Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]S(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C@@H:19]1[C@H:24]2[N:25]=[C:26]([N:28]([CH3:30])[CH3:29])[S:27][C@H:23]2[CH2:22][C@H:21]([CH2:31][OH:32])[C@H:20]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C[Mg+].[Br-]>C(Cl)Cl.C1COCC1>[CH2:11]([O:18][C@@H:19]1[C@H:24]2[N:25]=[C:26]([N:28]([CH3:30])[CH3:29])[S:27][C@H:23]2[CH2:22][C@H:21]([CH:31]([OH:32])[CH3:1])[C@H:20]1[O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO)C[C@@H]2S1
Reactant: CS(C)=O
Agent: C[Mg+]
Agent: O=C(Cl)C(=O)Cl
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(O)[C@H]1C[C@@H]2SC(N(C)C)=N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.75 h

Procedure:
To a solution of DMSO (0.193 g, 2.46 mmol) in anhydrous DCM (10 mL) at −78° C. under N2 was added oxalyl chloride (0.268 g, 2.11 mmol) slowly, and the mixture was stirred at −30° C. for 45 min. The mixture was then cooled at −78° C., and a solution of ((3aR,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-2-(dimethylamino)-3a,4,5,6,7,7a-hexahydrobenzo[d]thiazol-6-yl)methanol (14) (0.330 g, 0.704 mmol) in anhydrous DCM (5 mL) was added slowly. After stirring at −30° C. for 2 h the reaction mixture was cooled back at −78° C., and triethylamine (0.50 g, 5.0 mmol) was added. The mixture was stirred at −30° C. for another 30 min, and then quenched with water (30 mL). The organic layer was collected, and the aqueous was extracted with DCM (3×20 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure to give a sticky pale yellow foam. Under N2 the pale yellow foam was dissolved in anhydrous THF (15 mL), and MeMgBr (1.4 M in THF/toluene, 1.5 mL, 2.1 mmol) was added. After addition the mixture was stirred at room temperature for 1.5 h. The reaction was quenched with saturated aqueous NaHCO3 (20 mL), and then extracted with DCM (3×15 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc), affording mixed 15a & 15b as a sticky pale yellow foam (0.23 g, 74%) with a ratio of 15a:15b=1:3 based on 1H NMR.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:8][C:7]1[C:2]2[N:1]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:17][C:3]=2[N:4]=[CH:5][N:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1c(Cl)ncnc1Cl
Product: Clc1ncnc2oc(-c3ccccc3)nc12
Yield: 77.6 %

Procedure:
A mixture of 5-amino-4,6-dichloropyrimidine (1.05 g, 0.00640 mol) and benzoyl chloride (0.89 mL, 0.0077 mol) was subjected to microwave irradiation (100° C.) for 2 hours. The reaction was cooled and the residue was triturated with diethyl ether, filtered and collected to obtain 1.15 g (77.5%) of a yellow solid. LC/MS: Rt=1.84 min, ES+ 232.19 (AA standard).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12](/[CH:21]=[CH:22]/[C:23]([O:25]C)=O)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.FC1C=CC([CH2:34][NH:35][C:36](C2C(O)=C3C(C=CC=N3)=C(CCC(OC)=O)N=2)=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12](/[CH:21]=[CH:22]/[C:23]([N:35]([CH3:36])[CH3:34])=[O:25])[N:11]=2)=[O:9])=[CH:27][CH:28]=1
Reactant: COC(=O)/C=C/c1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Reactant: COC(=O)CCc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Product: CN(C)C(=O)/C=C/c1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12

Procedure:
The title compound was prepared using a procedure similar to that described in Example 147, Step 2, except that methyl (2E)-3-(7-{[(4-fluorobenzyl)amino]carbonyl}-8-hydroxy[1,6]-naphthyridin-5-yl)-2-propenoate (Example 137, Step 1) was substituted for methyl 3-(7-{[(4-fluorobenzyl)amino]carbonyl}-8-hydroxy[1,6]-naphthyridin-5-yl)propanoate.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1([C:15]([OH:17])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.[CH2:18](O)[CH3:19]>>[NH2:5][C:6]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: CCO
Reactant: NC1(C(=O)O)CCc2ccccc21
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1(N)CCc2ccccc21
Yield: 84 %

