Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCC.C([Li])CCC.[Br-].[CH2:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]2[O:53][C:52]([CH:54]=O)=[CH:51][C:50]=2[C:56]=1[C:57]([CH3:60])([CH3:59])[CH3:58])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]2[O:53][C:52]([CH:54]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:51][C:50]=2[C:56]=1[C:57]([CH3:58])([CH3:60])[CH3:59])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCC=Cc1cc2c(C(C)(C)C)c(OCc3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
A pentane solution (2.6 ml, 4.2 mmol) of 1.6M n-butyllithium was added dropwise to a solution of n-heptyltriphenylphosphonium bromide (1.84 g, 4.2 mmol) in tetrahydrofuran (10 ml) under a nitrogen atmosphere. After stirring the mixture at room temperature for 30 min, a solution of 5-benzyloxy-4-tert-butyl-2-formylbenzofuran (1.0 g, 3.2 mmol) in tetrahydrofuran (10 ml) was added dropwise. Subsequently, the mixture was stirred at room temperature for 30 min, poured into ice water and subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, then dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica Gel chromatography (chloroform) to afford 5-benzyloxy-4-tert-butyl-2-(1-octenyl)benzofuran [1.14 g (yield, 91%)].
Reaction SMILES: CN(C)[CH:3]=[C:4]([N:9]=[CH:10]N(C)C)[C:5]([O:7][CH3:8])=[O:6].[CH3:15][N:16]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17]1>C(O)(=O)C.C(O)(C(F)(F)F)=O>[CH3:15][N:16]1[C:20]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[N:9]=[CH:10][C:19]=2[C:18]([CH3:21])=[CH:17]1
Reactant: COC(=O)C(=CN(C)C)N=CN(C)C
Reactant: Cc1ccn(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(cn1)c(C)cn2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
In a 500 ml round bottom flask, methyl 3-(dimethylamino)-2-((dimethylamino)methyleneamino)acrylate (1A, 12 g, 61 mmol) was dissolved in acetic acid (45 ml) and TFA (15 ml). 1,3-Dimethyl-1H-pyrrole (5.8 g, 61 mmol) was added and the mixture was stirred at room temperature for an hour and then at 110° C. for 4 hours. Volatiles were then evaporated from the reaction mixture, the residue was cooled in an ice bath and ice cold saturated K2CO3 solution (200 ml) was slowly added to it. The mixture was extracted with EtOAc (3×250 ml). Combined organic layers were then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified on a silica column using hexane-EtOAc (0-100%). Desired product methyl 1,3-dimethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1J, 6.8 g, 55%) was obtained.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([O:44][CH2:45][CH2:46][C:47]([CH3:62])([CH3:61])[CH2:48][CH2:49]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:43])=[O:42])=[CH:37][CH:36]=1>CN(C=O)C.O>[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([O:44][CH2:45][CH2:46][C:47]([CH3:61])([CH3:62])[CH2:48][CH2:49][O:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:24]=2)(=[O:43])=[O:42])=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: Oc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCCC(C)(C)CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
To a stirred solution of 2-(1-trityl-1H-imidazol-4-yl)phenol (1.50 g, 3.73 mmol) in anhydrous DMF (10 mL) was added NaH (4.10 mmol) portion wise at 0° C. The resulting suspension was allowed to stir for 15 min. To the resulting suspension was added a solution of 3,3-dimethylpentane-1,5-diyl bis(4-methylbenzenesulfonate) (3.28 g, 7.45 mmol) in DMF (8 mL) and the mixture was allowed to stir overnight at rt. The reaction mixture was diluted with water (50 mL) and the aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford a yellow oil which was purified by flash column chromatography on silica gel to afford the desired product (1.60 g, 64% yield). 1H NMR (A): 0.84 (s, 6H), 1.34 (t, 2H, J=7.32 Hz), 1.52 (t, 2H, J=7.20 Hz), 2.38 (s, 3H), 3.85 (t, 2H, J=7.32 Hz), 4.02 (t, 2H, J=7.32 Hz), 6.79 (d, 1H, J=8.19 Hz), 7.03 (t, 1H, J=7.47 Hz, 7.14-7.35 (m, 18H), 7.44 (s, 1H), 7.50 (s, 1H), 7.72-7.77 (m, 2H), 8.23 (d, 1H, J=5.64 Hz). 1H NMR (B): 1.08 (s, 6H), 1.95 (t, 4H, J=7.08 Hz), 4.16 (t, 4H, J=6.96 Hz), 6.92-7.02 (m, 4H), 7.20 (m, 2H), 7.45 (s, 2H), 7.65 (s, 2H), 7.86 (d, 2H, J=6.12 Hz), 8.19 (br s, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([F:10])[CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1)=[O:20]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=2)=[O:20])[CH:7]=[C:8]([F:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(F)c[nH]1
