Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[CH:11]([N:14]=[C:15]=[N:16][CH:17]([CH3:19])[CH3:18])([CH3:13])[CH3:12]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:15](=[N:14][CH:11]([CH3:13])[CH3:12])[NH:16][CH:17]([CH3:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cc1
Reactant: CC(C)N=C=NC(C)C
Product: COc1ccc(COC(=NC(C)C)NC(C)C)cc1
Temperature: 60 °C

Procedure:
Anhydrous cupric chloride (8 mg) is added to a mixture of 4-methoxybenzyl alcohol (2.76 g) and 1,3-diisopropylcarbodiimide (3.13 mL) under a nitrogen atmosphere. The reaction is quite exothermic and it is cooled with an ice bath for 1 h. The mixture is then heated for 3.5 h at 60° C. The product was purified by distillation to give O-p-methoxybenzyl-N,N'-diisopropylisourea (4 g).
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[C:9]([F:27])=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])(=[O:18])=[O:17])[CH:11]=[CH:12][C:13]=2[F:14])=[N:4][N:5]([CH3:7])[CH:6]=1.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][N:5]1[CH:6]=[C:2]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[C:3]([C:8]2[C:9]([F:27])=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])(=[O:18])=[O:17])[CH:11]=[CH:12][C:13]=2[F:14])=[N:4]1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: Cn1cc(Br)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccncc2)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
To a solution of tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.1 mmol) in dimethoxyethane (3 mL), N-[3-(4-bromo-1-methyl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluorobenzenesulfonamide (0.14 g, 0.3 mmol) in dimethoxyethane (3 mL) was added and the mixture was insufflated with nitrogen for 5 min. A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.63 mmol) in dimethoxyethane (3 mL) was added and the mixture was insufflated with nitrogen for 10 min, then 2 M sodium carbonate solution (2.5 mL) was added and the mixture was heated at 110° C. in a microwave cavity for 3 h. The mixture was cooled and the organic phase was concentrated. The crude oil was purified by flash chromatography (eluant: dichloromethane/ethyl acetate 1:1). The title compound was obtained as a white solid (0.05 g, 36%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2.I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[C:13]1([C:5]2[CH2:4][C:3]3[C:7]([CH:6]=2)=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=3[CH3:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Ic1ccccc1
Reactant: Cc1ccc(C)c2c1C=CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: Cc1ccc(C)c2c1C=C(c1ccccc1)C2
Temperature: -20 °C