Procedure:
Thionyl chloride (0.617 mL, 8.465 mmol) was added dropwise to anhydrous ethanol (6 mL) cooled to −30° followed by 1-amino-2,3-dihydro-1H-indene-1-carboxylic acid (0.300 g, 1.693 mmol) the reaction was then refluxed for 4 hours. The reaction was concentrated by rotary evaporation and diluted with water (5 mL) and the pH was adjusted to 9 with 6N aqueous sodium hydroxide. The solution was extracted with ethyl acetate (2×25 mL) and the organic extracts were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated by rotary evaporation to afford the title compound as an oil (0.293 g, 1.43 mmol, 84%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.12 (t, J=7.17 Hz, 3 H) 1.85-2.07 (m, 1 H) 2.31 (s, 2 H) 2.51-2.66 (m, 1 H) 2.93 (t, J=6.99 Hz, 2 H) 3.90-4.21 (m, 2 H) 7.13-7.34 (m, 4 H). MS (DCI) m/z 206 (M+H)+, 223 (M+NH4)+.
Reaction SMILES: [OH:1][C:2]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[OH:21])[C:11](=[O:22])[C:10]=2[C:9]([OH:23])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([O:24]C(=O)C)[CH2:7]2.Cl>CO>[OH:24][CH:6]1[CH2:5][CH2:4][C:3]2[C:8](=[C:9]([OH:23])[C:10]3[C:11](=[O:22])[C:12]4[C:17]([C:18](=[O:20])[C:19]=3[C:2]=2[OH:1])=[C:16]([OH:21])[CH:15]=[CH:14][CH:13]=4)[CH2:7]1
Reactant: CC(=O)OC1CCc2c(O)c3c(c(O)c2C1)C(=O)c1cccc(O)c1C3=O
Agent: Cl
Solvent: CO
Product: O=C1c2cccc(O)c2C(=O)c2c(O)c3c(c(O)c21)CC(O)CC3
Yield: 108.4 %

Procedure:
The ester of Example 19 (50 mg) was suspended in a 1 N solution of hydrochloric acid in 1:1 aqueous methanol and this was heated for one hour on the steam bath. The excess solvent was removed by concentration on a hot plate and the suspension cooled and filtered to give 48 mg of 2,5,7,12-tetrahydroxy-1,2,3,4,6,11-hexahydro-6,11-dioxonaphthacene (formula 17) as a red powder.
Reaction SMILES: [CH3:1][CH2:2][N:3]([C:6]([NH:8][C@@H:9]1[CH2:24][N:23]([CH3:25])[C@H:22]2[C@@H:11]([C:12]3[C:17]4[C:18]([CH2:21]2)=[CH:19][NH:20][C:16]=4[CH:15]=[CH:14][CH:13]=3)[CH2:10]1)=[O:7])[CH2:4][CH3:5].[I:26]N1C(=O)CCC1=O.C(=O)(O)[O-]>O1CCOCC1>[CH2:4]([N:3]([CH2:2][CH3:1])[C:6]([NH:8][C@H:9]1[CH2:10][C@H:11]2[C@@H:22]([CH2:21][C:18]3[C:17]4[C:16](=[CH:15][CH:14]=[CH:13][C:12]2=4)[NH:20][C:19]=3[I:26])[N:23]([CH3:25])[CH2:24]1)=[O:7])[CH3:5]
Reactant: O=C1CCC(=O)N1I
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(I)c(c34)C[C@H]2N(C)C1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A solution is prepared from 1 mmol of terguride in 20 ml of anhydrous dioxane, combined with about 1.5 ml of N-iodosuccinimide at room temperature and stirred for 30 minutes. The reaction mixture is then poured into a saturated bicarbonate solution, extracted with methylene chloride and the organic phase is dried with magnesium sulfate. After evaporation of the solvent, the residue is chromatographed on silica gel, thus obtaining in a 76% yield 1,1-diethyl-3-(2-iodo-6-methyl-8α-ergolinyl)urea.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].S(Cl)(Cl)=O.N1C=CC=CC=1.[NH2:25][C:26]1[S:27][C:28]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[C:29]([C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1>ClCCl>[CH3:14][N:2]([CH3:1])[C:3]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]([NH:25][C:26]2[S:27][C:28]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[C:29]([C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[O:13])[CH2:9][CH2:10]1)=[O:4]
Reactant: CN(C)C(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C(=O)N1CCC(C(=O)Nc2nc(-c3ccco3)c(N3CCOCC3)s2)CC1
Yield: 78.9 %

