Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([OH:10])=[C:5]([CH3:11])[CH:4]=1)#[N:2].[OH-].[K+].[I-].[K+].Cl[CH:17]([CH3:26])[CH2:18][C:19]1[O:23][N:22]=[C:21]([CH2:24][CH3:25])[CH:20]=1>C(#N)C>[CH3:11][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[C:7]([CH3:9])[C:6]=1[O:10][CH2:26][CH2:17][CH2:18][C:19]1[O:23][N:22]=[C:21]([CH2:24][CH3:25])[CH:20]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: CCc1cc(CC(C)Cl)on1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCc1cc(CCCOc2c(C)cc(C#N)cc2C)on1
Yield: 66 %

Procedure:
To a mixture of 7.84 g 4-cyano-2,6-dimethylphenol, 3.57 g potassium hydroxide and 10.6 g potassium iodide in 200 ml acetonitrile was added 12 g 5-(2-chloropropyl)-3-ethylisoxazole, and the mixture was heated at reflux for about 16 hrs. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was washed with aqueous sodium hydroxide (10%) until the excess starting phenol was removed, and the solution concentrated to give 10 g of 5-[3-(2,6-dimethyl-4-cyanophenoxy)propyl]-3-ethylisoxazole as a yellow oil. A sample of the latter was obtained in crystalline form, m.p. 50°-51° C. by crystallization from methanol at -50° C.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][CH2:7][OH:8])[CH2:4][CH2:3][CH2:2]1.[C:9]([C@H:13]1[C:40](=[O:41])[N:39]2[CH2:42][C@@H:36]([CH2:37][C@H:38]2[C:43]([NH:45][C@:46]2([C:51](=[O:60])[NH:52][S:53]([C:56]3([CH3:59])[CH2:58][CH2:57]3)(=[O:55])=[O:54])[CH2:48][C@H:47]2[CH:49]=[CH2:50])=[O:44])[O:35][C:25]2=[N:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[C:33](O)=[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[CH2:61][C@H:17]2[O:16][C:15](=[O:62])[NH:14]1)([CH3:12])([CH3:11])[CH3:10]>>[N:1]1([CH2:5][CH2:6][CH2:7][O:8][C:33]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[C:25]3[O:35][C@H:36]4[CH2:42][N:39]([C:40](=[O:41])[C@H:13]([C:9]([CH3:11])([CH3:10])[CH3:12])[NH:14][C:15](=[O:62])[O:16][C@@H:17]5[CH2:61][C@H:18]5[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]=23)[C@H:38]([C:43]([NH:45][C@:46]2([C:51](=[O:60])[NH:52][S:53]([C:56]3([CH3:59])[CH2:57][CH2:58]3)(=[O:55])=[O:54])[CH2:48][C@H:47]2[CH:49]=[CH2:50])=[O:44])[CH2:37]4)[CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1(C)CC1
Reactant: OCCCN1CCC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OCCCN1CCC1)O2)C(=O)NS(=O)(=O)C1(C)CC1

Procedure:
The title compound was prepared using the same method as described in Example 75, using the 3-(azetidin-1-yl)propan-1-ol and (1aR,5S,8S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-2-ethenyl-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-17-hydroxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-8-carboxamide (Example 120). LRMS (ES+) m/z 863.50 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH2:11][C:10](=[O:14])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[C:8]2=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[N:35]([CH2:38][C:39]([O:41]CC)=[O:40])=[C:36]=[S:37]>C(Cl)(Cl)Cl>[C:39]([CH2:38][NH:35][C:36]([C:11]1[C:12](=[O:13])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8](=[O:25])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:10]=1[OH:14])=[S:37])([OH:41])=[O:40]
Reactant: CCOC(=O)CN=C=S
Reactant: CCOC(=O)CCCCCN1C(=O)CC(=O)N(C2CCCCC2)C1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCCCn1c(O)c(C(=S)NCC(=O)O)c(=O)n(C2CCCCC2)c1=O
Reaction time: 168 h
Yield: 60.2 %

Procedure:
A mixture of ethyl 6-(3-cyclohexyl-2,4,6-trioxotetrahydro-1(2H)-pyrimidinyl)hexanoate (330 mg, 0.94 mmoles), diisopropylethylamine (324 uL, 1.87 mmoles) and ethyl isothiocyanatoacetate (139 uL, 1.12 mmoles) in chloroform (20 mL) was stirred for 7 days. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The residue was purified by flash chromatography (hexane—20% ethyl acetate in hexane) to give the title compound as a clear oil (250 mg, 60%). The diester was dissolved in ethanol (3 mL) and treated with 1 molar sodium hydroxide (2 mL). The mixture was stirred overnight, taken up in ethyl acetate and washed with 1 molar hydrochloric acid (×2), dried and evaporated. Crystallization from acetic acid afforded the title compound (160 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (br s, 1 H), 12.50 (s, 1 H), 12.03 (br s, 1 H), 4.71 (m, 1 H), 4.35 (d, J=5.05 Hz, 2 H), 3.84 (t, J=7.20 Hz, 2 H), 2.10-2.38 (m, 4 H), 1.80 (d, J=12.63 Hz, 2 H), 1.42-1.71 (m, 7 H), 1.21-1.42 (m, 4 H), 1.01-1.22 (m, 1 H).