Procedure:
20 ml of triethylamine, 2.88 g (20 mmole) of 4,7-dimethyl-indene, 4.08 g (20 mmole) of iodobenzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 12 h. After it all the triethylamine was removed under reduced pressure. The residue was treated with the mixture 50 ml of water and 50 ml of diethyl ether. Etherial layer was separated, washed twice with water, filtered and dried over Na2SO4. Ether was removed and some 20 ml of pentane were added to the reaction mixture. It was cooled down to −20° C. and product was crystallized as white crystals, which were filtered, washed with small portion of cold pentane and dried in vacuum. The yield of product was 38%.
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=O)[CH2:10]1)(OC(C)(C)C)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[F:51][C:52]([F:62])([F:61])[C:53]1[CH:60]=[CH:59][CH:58]=[CH:57][C:54]=1[CH2:55][NH2:56]>CN(C)C=O>[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([NH:56][CH2:55][C:54]2[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=2[C:52]([F:51])([F:61])[F:62])=[O:17])[CH2:10]1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC1CCCC(C(=O)NCc2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(Boc-amino)cyclohexanecarboxylic acid (500 mg, 2.055 mmol, 1 equivalent) in dimethylformamide (10 ml) was added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 781 mg, 2.055 mmol, 1 equivalent) and diisopropylethylamine (0.716 ml, 4.11 mmol, 2 equivalents). 2-trifluoromethyl benzylamine (360 mg, 2.055 mmol, 1 equivalent) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated to give the crude product, which was purified with RP-HPLC. The purified compound was treated with 50% TFA in DCM (20 ml) at room temperature for 2 hours, and then the solvents were removed in vacuo. The product (103 mg, 12% yield) was carried onto the next step without further purification. MS (ES+): m/e 301.06 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:30][C:31]([F:59])([F:58])[C:32]([O:50][Si:51]([CH2:56][CH3:57])([CH2:54][CH3:55])[CH2:52][CH3:53])([C:46]([F:49])([F:48])[F:47])/[CH:33]=[CH:34]\[CH2:35][C:36]([CH3:45])([CH3:44])[CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]/[CH2:42]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:59][C:31]([F:30])([F:58])[C:32]([O:50][Si:51]([CH2:56][CH3:57])([CH2:54][CH3:55])[CH2:52][CH3:53])([C:46]([F:48])([F:49])[F:47])/[CH:33]=[CH:34]\[CH2:35][C:36]([CH3:44])([CH3:45])[CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]/[CH2:42][S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CC[Si](CC)(CC)OC(/C=C\CC(C)(C)CCC/C=C/CO)(C(F)(F)F)C(F)(F)F
Reactant: Sc1nc2ccccc2s1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(/C=C\CC(C)(C)CCC/C=C/CSc1nc2ccccc2s1)(C(F)(F)F)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 6.59 g of 2-mercapto-benzothiazole and 7.87 g of triphenylphosphine in 65 ml of THF was added at 0° a solution of 9.25 g of (2E,9Z)-12,12,12-Trifluoro-7,7-dimethyl-11-triethylsilanyloxy-11-trifluoromethyl-dodeca-2,9-dien-1-ol in 35 ml of THF which was followed by addition of 8.09 g of diisopropyl azodicarboxylate over 20 min and stirring was continued at 0° for 1 h after which time t.l.c. indicated completion of the reaction. The mixture was washed with sat. aqueous NH4Cl- and NaCl-solution, the organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica with hexane/AcOEt 9:1 to give 11.13 g of the pure (t.l.c.) title compound as a yellow oil. IR (neat): 1663w (C═C). MS (EI): 611/7 (M).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][N:6]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)C1CCNC(Cc2cc(F)ccc2F)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)ccc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of methyl 2-(2,5-difluorobenzyl)piperidine-4-carboxylate (6.65 g, 24.69 mmol) in DCM (100 mL) and DIPEA (5.16 mL, 29.63 mmol) was added methyl carbonochloridate (2.53 mL, 32.10 mmol) dropwise at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with 0.15 M HCl (250 mL). The organic phase was separated, washed with satd NaHCO3, dried using a phase separator and evaporated to yield dimethyl 2-(2,5-difluorobenzyl)piperidine-1,4-dicarboxylate (8.1 g, 100%). MS m/z 328 (M+H)+
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C(C)=CC=CC=1>[Br-:1].[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([CH3:2])=[C:4]([P+:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccc(-c2nc3ccccc3o2)cc1[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A stirred solution of 28.8 g (0.1 mole) of 2-(4-bromomethylphenyl)benzoxazole and 28.8 g (0.1 mole) of triphenylphosphine in xylene is heated at reflux for 19 hours. The product is then isolated by filtration, washed with additional portions of xylene, and dried.
Reaction SMILES: [C:1]([C:4]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][CH2:7][CH:8]([OH:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])(=[O:3])[CH3:2].[O-:24][CH2:25][CH3:26].[Na+].[Na].C([OH:31])C>C(OCC)(=O)C(OCC)=O.C1C=CC=CC=1>[C:25]([C:26]1[O:23][C:22]2[C:4]([C:1](=[O:3])[CH:2]=1)=[C:5]([O:6][CH2:7][CH:8]([OH:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH:19]=[CH:20][CH:21]=2)([OH:31])=[O:24]
Reactant: CCO
Reactant: CC[O-]
Reactant: CC(=O)c1c(O)cccc1OCC(O)COc1ccccc1C
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(=O)C(=O)OCC
Solvent: c1ccccc1
Product: Cc1ccccc1OCC(O)COc1cccc2oc(C(=O)O)cc(=O)c12