Reactant: CC(C)(C)c1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)cn1CC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 50 °C

Procedure:
A suspension of 93.7 mg (0.655 mmol) 4-fluoro-1H-pyrrole-2-carboxylic acid methyl ester (synthesis described in J. Leroy et al. Tetrahedron 58, p. 6713, 2002) and 640 mg (1.96 mmol) cesium carbonate in 1.3 ml DMF is heated to 50° C. under stirring. 167 mg (0.655 mmol) 2-bromo-1-(4-tert-butyl-phenyl)ethanone is added and the reaction mixture is stirred for 18 hours at 50° C. The reaction mixture is filtered with suction and the filtrate is evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 1-[2-(4-tert-butyl-phenyl)-2-oxo-ethyl]-4-fluoro-1H-pyrrole-2-carboxylic acid methyl ester as brown amorphous solid; HPLC/MS 3.26 min (B), [M+H] 318.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[S:46]1[C:50](B(O)O)=[CH:49][C:48]2[CH:54]=[CH:55][CH:56]=[CH:57][C:47]1=2.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:50]2[S:46][C:47]3[CH:57]=[CH:56][CH:55]=[CH:54][C:48]=3[CH:49]=2)=[CH:40][CH:39]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Reactant: OB(O)c1cc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2cc3ccccc3s2)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method B, using 19 (83.4 mg, 0.123 mmol), benzo[b]thiophene-2-boronic acid (109 mg, 0.613 mmol), Pd(PPh)3Cl2 (4.32 mg, 0.00615 mmol), 2 M Na2CO3 (aq., 0.185 mL, 0.369 mmol), EtOH (0.4 mL) and DME (1.6 mL). Purification by RP-LC-MS (35 min gradient of 20-100% CH3CN in 0.05% aqueous formic acid) afforded the product (56.4 mg, 62%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH:6]=[N:7][NH:8][C:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][O:11][N:10]=1>C1(C)C(C)=CC=CC=1>[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:9]1[NH:8][N:7]=[C:6]([C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:10]=1
Reactant: COc1cccc(C=NNC2=NOCc3ccccc32)c1
Solvent: Cc1ccccc1C
Product: COc1cccc(-c2n[nH]c(-c3ccccc3CO)n2)c1

Procedure:
A suspension of 16 g of 4-[2-(3-methoxybenzyliden)hydrazino]-1H-2,3-benzoxazine in 160 cc of anhydrous xylene is refluxed for 45 minutes and then, cooled in an ice bath. The solid which precipitates is recovered by filtration and recrystallized from ethanol yielding 14.7 g of the compound of the title. M.p. 157°-59° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]([F:30])([F:29])[C:23]1[CH:27]=[C:26]([NH2:28])[NH:25][N:24]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][C:26]2[NH:25][N:24]=[C:23]([C:22]([F:30])([F:29])[F:21])[CH:27]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1cc(C(F)(F)F)n[nH]1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1cc(C(F)(F)F)n[nH]1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 3-(trifluoromethyl)-1H-pyrazol-5-amine (18.0 mg, 0.12 mmol). The title compound was obtained as a solid (13.0 mg, 27% yield). MS m/z: 483.93, 485.93 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[CH2:15]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[F:1])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F

Procedure:
To a solution of 2-fluoro-4-nitrobenzoic acid (1.15 g, 6.22 mmol) in absolute ethyl alcohol (20 mL) was added p-toluenesulfonic acid monohydrate (100 mg). After 16 h at reflux, the reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel (eluted with 5% ethyl acetate in hexane) to give 770 mg (Y: 58%) of the title product; 1H-NMR (CDCl3): δ 8.16-8.00 (m, 3H), 4.45 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). MS (DCI) m/e: 214 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([C@H:6]([CH3:17])[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:16])[CH:8]=1)[NH2:5].[C:19]([O:23][C:24]([NH:26][C@@H:27]([C:35](O)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([CH:6]([CH3:17])[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:16])[CH:8]=1)[NH:5][C:35](=[O:36])[C@@H:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccn1)C(=O)O