Procedure:
1-(N,N-dimethylcarbamoyl)piperidine-4-carboxylic acid (300 mg, 1.50 mmol) obtained in Step 2 was dissolved in dichloromethane (15 mL), and thionyl chloride (0.547 mL, 7.50 mmol) was added thereto, followed by stirring under heating and reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform (5 mL). The resulting solution was added to a pyridine (10 mL) solution of 2-amino-4-(2-furyl)-5-morpholinothiazole (126 mg, 0.50 mmol) obtained in Step 1 of Example 29, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (ethyl acetate:methanol=9:1) to afford the entitled Compound 55 (171 mg, 81%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:19]S(C)(=O)=O)[C:6]2[O:10][C:9]([N:11]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:8][C:7]=2[CH:18]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([NH:19][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[C:6]2[O:10][C:9]([N:11]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:8][C:7]=2[CH:18]=1
Reactant: CC(C)C(=O)Cl
Reactant: CS(=O)(=O)Nc1cc(Cl)cc2nc(N3CCCNCC3)oc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1cc(Cl)cc2nc(N3CCCNCC3)oc12
Reaction time: 3 h

Procedure:
The compound of Example 14 (a) (7-amino-5-chloro-2-[1-(4-tert-butyloxycarbonyl) homopiperazinyl]benzoxazole, 58 mg, 0.159 mmol) was dissolved in methylene chloride (2 ml), and the solution was successively added with triethylamine (0.067 ml) and isobutyroyl chloride (0.013 ml) at 0° C. After the reaction mixture was stirred for 3 hours, the reaction was stopped by using saturated aqueous solution of sodium hydrogencarbonate. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solution was added with 4 N hydrochloric acid in ethyl acetate (1 ml), and the deposited solids were collected by filtration to obtain the title compound (45 mg).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:25])([F:24])[C:5]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]2[CH3:23])=[N:15][CH:16]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(Cl)Cl.C(N(CC)CC)C.[Br:36][C:37]1[S:41][C:40]([S:42](Cl)(=[O:44])=[O:43])=[CH:39][CH:38]=1>O>[Br:36][C:37]1[S:41][C:40]([S:42]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[N:15]=[CH:16][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:24])[F:25])=[CH:12][N:13]=3)[C@@H:18]([CH3:23])[CH2:19]2)(=[O:44])=[O:43])=[CH:39][CH:38]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: C[C@H]1CNCCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(S(=O)(=O)c2ccc(Br)s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
A 250-mL round-bottomed flask was charged with (1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol dihydrochloride (1.48 g, 3.55 mmol), 25 mL of CH2Cl2, and triethylamine (1.48 mL, 10.7 mmol). After cooling to 0° C., 5-bromothiophenesulfonyl chloride (0.93 g, 3.55 mmol. Sigma-Aldrich, St. Louis, Mo.) was added and the solution was stirred for 15 min at 0° C. 100 mL of water was then added and the layers were separated. The organics were dried (MgSO4), filtered, and concentrated to give a tar that was purified by column chromatography on silica gel (0-60% EtOAc in hexanes) to give 2-(2-((2S)-4-((5-bromo-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (2.01 g) as an off-white foam.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[CH3:39][NH:40][CH2:41][C@@H:42]([C@H:44]([C@H:46]([C@@H:48]([CH2:50][OH:51])[OH:49])[OH:47])[OH:45])[OH:43]>>[CH3:30][C:29]1[CH:28]=[CH:27][O:26][C:25]=1[C:23]([NH:22][C:18]1[CH:17]=[C:16]([C:15]#[C:14][C:12]2[CH:11]=[N:10][CH:9]=[C:8]([CH:13]=2)[C:7]([N:6]=[S:5]([CH2:4][CH2:3][CH2:2][N:40]([CH3:39])[CH2:41][C@H:42]([OH:43])[C@@H:44]([OH:45])[C@@H:46]([OH:47])[C@H:48]([OH:49])[CH2:50][OH:51])(=[O:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:31])[CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: CNC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCN(C)C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 1-deoxy-1-(methylamino)-D-galactitol were converted to the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:5]2[C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].[PH2]([O-])=O.[Na+]>[Pd].O1CCOCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:5]2[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(=O)c1c(-c2ccccc2)[nH]c2ccc(C)cc12
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1c(-c2ccccc2)[nH]c2ccc(C)cc12
Yield: 45.8 %