Procedure:
A solution of 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-o-cresyloxypropane (18.96 g) in diethyl oxalate (22.5 ml) was added to a suspension of sodium ethoxide, prepared from sodium (4.5 g) and ethyl alcohol (4.5 ml), in benzene (150 ml). The mixture was heated under reflux for 1.5 hours, cooled, and filtered after pouring into ether (150 ml). The residual solid was washed with ether and dried, and then added to a mixture of glacial acetic acid (120 ml) and concentrated hydrochloric acid (45 ml) and heated under reflux for 1 hour. After cooling, the residue was poured with stirring into cold water (1 L). The precipitated gum solidified after decanting the liquor and washing with water. The beige solid was recrystallized twice from ethyl acetate and finally from alcohol to give 1-(2-carboxy-chromon-5-yloxy)-2-hydroxy-3-o-cresyloxypropane (6.0g) as an off white solid, m.p. 95°-97° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[O:13])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[BH4-].[Na+].C1(C)C=CC=CC=1.O>C(O)C>[CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][OH:13])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1=C(C)C(c2ccccc2CO)C(C)=C1C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (2.26 g, 10.0 mmol) in ethanol (29.0 mL) was added sodium borohydride (0.42 g, 11.0 mmol) at room temperature and the mixture was stirred for 3 hrs. To the reaction mixture solution were added toluene (20.0 mL) and deionized water (20.0 mL) to separate an organic layer and an aqueous layer. The organic layer was dried over sodium sulfate and the solvent was then distilled off to give 2-(2,3,4,5-tetramethylcyclopentadienyl)benzylalcohol (2.23 g, yield 96.0%) as a pale oily substance.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][S:6][CH2:5][C:4]1=[O:9].I[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1>[Cu]Br.CN(C=O)C>[Cl:17][C:14]1[CH:15]=[C:16]([N:3]2[CH2:8][CH2:7][S:6][CH2:5][C:4]2=[O:9])[CH:11]=[CH:12][C:13]=1[Cl:18]
Reactant: O=C1CSCCN1
Reactant: Clc1ccc(I)cc1Cl
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CSCCN1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 81 %

Procedure:
Under a nitrogen atmosphere in a flame-dried flask, sodium hydride (72 mg, 1.79 mmol, 60% oil dispersion) was washed with hexanes and then treated with 6 mL of anhydrous DMF, and cooled to 0° C. Thiomorpholin-3-one (200 mg, 1.71 mmol) was added in one portion with stirring. After gas evolution had stopped (ca. 30 min), 4-iodo-1,2-dichlorobenzene (700 mg. 2.56 mmol) was added, followed after 5 minutes by copper (I) bromide (490 mg, 3.42 mmol). After heating at 75° C. overnight, the mixture was partitioned between ethyl acetate and 1N lithium chloride, filtered through diatomaceous earth and combined with additional ethyl acetate washes of the diatomaceous earth filter cake. The organic layers were washed with additional 1N lithium chloride, brine (saturated sodium chloride) and dried over calcium sulfate (CaSO4). Concentration in vacuo gave 363 mg of light brown oil which was flash chromatographed (30-50% ethyl acetate in hexanes) to give a white solid, 108 mg.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][N:9]=1.[Cl-:12].[NH4+:13]>CO>[ClH:12].[CH3:10][C:7]1([CH3:11])[CH2:8][NH:9][C:3](=[NH:13])[CH2:4][CH2:5][CH2:6]1
Reactant: [Cl-]
Reactant: COC1=NCC(C)(C)CCC1
Reactant: [NH4+]
Solvent: CO
Product: CC1(C)CCCC(=N)NC1
Product: Cl
Yield: 91.3 %

