Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH3:18])=[N:16][N:17]=3)[N:14]=2)[CH:4]=1.[CH2:19]=[C:20]1[O:24][C:22](=[O:23])[CH2:21]1>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH3:18])=[N:16][N:17]=3)[N:14]=2)[CH:4]=1)[C:22](=[O:23])[CH2:21][C:20](=[O:24])[CH3:19]
Reactant: C=C1CC(=O)O1
Reactant: CNc1cccc(-c2ccc3nnc(C)n3n2)c1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1

Procedure:
A mixture of 2.0 g of -N-methyl-3-(3-methyl-1,2,4-triazolo-[4,3-b]pyridazin-6-yl)benzenamine and 2.14 ml of diketene in 250 ml of dry toluene was heated to reflux for 2 days. The solution was concentrated in vacuo and the residue partitioned between 300 ml dichloromethane and 200 ml of water. The aqueous layer was extracted with 150 ml portions of dichloromethane. The organic layer and extracts were combined, dried and concentrated in vacuo. The residue was chromatographed on 300 g of silica gel with dichloromethane-methanol (97:3). The fractions containing product were combined, evaporated in vacuo and the solid recrystalized from dichloromethane-hexane to give 1.15 g of tan crystals, mp 138°-141° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[F:14][CH:15]([F:25])[O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:21][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH:15]([F:14])[F:25])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: FC(F)Oc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(Cc3ccc(OC(F)F)cc3)c2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 21.1 %

Procedure:
To a solution of commercially available 1H-indole-6-carboxylic acid methyl ester (0.35 g, 2.0 mmol) and 4-difluoromethoxy-benzyl bromide (0.52 g, 2.2 mmol) in DMF (2 mL) was added sodium hydride (92 mg, 2.3 mmol). After stirring at room temperature for 3.5 hr, the solution was diluted with water (25 mL) and ethyl acetate (75 mL), the organic layer was washed again with dilute NaHCO3 (25 mL) and then brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 1:5) to provide 1-(4-difluoromethoxy-phenylmethyl)-1H-indole-6-carboxylic acid methyl ester as a colorless oil (0.14 g, 21% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.S(Cl)(Cl)=O.CC[N:18]([CH:22]([CH3:24])[CH3:23])C(C)C.C1(N)CC1>C(Cl)Cl.CCOC(C)=O>[CH:22]1([NH:18][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=2)[CH2:24][CH2:23]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: NC1CC1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1I
Reaction time: 3 h

Procedure:
To 3-iodo-4-methylbenzoic acid (3.5 g, 13 mmol) was added thionyl chloride (10 mL) before heating the mixture to reflux for 1.5 h. The reaction mixture was concentrated in vacuo, and dissolved in DCM (50 mL) and Hünigs base (4.6 mL, 27 mmol). After the addition of cyclopropylamine (1.87 mL, 27 mmol) at −78° C., the reaction mixture was stirred at ambient Temp. for about 3 h. The mixture was diluted with 100 mL DCM, washed with 20 mL saturated, aqueous NaHCO3 and 20 mL 3 N HCl, and dried over anhydrous Na2SO4. The solid obtained was suspended in EtOAc and filtered to give the title compound. MS (ES+): 302 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[C:9]([O:27][CH3:28])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[C:9]([O:27][CH3:28])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2]
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OCC1CCNCC1
Yield: 88.1 %

Procedure:
2-nitro-4-((1-tert-butyloxycarbonylpiperidin-4-yl)methoxy)-5-methoxybenzonitrile (1.17 g, 3 mmol) in CH2Cl2 (12 ml) was treated with TFA (2.4 ml) for 1 hour at room temperature. The solvent was evaporated, the residue was taken up in a mixture of CH2Cl2 and concentrated sodium bicarbonate, extracted with CH2Cl2. The organic phase was dried over MgSO4, concentrated to give title compound as a solid (770 mg, 88%).
Reaction SMILES: [Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][O:9][CH2:8]2)=[CH:4][C:3]=1[CH3:15].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][O:9][CH2:8]2)=[CH:4][C:3]=1[CH2:15][Br:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(O[C@@H]2CCOC2)cc(C)c1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(O[C@@H]2CCOC2)cc(CBr)c1Br
Temperature: 60 °C
Reaction time: 12 h
Yield: 24.1 %