Procedure:
A suspension of palladium on carbon (10%, 1 g) in dioxane (50 mL) was added to a solution of ethyl 5-methyl-α-oxo-2-phenyl-1H-indole-3-acetate (Description 4, 3.66 g) in dioxane (250 mL). A solution of sodium hypophosphite (10 g) in water (10 mL) was added and the mixture was heated under reflux for 10 h. Further palladium on carbon (10%, 1 g) and sodium hypophosphite (10 g) were added and the mixture was heated under reflux for 24 h. Further palladium on carbon (10%, 1 g) and sodium hypophosphite (10 g) were added and the mixture was heated under reflux for 24 h. The mixture was cooled, filtered through celite and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc (90:10) to give the title compound as a colourless solid (1.6 g, 47%). 1H NMR (360 MHz, CDCl3) δ0.86 (3H, t, J 7 Hz), 2.43 (3H, s), 3.73 (2H, s), 4.11-4.16 (2H, m), 6.96 (1H, dd, J 8, 1.8 Hz), 7.18 (1H, d, J 10.8 Hz), 7.28-7.46 (5H, m), 7.58 (1H, d, J 7.2 Hz), and 7.98 (1H, br s). m/z (ES+) 294 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(Br)c([N+](=O)[O-])c1

Procedure:
4-Bromo-3-nitrobenzoic acid (500 mg) in thionyl chloride (3 ml) was heated at 110° C. for 2 hrs. The excess thionyl chloride was evaporated in vacuo to give 4-bromo-3-nitrobenzoyl chloride as a yellow solid (502 mg).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]2[CH:32]=[CH:31][N:30]3[N:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:29]3[N:28]=2)[C:16]1=[O:41].CO.C1COCC1.NN.O>O>[NH2:3][CH2:12][CH2:13][CH2:14][N:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]2[CH:32]=[CH:31][N:30]3[N:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:29]3[N:28]=2)[C:16]1=[O:41]
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(CCCN4C(=O)c5ccccc5C4=O)c3=O)nc12
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(CCCN)c3=O)nc12
Temperature: 50 °C
Yield: 71.3 %

Procedure:
To a solution of (R)-ethyl 5-(2-(1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.20 g, 0.36 mmol) in 1:1 MeOH/THF (12 mL) was added hydrazine-H2O (0.18 g, 3.6 mmol). The reaction mixture was heated at 50° C. for 24 hours. After cooling, the reaction mixture was poured into water and extracted with DCM (3×20 mL). The combined organics were dried (MgSO4), filtered, and concentrated to afford the desired product (0.11 g, 72% yield). MS (apci) m/z=429.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:19](=O)[CH2:20][CH3:21]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(F)cc1)C(=O)OC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(F)cc1
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.80 g), 2-(4-fluorobenzyl)-3-oxopentanoic acid methyl ester (1.0 g), polyphosphoric acid (10 g) and dioxane (10 mL) was heated at 130° C. for 17 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phases washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound, 1.5 g.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=1)[C:22](O)=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=1)[C:22]([NH:1][CH2:2][CH:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:23]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cncc(Br)c1
Yield: 34 %