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:3]=1.O[CH2:16][CH2:17][O:18][C:19](=[O:22])[CH:20]=[CH2:21]>CN(C)C=O>[C:19]([O:18][CH2:17][CH2:16][O:13][C:12]([CH2:11][C:4]1[CH:3]=[C:2]([OH:1])[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=1)=[O:14])(=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)OCCO
Reactant: O=C(O)Cc1cc(O)n2ncnc2n1
Solvent: CN(C)C=O
Product: C=CC(=O)OCCOC(=O)Cc1cc(O)n2ncnc2n1
Reaction time: 8 h

Procedure:
19.4 g of 7-hydroxy-5-carboxymethyl-1,2,4-triazolo[1,5-a]pyrimidine and 12 g of hydroxyethylacrylate were dissolved in 150 ml of dimethylformamide (DMF) and thereto, a solution of 20.6 g of N,N-dicyclohexylcarbodiimide in 30 ml of DMF was added dropwise at a room temperature for 10 minutes. Thereafter, stirring was continued at a room temperature for 8 hours, and the precipitate produced was removed by filtration. The filtrate was condensed under a reduced pressure and low temperature. The thus obtained residue was chromatographed through silica gel put in a column in order to separate it into components and purify. The intended compound was obtained in a form of crystal. It was recrystallized from ethyl acetate. Thus, 6 g of white crystal having a melting point of 108° to 109° C. (intended compound) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].CCN=C=NCCCN(C)C.Cl.[CH3:23][NH:24][O:25][CH3:26].Cl>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:24]([O:25][CH3:26])[CH3:23])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 3-fluorobenzoic acid (30 g, 214.1 mmol) in DCM (300 mL) were added EDC.HCl (45 g, 235 mmol) and N,O-dimethylhydroxylamine.HCl (23 g, 235 mmol) at 0° C. under N2. The reaction mixture was stirred at rt for 3 h, then diluted with water (1000 mL) and extracted with DCM (3×200 mL). The organics were washed with brine, dried over Na2SO4, and concentrated to obtain the 3-fluoro-N-methoxy-N-methylbenzamide (24 g, 61%). (183.91 [M+H]) 1H NMR: (400 MHz, CDCl3) δ: 3.38 (s, 3H), 3.57 (s, 3H), 7.14-7.19 (m, 1H), 7.37-7.43 (m, 2H), 7.48-7.50 (d, J=7.6, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:21][C:22](=[O:25])[CH2:23]Cl)[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4].[CH:27]([NH2:30])([CH3:29])[CH3:28]>CN(C)C=O>[CH:27]([NH:30][CH2:2][C:3]([NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:21][C:22](=[O:25])[CH2:23][NH:5][CH:6]([CH3:19])[CH3:7])[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4])([CH3:29])[CH3:28]
Reactant: O=C(CCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCl)cccc1C2=O
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NCC(=O)Nc1cccc2c1C(=O)c1c(NC(=O)CNC(C)C)cccc1C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Add 0.4 g, 1.0 mmol 1,8-bis(chloroacetamido)anthraquinone (compound 3) with 0.5 ml TEA, and 0.6 ml, 6 mmole isopropylamine, dissolved in 20 ml dehydrated dimethylformamide (DMF). The mixture is reacted in a mini-reactor. The reaction temperature is 120° C. in the oil bath and the reaction time is 30 minutes. The reacted mixture is poured into a little bit ice water and is filtered to collect precipitate. The precipitate is recrystallized from ethanol to get yellow compound 3o.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[CH:2]=[CH2:3].Br[C:18]1[C:19]([Cl:30])=[CH:20][N:21]=[C:22]2[C:27]=1[N:26]=[C:25]([O:28][CH3:29])[CH:24]=[CH:23]2.[Cl-].[Li+].C(OCC)(=O)C>CN(C)C=O.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>[CH2:3]([C:18]1[C:19]([Cl:30])=[CH:20][N:21]=[C:22]2[C:27]=1[N:26]=[C:25]([O:28][CH3:29])[CH:24]=[CH:23]2)[CH:2]=[CH2:1]