Procedure:
(R)-3-(4-Bromo-3,5-dimethylphenoxy)tetrahydrofuran 35a (2.27 g, 8.37 mmol), N-bromosuccinimide (1.79 g, 10.04 mmol) and azobisisobutyronitrile (64 mg, 0.42 mmol) were dissolved in 50 mL of carbon tetrachloride. The reaction solution was heated to 60° C. and stirred for 12 hours. The resulting solution was concentrated under reduced pressure, mixed with 50 mL of tert-butyl methyl ether, stirred for 10 minutes, filtered and washed with tert-butyl methyl ether (20 mL×2). The combined filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound (R)-3-(4-bromo-3-(bromomethyl)-5-methylphenoxy)tetrahydrofuran 35b (707 mg, yield 24.2%) as a light yellow solid.
Reaction SMILES: O[C:2]1[C:11]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:13]2[O:20][C:2]3[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=3[N:12]=2)[CH:15]=1
Reactant: COC(=O)c1cccc(NC(=O)c2cccnc2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2nc(-c3cccnc3)oc12
Yield: 67.2 %

Procedure:
Methyl 2-hydroxy-3-(nicotinamido)benzoate (215 mg, 0.79 mmol) and 4-methylbenzenesulfonic acid (400 mg, 2.0 mmol) were added to toluene (10 mL) and the mixture was stirred at reflux for 10 hr. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated to obtain methyl 2-(pyridin-3-yl)benzo[d]oxazole-7-carboxylate as a solid (135 mg, yield 67%); LC-MS (ESI) m/z 255 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].[Cl:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][CH:14]([C:16]1[S:20][C:19]([N:21]=[C:22]=[O:23])=[N:18][N:17]=1)[CH3:15]>C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][CH:14]([C:16]1[S:20][C:19]([NH:21][C:22](=[O:23])[N:5]([CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])[CH3:6])=[N:18][N:17]=1)[CH3:15]
Reactant: CNCC(OC)OC
Reactant: CC(Oc1cccc(Cl)c1)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2cccc(Cl)c2)s1)OC

Procedure:
4.9 grams (0.036 mole) of methylaminoacetaldehyde dimethylacetal was slowly added to a warm 30 milliliter benzene solution containing 10.2 grams (0.036 mole) of the 5-[1-(3-chlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting solution was refluxed for 15 minutes, cooled, topped on a roto-vac at 70° C. to 14.5 grams of a pink solid residue which was recrystallized from a minimum amount of ethylacetate/hexane solution. The fluffy precipitate was filtered off, and dried in a vacuum oven at 80° C. to 10.3 grams of fluffy white crystals of 3-[5-[1-(3-chlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl]-1-methyl-1-(2,2-dimethoxyethyl)urea. Melting point 127°-130° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>>[O:8]=[C:6]1[NH:7][C@@H:3]([CH2:2][O:1][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH2:4][CH2:5]1
Reactant: O=C1CC[C@H](CO)N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC(=O)N2)cc1
Yield: 66.4 %

Procedure:
Using (R)-5-hydroxymethylpyrrolidin-2-one (1.68 g) and p-toluenesulfonyl chloride (2.92 g) and by the reaction and treatment in the same manner as in Preparation Example 219, the title compound (2.61 g) was obtained.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])=[CH:16][CH:15]=1)=[C:8]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:7]([CH3:32])=[CH:6]2.B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])=[CH:16][CH:15]=1)=[C:8]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:7]([CH3:32])=[CH:6]2
Reactant: CCS(=O)(=O)Nc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(O)ccc23)cc1
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To a stirring solution of 271 (0.14 g, 0.31 mmol) in 6 mL CH2Cl2 (6 mL), chilled to −20° C. under N2, was added BBr3 (0.24 g, 0.94 mmol) dropwise, via syringe, over 1 minute. After 90 min at −20° C. the r×n was poured over 50 g ice followed by EtOAc (50 mL). The EtOAC layer was washed with brine (50 mL), dried (Na2SO4) and concentrated to a viscous yellow oil that was purified by column chromatography using a gradient of 100% DCM to 1% MeOH: CH2Cl2 to yield a foam. The foam is crystallized from EtOAc/hexanes to yield the title compound 272, as a light yellow solid (72 mg, 55%). 1H NMR (400 MHz, DMSO-d6): δ 1.13 (t, J=7.3 Hz, 3H), 2.13 (s, 3H), 4.01 (q, J=7.3 Hz, 2H), 6.53 (d, J=8.9 Hz, 2H), 6.94 (d, J=8.9 Hz, 2H), 6.97 (dd, J1=2.3 Hz, J2=9.1 Hz, 1H), 7.11-7.30 (m, 5H), 7.54 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 9.40 (s, 1H), 9.81 (s, 1H).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH:28]3[CH2:30][CH2:29]3)=[CH:20][CH:19]=2)[C:6]([S:9][C:10]([CH3:17])([CH3:16])[C:11]([O:13]CC)=[O:12])=[N:7][N:8]=1>C1COCC1.CO>[Br:3][C:4]1[N:5]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH:28]3[CH2:30][CH2:29]3)=[CH:20][CH:19]=2)[C:6]([S:9][C:10]([CH3:17])([CH3:16])[C:11]([OH:13])=[O:12])=[N:7][N:8]=1
Reactant: CCOC(=O)C(C)(C)Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
Lithium hydroxide solution (1M aqueous, 358 μL, 0.358 mmol, 3 eq) was added to a solution of ethyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate (55 mg, 0.119 mmol) in THF (1 mL) and methanol (0.5 mL), and the mixture stirred for 2 hours at room temperature. The crude reaction mixture was then concentrated, acidified with HCl (1N) and sonicated to break up solids. Filtration gave 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoic acid as an off-white solid (39 mg, 76%).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[C:10]([O:12]C)[CH:9]=[C:8]([O:14]C)[C:7]=1[C:16](=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1>ClCCCl>[Cl:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([OH:14])[C:7]=1[C:16](=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: COc1ccc(CC(=O)c2c(Cl)cc(OC)cc2OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCCl
Product: O=C(Cc1ccc(O)cc1)c1c(O)cc(O)cc1Cl
Temperature: 70 °C
Reaction time: 90 h
Yield: 74.4 %