Reactant: COC(=O)[C@H](N)[C@H](C)c1cn(C)c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)[C@H](NC(=O)[C@@H](Cc1ccccn1)NC(=O)OC(C)(C)C)C(C)c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.3 %

Procedure:
To a solution of (αR,βR)-1,β-dimethyltryptophan methyl ester (6.36 g) and Nα -t-butoxycarbonyl-3-(2-pyridyl)-D-alanine (6.65 g) in dry methylene chloride (250 ml) was added dicyclohexylcarbodiimide (5.15 g), and resulting mixture was stirred for 1.5 hours at room temperature. After evaporation of the solvent, crude residue was taken up with ethyl acetate (200 ml), filtered, washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate, treated with active charcoal, and evaporated. Nα -[N-t-Butoxycarbonyl-3-(2-pyridyl)-D-alanyl]-1,β-dimethyl-D-tryptophan methyl ester (10.54 g) was obtained as an oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][CH2:8][CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCN1CCCC1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
Pyrrolidine (50 g, 700 mmol), 3-chloropropanol (58.5 ml, 700 mmol) and potassium carbonate (145 g, 1.05 mol) were refluxed in acetonitrile (1 l) for 20 hours. Upon cooling to ambient temperature the precipitate was filtered off and rinsed with acetonitrile. The solvent was evaporated off and the residual oil purified by distillation under vacuum to give 3-(pyrrolidin-1-yl)propan-1-ol (62.1 g, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][OH:11])[N:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][OH:11])[N:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccn(CCO)n1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccn(CCO)n1
Reaction time: 1 h
Yield: 107.9 %

Procedure:
A solution 2-(3-nitro-pyrazol-1-yl)-ethanol (3.46 g, 22.02 mmol) in ethanol (40 mL) was placed in a Parr shaker bottle and treated with 10% palladium on carbon (350 mg). The bottle was then put on the Parr shaker and charged with hydrogen to 50 psi and let shake for 1 h. After this time, the reaction mixture was filtered through celite and the celite washed with ethanol. The filtrate was then concentrated in vacuo and azeotroped with acetonitrile and then chloroform to afford 2-(3-amino-pyrazol-1-yl)-ethanol (3.02 g, >quant.) as a light yellow viscous oil: 1H NMR (300 MHz, DMSO-d6 δ ppm 7.26 (d, J=1.83 Hz, 1H), 5.34 (d, J=2.20 Hz, 1H), 4.76 (t, J=5.31 Hz, 1H), 4.50 (s, 2H), 3.78-3.88 (m, 2H), 3.62 (q, J=5.74 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][C:6]=1[NH2:7])([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNC1
Product: Nc1cc(N2CCCC2)ccc1[N+](=O)[O-]
Yield: 93 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (1.73 g, 10 mmol) and pyrrolidine (1.42 g, 20 mmole) was refluxed in a pressure vessel for 6 h. Solvent was evaporated and the residue was diluted with ethyl acetate. The resulting mixture was washed with aqueous NaHCO3 (5%) and distilled water, dried over MgSO4, and concentrated to afford 2-nitro-5-(pyrrolidin-1-yl)benzenamine as a solid (93% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.80 (d, J=8 Hz, 1H, 3-H), 7.22 (s, 2H, NH2), 6.05 (dd, J=8, 2 Hz, 1H, 4-H), 5.81 (d, J=2 Hz, 1H, 6-H), 3.30-3.27 (m, 4H, 2′,5′-H), 1.97-1.91 (m, 4H, 3′,4′-H). 13C NMR (100 MHz, CDCl3-d1) δ (ppm): 151.9, 148.3, 127.4, 122.1, 104.7, 94.5, 47.3, 47.3, 24.8, 24.8; EIMS: m/z 207 (M+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[CH:8][CH:9]=[CH:10][C:2]1=2.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.CCN(CC)CC>C1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7](/[CH:11]=[CH:12]/[C:13]([N:30]=[N+:31]=[N-:32])=[O:15])=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)/C=C/c1cccc2c1OCCO2
