2,2-dimethyl-7-(2'-chloro-ethoxy)-benzofuran (prepared according to Examples 1 or 2) and 49.86 g. (0.3 mole) triethylphosphite are stirred at 140°-146° C. for 60 hours and heated. When the reaction is completed the obtained yellowish brown oily product is purified by vacuum distillation by distilling off the volatile contaminations at 0.5 torr. The cuts are collected until 148° C. and the distillation residue is a pure product according to gas chromatographic analysis. The product is a pale yellow oily liquid, nD24.5 =1.5101 (compound No. 1).