Reactant: COc1ccc2ncc(Cl)c(Br)c2n1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1c(Cl)cnc2ccc(OC)nc12
Temperature: 105 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
Allyltributylstannane (7.3 g, 21.9 mmol, 1.2 eq) is added at room temperature to a stirred solution of 8-bromo-7-chloro-2-methoxy-[1,5]naphthyridine (5.0 g, 18.3 mmol, 1.0 eq) in N,N-dimethylformamide (100 mL), followed by tetrakis(triphenylphosphine)palladium(0) (0.63 g, 0.55 mmol, 0.03 eq) and lithium chloride (2.9 g, 67.6 mmol, 3.7 eq). After 1 hour stirring at 105° C., the reaction mixture is cooled down to room temperature and filtered through decalite. The filtrate is concentrated to give a crude product that is extracted with ethyl acetate (3×100 mL) and a 10% ammonium hydroxide aqueous solution (100 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product that is purified column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 30:1, v/v) to afford 8-allyl-7-chloro-2-methoxy-[1,5]naphthyridine as a colorless oil (2.5 g, 58% yield).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(=O)([O-])[O-].[K+].[K+].[C:11]1([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[CH3:2][O:3][N:4]=[C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CON
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=NOC)c1ccccc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
1.4 g (16.8 mmol) of O-methylhydroxylamine hydrochloride and 1.16 g (8.4 mmol) of potassium carbonate were added to a solution of 0.50 g (2.8 mmol) of ethyl phenylglyoxylate in N,N-dimethylformamide, and the resulting mixture was stirred at 90° C. for 4 hours. At the end of this time, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography through silica gel, eluted with a stepwise gradient of ethyl acetate (10-30%) in hexane, to give 0.47 g (67% yield) of the less polar isomer of the title compound and 0.13 g (19% yield) of the more polar isomer of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.[Cl:14]N1C(=O)CCC1=O.Cl.CCOCC>C(Cl)(Cl)Cl>[Cl:14][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1c(Cl)[nH]c2ccccc12
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A stirred suspension of methyl indole-3-carboxylate (6.0 g, 0.034 mole) in chloroform (200 ml) was treated with N-chlorosuccinimide (5.04 g, 0.038 mole) to afford a clear solution within 15 minutes. After 2 h at room temperature this was treated with 1M HCl/ether (34 ml, 0.034 mole) and allowed to stir for a further 1 h, then treated with excess 10% Na2 CO3 solution and the chloroform layer separated, dried (Na2 SO4) and concentrated in vacuo. The residual yellow solid was recrystallised from chloroform/60-80 petrol to afford the title compound (D 11a) as a beige solid (3.4 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([Li])CCC.Cl[C:15]([O:17][CH3:18])=[O:16]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]([O:17][CH3:18])=[O:16])=[C:4]([F:8])[N:3]=1
Reactant: Fc1cccc(Cl)n1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)nc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-6-fluoropyridine (298 mg, 2.3 mmol) was taken up in tetrahydrofuran (11.4 mL) and cooled to −78° C. n-Butyllithium (1.42 mL of 1.6 M in hexanes, 2.3 mmol) was added dropwise over 5 min. The solution was stirred for 30 minutes and methyl chloroformate (0.3 mL, 3.9 mmol) was added dropwise over 15 minutes. The resulting mixture was stirred at −78° C. for 2 hrs and then warmed to 0° C. and stirred for 3 hours. The reaction was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (silica, 0-17% ethyl acetate/hexanes) to afford the title compound as a white solid.