Procedure:
A solution of 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (326 mg, 1.58 mmol), 5-bromonicotinic acid (300 mg, 1.5 mmol), HATU (627 mg, 1.65 mmol) and TEA (181.8 mg, 1.8 mmol) in DCM (15 mL) was stirred at 22° C. for 2 h, at which time the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried and concentrated and the residue was purified by column chromatography to give title compound that was used in the next step without further purification (200 mg, Yield 34%). LCMS (m/z): 390/392 (M+1/M+2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[C:8](=[CH:20][C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: COc1ccc2c(c1)OCCC2=O
Product: COc1ccc2c(c1)OCC(=Cc1cccnc1)C2=O

Procedure:
By the method of Example 1, 7-methoxy-4-chromanone (10 g, 56 mmol) and 3-pyridine carbaldehyde (5.2 g, 73 mmol) were converted to present title product, isolated directly from the reaction mixture by cooling to 0° C., 11.9 g; m.p. 176°-178° C.; MS 267 (M+, base peak).
Reaction SMILES: [OH:1][C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[C:3]([OH:5])=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[N:34]12[CH2:41][CH2:40][CH:37]([CH2:38][CH2:39]1)[C@@H:36](O)[CH2:35]2>C1COCC1.C(OCC)(=O)C>[N:34]12[CH2:41][CH2:40][CH:37]([CH2:38][CH2:39]1)[C@@H:36]([O:4][C:3](=[O:5])[C:2]([OH:1])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH2:35]2
Reactant: COc1cccc(C(O)(C(=O)O)c2cccc(OC)c2)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(C(O)(C(=O)O[C@H]2CN3CCC2CC3)c2cccc(OC)c2)c1

Procedure:
To a stirred solution of hydroxy-bis-(3-methoxy-phenyl)-acetic acid (Intermediate J) (1.384 g, 4.8 mmol) in dry THF (20 ml) is added CDI (0.870 g, 5.3 mmol) and the mixture is heated to reflux for 90 minutes. (R)-1-aza-bicyclo[2.2.2]octan-3-ol (0.67 g, 5.3 mmol) is then added. After refluxing for 16 hours, the reaction mixture is diluted with ethyl acetate and washed with water. The organic layer is then extracted with 2M HCl and the aqueous portion is treated with potassium carbonate to basify the solution. The aqueous portion is re-extracted with ethyl acetate. The organic portions are combined, dried over MgSO4 and concentrated in vacuo to yield a crude residue which is purified using C-18 reverse phase column chromatography (eluent: water-acetonitrile), to afford the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].ClC1C=CC=CN=1>[Zn]>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: Clc1ccccn1
Agent: [Zn]
Product: Clc1cc(Cl)c(Cl)nc1Cl

Procedure:
at 96.75 percent pentachloropyridine conversion. Of the metallic zinc used in the reaction, 95.61 percent reacts with chloropyridine with 91.71 percent resulting in the formation of 2,3,5,6-tetrachloropyridine. Of the metallic zinc added, 100 percent oxidizes during the reaction with 99.16 percent of it accounted for in the final products.
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]1>>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][C:33]3=[O:37])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Reactant: CN1CCNC(=O)C1
Product: COc1ccc(COc2ccc(Cn3cnc4cc(N5CCN(C)CC5=O)ccc43)cc2OC)cn1

Procedure:
1-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-4-methylpiperazin-2-one was prepared from 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (Step 5, Example 6) and 4-methylpiperazin-2-one using the procedure outlined for Example 3-14: 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.70-7.68 (m, 2H), 7.34 (d, J=8.5 Hz, 1H), 7.22 (dd, J=8.5, 1.5 Hz, 1H), 6.90-6.89 (m, 1H), 6.78-6.74 (m, 3H), 5.29 (s, 2H), 5.05 (s, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.79 (t, J=5.5 Hz, 2H), 3.35 (s, 2H), 2.86 (t, J=5.5 Hz, 2H), 2.46 (s, 3H) ppm; (M+1)=488.