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: [N-]=[N+]=NC(=O)/C=C/c1cccc2c1OCCO2
Reaction time: 16 h
Yield: 84.5 %

Procedure:
(E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)acrylic acid (5 g, 24.25 mmol), diphenylphosphoryl azide (4.96 mL, 23.04 mmol), and Et3N (6.76 mL, 48.5 mmol) were dissolved in benzene and stirred for 16 h. The solution was concentrated under vacuum and the residue was purified by silica gel chromatography using 20% EtOAc/Hexanes to give 4.5 g of (E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)acryloyl azide as a yellow solid, which was taken into PhCH2Ph (50 mL). The resulting solution was slowly heated to 80° C. for 1 h and then to reflux for 3 h. After cooling to rt, the solid was collected washing with benzene to give 3.5 g of the desired product 2,3-dihydro-[1,4]dioxino[2,3-f]isoquinolin-7-ol as a solid. 1H NMR (400 MHz, CD3OD) δ ppm 4.37 (m, 4H), 6.83 (d, J=7.09 Hz, 1H), 7.02 (d, J=8.80 Hz, 1H), 7.12 (d, J=7.34 Hz, 1H), 7.79 (d, J=8.80 Hz, 1H); MS: (M+H)+ 204.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].CN(C)C(N(C)C)=N.[CH:19]#[C:20][CH3:21].[Na+].[Cl-]>CN(C=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[CH:19]=[C:20]([CH3:21])[O:10][C:3]=2[CH:4]=1
Reactant: COc1ccc(I)c(O)c1
Reactant: C#CC
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cc(C)oc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
A pressure tube was charged with a stir bar 2-Iodo-5-methoxyphenol (500 mg, 2.0 mmol) (prepared according to Heterocycles 45, (6), 1997, 1137), Cl2Pd(PPh3)2 (70 mg, 0.1 mmol), Cul (19 mg, 0.1 mmol), 1,1,3,3-Tetramethylguanidine (2.5 ml, 20.0 mmol) and DMF (10 ml), then cooled to −78° while propyne gas was condensed. The tube was sealed and allowed to warm to room temperature. After 18 hours, the contents of the tube were poured into sat NaCl solution and extracted with EtOAc (2×). The combined organic layers were washed with brine (3×), dried (MgSO4) and concentrated under reduced pressure. The residue was flash chromatographed on silica gel eluting 3:1 (hexanes/ethyl acetate) to give 239 mg (74%) of an amber liquid. 1H NMR (DMSO-d6) δ 7.31 (1H, d, J=8.3 Hz), 6.95 (1H, d, J=2.2 Hz), 6.80 (1H, dd, J=2.2, 8.3 Hz), 6.27 (1H, s), 3.85 (3H, s), 2.40 (3H, s). Anal. Calcd for C10H10O2.0.05 hexanes: C, 74.30; H, 6.48. Found: C, 74.63; H, 6.48.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[N:20]1([C:26]2[CH:48]=[CH:47][C:29]([NH:30][C:31]3[N:36]=[C:35]([C:37]4[N:41]([CH:42]([CH3:44])[CH3:43])[C:40]([CH3:45])=[N:39][CH:38]=4)[C:34]([Cl:46])=[CH:33][N:32]=3)=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)Cl>[OH:1][C:2]([CH3:7])([CH3:6])[C:3]([N:23]1[CH2:24][CH2:25][N:20]([C:26]2[CH:27]=[CH:28][C:29]([NH:30][C:31]3[N:36]=[C:35]([C:37]4[N:41]([CH:42]([CH3:44])[CH3:43])[C:40]([CH3:45])=[N:39][CH:38]=4)[C:34]([Cl:46])=[CH:33][N:32]=3)=[CH:47][CH:48]=2)[CH2:21][CH2:22]1)=[O:4]
Reactant: CC(C)(O)C(=O)O
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CCNCC4)cc3)ncc2Cl)n1C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1ncc(-c2nc(Nc3ccc(N4CCN(C(=O)C(C)(C)O)CC4)cc3)ncc2Cl)n1C(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Hydroxyisobutyric acid (162 mg. 1 mmol) was added to a solution of 1,1′-carbonyldiimidazole (162 mg. 1 mmol) in DCM (4 ml) and stirred at room temperature for 15 minutes. A solution of 2-[4-(piperazin-1-yl)anilino]-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)-5-chloropyrimidine (Example 34. 400 mg. 0.97 mmol) in DCM (8 ml) was added and stirring continued for 19 hours. DCM (25 ml) was added and the organic layer was washed with 5% (v/v) acetic acid (15 ml), water (15 ml), brine (15 ml) and dried before evaporating under reduced pressure. Chromatography on silica gel with MeOH:DCM (4:96 to 8:92) gave the title compound, after ether trituration, as a solid. (67 mg 14%). NMR: (500 MHz) 1.30 (d, 6H), 1.34 (d, 6H), 2.48 (s, 3H), 3.04 (t, 4H), 3.62 (b s, 4H), 4.00 (b s, 4H), 4.79 (septuplet, 1H), 5.41 (s, 1H), 6.90 (d, 2H), 7.22 (s, 1H), 7.48 (d, 2H), 8.51 (s, 1H), 9.49 (s, 1H); m/z 498.