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[NH2:7][CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)[CH:12]=[CH:11][C:10]1=2.[BH4-].[Na+]>CO>[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][NH:7][CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CC(C)CC=O
Reactant: NCC1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCC1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.9 %

Procedure:
Add isovaleraldehyde (64.5 mg, 0.750 mmol) to a solution of 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide (intermediate 21, 148 mg, 0.500 mmol) dissolved in MeOH (5 mL) and stir at ambient temperature for 1.5 hours before adding NaBH4 (38 mg, 1.00 mmol). After stirring for an additional two hours, concentrate the reaction mixture and redissolved in EtOAc. Wash the EtOAc solution with 5% aq. KOH and brine before drying (MgSO4) and concentrating. Purify on silica gel (5% (1N NH3/MeOH)/DCM) to obtain 123 mg of the title compound as a white foam. Mass spectrum (ion spray): m/z=368 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.15 (d, 1H), 7.25 (d, 1H), 6.94 (d, 1H), 6.89 (d, 1H), 6.85 (s, 1H), 5.82 (br. s, 2H), 2.97 (m, 1H), 2.84 (m, 2H), 2.76 (m, 2H), 2.66 (m, 2H), 1.85 (m, 3H), 1.74 (m 1H), 1.62 (m, 1H), 1.41 (m, 2H), 0.90 (d, 6H).
Reaction SMILES: I[C:2]1[S:6][CH:5]=[C:4]([CH2:7][OH:8])[CH:3]=1.[CH3:9][N:10](C=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].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>[OH:8][CH2:7][C:4]1[CH:3]=[C:2]([C:9]#[N:10])[S:6][CH:5]=1
Reactant: OCc1csc(I)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(CO)cs1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of (5-iodothiophene-3-yl)methanol (42 g, 176 mmol) in 150 mL of DMF is added Zn(CN)2 (12.4 g, 106 mmol) and Pd(PPh3)4 (8.13 g, 7.04 mmol). The solution is heated to 80° C. After 6 hours, the solution is diluted with 3 L of EtOAc. The resulting solution is washed with 1 N NH4OH, H2O and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with gradient of 20% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (10 g, 72 mmol) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][CH2:11][CH2:10]O2)=[CH:4][CH:3]=1.Br[C:14]1[CH:19]=[CH:18]C=[CH:16][C:15]=1COCOC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([B:8]2[C:16]3[CH:15]=[CH:14][CH:19]=[CH:18][C:10]=3[CH2:11][O:12]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(B2OCCO2)cc1
Reactant: COCOCc1ccccc1Br
Product: Clc1ccc(B2OCc3ccccc32)cc1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(4-chlorophenyl)-[1,3,2]-dioxaborolane and 1-bromo-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10]CC2C=CC=CC=2)[CH:7]=[C:6]([CH2:18][CH:19]=[CH2:20])[C:5]=1[OH:21])[CH:2]=[CH2:3].Br[CH:23]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].CCOCC>CN(C=O)C>[CH2:18]([C:6]1[CH:7]=[C:8]([OH:10])[CH:9]=[C:4]([CH2:1][CH:2]=[CH2:3])[C:5]=1[O:21][CH:23]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25])[CH:19]=[CH2:20]
Reactant: C=CCc1cc(OCc2ccccc2)cc(CC=C)c1O
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCc1cc(O)cc(CC=C)c1OC(C(=O)OC)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2,6-diallyl-4-benzyloxyphenol (200 mg, 1.0 eq) in DMF (8 mL) were added methyl α-bromo-4-chlorobenzeneacetate (190 mg, 1.0 eq) and Cs2CO3 (285 mg, 1.2 eq). The reaction mixture was stirred at room temperature for 15 h, poured into ether, washed with water and brine, dried over MgSO4, filtered, and concentrated in vac. Purification by chromatography (SiO2, EtOAc/Hexanes 1:20) afforded the desired methyl α-(2,6-diallyl-4-hydroxyphenoxy)4-chlorobenzeneacetate.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[C:18]([C:33](OC)=[O:34])=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[CH2:11][CH2:10]1)=[O:8])[CH3:5].CO>C1COCC1>[OH:34][CH2:33][C:18]1[C:17]([O:16][CH2:15][CH:12]2[CH2:11][CH2:10][N:9]([C:7]([O:6][CH:4]([CH3:5])[CH3:3])=[O:8])[CH2:14][CH2:13]2)=[CH:22][CH:21]=[C:20]([C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[N:19]=1
Reactant: COC(=O)c1nc(-c2ccc(S(C)(=O)=O)cc2)ccc1OCC1CCN(C(=O)OC(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2CO)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