Procedure:
The product of EXAMPLE 63 (490 mg, 3.2 mmol) in 18 mL of MeOH was reacted with ammonium chloride (125 mg, 2.4 mmol) by the method of EXAMPLE 27 to yield 387 mg (69%) of the title material.
Reaction SMILES: O1CCO[CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C@H:14]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19].Cl>O1CCOCC1.C(O)C.FC(F)(F)C(O)=O.[Pd]>[CH3:13][O:12][C:10]1[CH:11]=[C:6]2[C:7]([C@H:14]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)[CH2:15][N:16]([C:17]([O:18][CH3:19])=[O:20])[CH2:2]2)=[CH:8][CH:9]=1
Reactant: COC(=O)NC[C@@H](c1ccc2ccccc2c1)c1ccc(OC)cc1C1OCCO1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1Cc2cc(OC)ccc2[C@H](c2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.9 %

Procedure:
To a solution of Compound 24 (0.10 g, 0.25 mmol) in 1,4-dioxane (10 mL) at 0° C. was added concentrated HCl (0.8 mL). The reaction solution was stirred at room temperature for 20 min, and then quenched with aqueous sodium bicarbonate and extracted with dichloromethane (2×). The combined organic extract was dried over sodium sulfate and concentrated in vacuo. The residue obtained was dissolved in a mixture of ethanol (30 mL) and trifluoroacetic acid (2 mL). Palladium on carbon (105 mg) was added and the reaction mixture was shaken under hydrogen (25 psi) for 15 min, then filtered through a pad of celite and concentrated in vacuo. The residue was dissolved in dichloromethane and the resulting solution was washed with aqueous sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. Purification by preparative thin layer chromatography (hexanes/ethyl acetate 75:25) provided Compound 25 (52 mg, 60%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.82-7.74 (m, 3H), 7.62-7.51 (m, 1H), 7.47-7.44 (m, 2H), 7.24 (d, J=9.0 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.80-6.68 (m, 2H), 4.83-4.60 (m, 2H), 4.40-3.90 (m, 2H), 3.81 (s, 3H), 3.76-3.42 (m, 4H); ESI MS m/z 348 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[CH2:21][O:20]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([OH:20])[CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C1CCNC1
Reactant: Brc1cnc2[nH]c(-c3ccc(OCC4CO4)cc3)nc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: OC(COc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1)CN1CCCC1
Temperature: 85 °C
Yield: 24 %

Procedure:
To a solution of 6-bromo-2-[4-(oxiran-2-ylmethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (119 mg, 0.35 mmol) in DMF (8 ml), pyrrolidine (144 μl, 1.73 mmol) was added. The mixture was heated at 85° C. for 10 h. 5% Aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic phase was filtered and concentrated. Purification by flash chromatography on silica using methylene chloride/methanol/ammonia as eluent afforded the title compound (35 mg, 24%).
Reaction SMILES: ON=C[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].P(Cl)(Cl)(Cl)=O.O.[C:18]([O-])(=O)[CH3:19].[Na+].C[N:24](C=O)C>C(#N)C>[CH3:19][C:18]1[O:11][C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[N:24]=1
Reactant: CN(C)C=O
Reactant: CC(=O)[O-]
Reactant: ON=Cc1ccc(O)cc1O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: Cc1nc2ccc(O)cc2o1
Reaction time: 1 h