Reaction SMILES: CN(C=O)C.[OH:6][CH2:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[O:25][CH3:26]>O>[CH3:26][O:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[O:6][CH2:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(CO)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1OCC(=O)N1CCCC1
Reaction time: 18 h

Procedure:
To a stirred solution of DMF (20 mL) containing 2-hydroxy-1-(pyrrolidin-1-yl)ethanone (2.00 g, 15.5 mmol) under N2 was added 60% NaH/paraffin (640 mg, 16 mmol). Once gas evolution ceased, 2-chloro-5-nitroanisole (1.9 g, 10 mmol) was added. After stirring for 18 hr at 20°, the reaction was diluted with H2O prior to being extracted with EtOAc 3×. The organic layers were washed twice with aq. Na2CO3, brine and dried over Na2SO4 prior to concentration. Chromatography on silica gel using 25% EtOAc/CH2Cl2 eluted 2.06 g of 2-(2-methoxy-4-nitrophenoxy)-1-(pyrrolidin-1-yl)ethanone (52%). 1H NMR (DMSO-d6) δ 1.73-1.79 (m, 2H), 1.86-1.92 (m, 2H), 3.29-3.32 (m, 2H), 3.43-3.46 (m, 2H), 3.04 (s, 3H), 4.93 (s, 2H), 7.02 (d, J=8.80 Hz, 1H), 7.73 (d, J=2.74 Hz, 1H), 7.84 (dd, J=8.80 Hz, 2.20 Hz, 1H); 13C NMR (DMSO-d6) δ 23.22, 25.35, 44.27, 45.30, 55.76, 66.23, 106.35, 111.93, 116.99, 140.51, 148.25, 153.28, 164.33; HPLC a) column: Phenomenex C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.2% H3PO4 to 90% MeOH/10% H2O/0.2% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 2.24 min retention time, (100%); HPLC b) column: Phenomenex C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 2.29 min retention time; MS (ES): m/z 281 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[S:17]([O:1][CH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][S:5]([NH2:8])(=[O:7])=[O:6])([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(CO)CS(N)(=O)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC(C)(C)CS(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of 5.0 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide in 18 ml of pyridine was added 6.3 g of p-toluenesulfonyl chloride under ice-cooling and stirring. After 2 hours, the reaction mixture was poured to a mixture of 300 ml of chloroform and 100 ml of ice-water. The separated chloroform layer was washed in turn with diluted hydrochloric acid and water, dried over anhydrous magnesium sulfate and to obtain 8.5 g of 3-tosyloxy-2,2-dimethyl-1-propanesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:25])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1.[H-].[Na+].[CH3:28][O:29][CH2:30][CH2:31]Br>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([O:25][CH2:31][CH2:30][O:29][CH3:28])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: CCC(O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(OCCOC)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (300 mg, 0.797 mmol) in N,N-dimethylformamide (3.0 mL) was added sodium hydride (60% in oil, 35.0 mg, 0.877 mmol), and the mixture was stirred at room temperature for 10 min. To the mixture was added 2-bromoethyl methyl ether (166 mg, 1.19 mmol), and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless amorphous (218 mg, 0.502 mmol, 63%).