NaBH4 (32 mg, 0.82 mmol) was added to a stirred solution of methyl 3-{[(1-{[(1-methylethyl)oxy]carbonyl}-4-piperidinyl)methyl]oxy}-6-[4-(methylsulfonyl)phenyl]-2-pyridinecarboxylate (Example 135, 0.20 g, 0.41 mmol) in THF (4 mL) at 0° C. MeOH (2 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 2 h, then allowed to warm to ambient temperature and stirred overnight. The mixture was heated at 70° C. for 2 h, more NaBH4 (100 mg, 2.56 mmol) was added. Heating was continued at 70° C. for 2 h, then more NaBH4 (100 mg, 2.56 mmol) was added. The mixture was heated at 70° C. for 2 h, cooled to ambient temperature, quenched with saturated aqueous NH4Cl and extracted with EtOAc (70 mL×2). The combined organic extracts were washed with brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a light brown oil. The crude material was purified by flash chromatography on a silica gel column eluted with 1:8 acetone/CH2Cl2 to give 0.153 g (81%) of 1-methylethyl 4-[({2-(hydroxymethyl)-6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.15 (d, 2H, J=8.5 Hz), 8.02 (d, 2H, J=8.5 Hz), 7.71 (d, 1H, J=8.6 Hz), 7.24 (d, 1H, J=8.6 Hz), 4.93 (septet, 1H, J=6.2 Hz), 4.82 (s, 2H), 4.22 (bs, 2H), 3.91 (d, 2H, J=6.1 Hz), 3.09 (s, 3H), 2.85-2.70 (m, 2H), 2.15-2.00 (m, 1H), 1.90_1.80 (m, 2H), 1.40-1.20 (m, 8H); LRMS (ESI), m/z 463 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:31])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si](C(C)(C)C)(C)C)=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:31])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:29])([CH3:30])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)benzamide (2E, 1.9 g, 1.0 equivalent) was dissolved in THF (0.4 M). Cooled mixture in ice bath, and followed by a slow addition of TBAF (1.0M THF solution, 6.5 equivalents). After addition, mixture was warmed to room temperature and then heated to 60° C. for 3 h. After stirring, water was added and followed by extraction with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography (SiO2, gradient of 1 to 5% MeOH/CH2Cl2) to give 2F (60%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 6H) 3.48 (s, 2H) 4.77 (br. s., 1H) 7.57 (d, J=8.59 Hz, 2H) 7.72 (d, J=8.34 Hz, 1H) 8.05-8.16 (m, 3H) 13.08 (s, 1H); ESI-MS: m/z 406.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]([C:31]3[S:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=3)=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>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.C1COCC1>[S:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[C:28]1[N:29]=[CH:30][C:25]([C:2]2[CH:7]=[N:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4s3)nc2)OC1(C)C
Reactant: Brc1ccc(-c2nc3ccccc3o2)nc1
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: O
Solvent: C1CCOC1
Product: c1ccc2oc(-c3ccc(-c4ccc(-c5nc6ccccc6s5)nc4)cn3)nc2c1
Yield: 84.8 %

Procedure:
Following the procedure for 17, 11 (0.558 g, 2.03 mmol), 16 (0.700 g, 2.07 mmol), tetrakis(triphenylphosphine)palladium(0) (117 mg, 102 μmol), Na2CO3 (1.59 g, 15.0 mmol), H2O (15 mL) and THF (25 mL) yielded an insoluble white solid (0.70 g, 84%) after filtration.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:13]/[C:14]1[NH:15][CH:16]=[CH:17][C:18]=1[O:19][CH3:20])/[C:5](=[O:12])[NH:6]2.[CH3:21][C:22](=O)[C:23](=O)[CH3:24]>C(O)C>[CH3:21][C:22]1[C:23]([CH3:24])=[N:11][C:10]2[CH:9]=[CH:8][C:7]3[NH:6][C:5](=[O:12])/[C:4](=[CH:13]\[C:14]4[NH:15][CH:16]=[CH:17][C:18]=4[O:19][CH3:20])/[C:3]=3[C:2]=2[N:1]=1
Reactant: CC(=O)C(C)=O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(N)c21
Solvent: CCO
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc3nc(C)c(C)nc3c21
Yield: 100 %

Procedure:
Using Method A above, (Z)-4,5-diamino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.22 mmol) (Starting Material 5) was condensed with 2,3-butanedione (135 μL) (Aldrich) in ethanol (3 ml) at reflux to give (Z)-7,9-dihydro-2,3-dimethyl-9-[(3-methoxy-1H-pyrrol-2-yl)methylene]-8H-pyrrolo-[3,2-f]quinoxalin-8-one in 100% yield.