Procedure:
A solution of 1.5 grams (0.009 mole) of 4-((hydroxyimino)methyl)benzene-1,3-diol in 5 mL of DMF and 15 mL of acetonitrile was stirred and 1.3 mL (0.014 mole) of phosphorus oxychloride was added portionwise. Upon completion of addition the reaction mixture was stirred for an additional one hour. After this time the reaction mixture was stirred with ice and water that contained 3.0 grams of sodium acetate, and extracted with diethyl ether. The extract was washed with water, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using mixtures of ethyl acetate and hexane, and finally 100% ethyl acetate, as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.75 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:18]C(=O)C(Br)C1C=CC=CC=1.NC1C=CC=CC=1S>CN(C=O)C.CCOC(C)=O.O>[C:1]1([CH:7]2[C:12](=[O:18])[NH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: c1ccc(C2CNc3ccccc3S2)cc1
Agent: Nc1ccccc1S
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2SC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Phenyl-3,4-dihydro-2H-1,4-benzothiazine: To bromo-phenyl-acetic acid methyl ester (4.88 g, 21 mmol) in DMF (15 mL) under an argon atmosphere was added 2-amino-benzenethiol (2.3 mL, 21 mmol) and the reaction was stirred at rt overnight. The reaction mixture was diluted with EtOAc (5 mL) and water (50 mL) and the crude product was collected by filtration, washed with warm EtOAc, and dried to give 2-phenyl-4H-1,4-benzothiazin-3-one as a white solid (3.49 g). LC/MS m/z 242 (M+H)+. To this intermediate (3.48 g, 14.4 mmol) in THF (50 mL) under an argon atmosphere was added 1M BH3.THF (50 mL, 50 mmol) and the reaction was stirred at rt overnight. The reaction was quenched with 1N HCl and extracted with ether. The combined organic fractions were dried over MgSO4 and concentrated. 201A was purified by recrystallization from hot EtOAc/hexanes to yield pale pink crystals (1.5 g). LC/MS m/z 228.2 (M+H)+.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25](Br)=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:28][O:29][CH2:30]/[CH:31]=[CH:32]/B(O)O.C(=O)(O)[O-].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]12([CH2:11][O:12][C:13]3[C:25](/[CH:32]=[CH:31]/[CH2:30][O:29][CH3:28])=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC/C=C/B(O)O
Reactant: CC(C)(C)OC(=O)c1cc(Br)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC/C=C/c1cc(C(=O)OC(C)(C)C)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 150 °C

Procedure:
To a mixture of tert-butyl 4-(adamantan-1-ylmethoxy)-5-bromo-2-fluorobenzoate (1.00 g, 2.28 mmol) in dioxane (15 mL) was added tetrakis(triphenylphosphine)palladium (0.263 g, 0.23 mmol), (E)-3-methoxy-1-propen-1-ylboronic acid, pinacol ester (1.36 g, 6.80 mmol), and 2 M sodium bicarbonate solution (4.5 mL, 9.00 mmol). The reaction mixture was thoroughly degassed by passing argon through it and then heated in a microwave at 150° C. for 30 minutes. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (100 mL) and filtered over anhydrous sodium sulfate. Removal of all volatiles under reduced pressure gave a residue which was purified by silica gel column chromatography using 0-50% ethyl acetate in hexanes as eluent to afford tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-3-methoxyprop-1-en-1-yl)benzoate (1.17 g, quant.) as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([O:8][CH3:9])=[O:7].Cl[C:11]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=1>CCOC(C)=O>[CH3:9][O:8][C:6]([C@@H:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:11]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=1)=[O:7]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N2CCC[C@H]2C(=O)OC)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
(S)-Methyl pyrrolidine-2-carboxylate (6.56 g, 50.8 mmol) was added to methyl 6-chloro-5-nitronicotinate (5.00 g, 23.1 mmol) and the reaction mixture was stirred at 90° C. for 10 min (exothermic reaction). It as cooled to room temperature, diluted with EtOAc (10 mL) and purified using flash column chromatography on silica gel (20-30% EtOAc in hexanes) to afford the title compound as a yellow oil (6.70 g, 94%). [M+H] calc'd for C13H15N3O6, 310; found, 310.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[FH:10].F.F.C(N(CC)CC)C.[Br:20]N1C(=O)CCC1=O>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([F:10])[CH2:7][Br:20])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=Cc1ccc(Br)cc1
Reactant: F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(CBr)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5.0 g (27.31 mmol) of 4-bromostyrene were dissolved in 40 ml of dichloromethane, the mixture was cooled to 0° C. and 13.21 g (81.94 mmol) of triethylamine trihydrofluoride were added. 5.83 g (32.78 mmol) of N-bromosuccinimide were then added in three portions. The mixture was stirred at RT overnight. After dilution with dichloromethane, the reaction mixture was added to ice-water. The organic phase was washed successively with 1 N hydrochloric acid, water and saturated sodium bicarbonate solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase pentane). This gave 4.14 g (53.8% of theory) of the title compound.