Procedure:
Boron tribromide (1.0 M soultion in dichloromethane, 5 mL) was added drop-wise to a solution of 1-(2-chloro-4,6-dimethoxyphenyl)-2-(4-methoxyphenyl)ethanone (1.34 g) in 1,2-dichloroethane (25 mL). The solution was heated to 70° C. for 24 h, cooled to room temperature and stirred for 90 h. Additional boron tribromide (1.0 M solution in dichloromethane, 5 mL) was added drop-wise, heating to 70° C. for 12 h. The solution was cooled to −45° C., quenched with methanol (45 mL) and concentrated in vacuo. The solids were redissolved in ethyl acetate (40 mL) and washed with saturated sodium bicarbonate (2×25 mL), 1.2 N HCl (2×25 mL) and brine (2×25 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil was triturated with dichloromethane (150 mL) to provide the title compound (866 mg). 1H NMR (DMSO-d6): 10.35 (s br, 1H), 10.02 (s br, 1H), 9.28 (s br, 1H), 6.94 (d, 2H, J=8.4 Hz), 6.65 (d, 2H, J=8.7 Hz), 6.27 (dd, 2H, J=10.2 Hz, 2.1 Hz), 3.92 (s, 2H); MS: 279 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([CH3:25])[C:9]2[C:14]3=[C:15]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)[N:16]=[C:17]([CH3:18])[N:13]3[N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH3:25])[C:9]2[C:14]3=[C:15]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[C:23]=4[C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=4)[N:16]=[C:17]([CH3:18])[N:13]3[N:12]=[CH:11][N:10]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CN(C)c2ncnn3c(C)nc(-c4cnn(C)c4)c23)cc1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(C)c2ncnn3c(C)nc(-c4cnn(C)c4-c4ccc(C(F)(F)F)cn4)c23)cc1
Temperature: 160 °C
Yield: 56.1 %

Procedure:
N-(4-Methoxybenzyl)-N,7-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[5,1-f][1,2,4]triazin-4-amine (10.0 g, 27.5 mmol), 2-bromo-5-(trifluoromethyl)pyridine (12.4 g, 54.9 mmol) and powdered potassium carbonate (11.4 g, 82.5 mmol) were combined in 1,4-dioxane (90 mL) and heated at reflux for 10 minutes. Allylpalladium chloride dimer (98%, 514 mg, 1.38 mmol) was added, and the reaction was heated for 22 hours at 160° C. in a sealed tube capped with a Q-Tube™ (Q Labtech). The reaction was cooled to room temperature and concentrated in vacuo. The residue was suspended in ethyl acetate, filtered through Celite and concentrated under reduced pressure. Silica gel chromatography (Gradient: 50% to 100% ethyl acetate in heptane) provided a pale brown foam (7.85 g), which was crystallized from heptane (˜100 mL) and ethyl acetate (˜5 mL) to provide the product as a pale brown powder. Yield: 7.00 g, 13.8 mmol, 50%. LCMS m/z 509.1 (M+1). 1H NMR (500 MHz, CDCl3) δ 2.54 (s, 3H), 2.72 (s, 3H), 3.75 (s, 3H), 4.14 (s, 3H), 4.34 (br s, 2H), 6.76 (br d, J=8.8 Hz, 2H), 6.94 (br d, J=8.5 Hz, 2H), 7.39 (d, J=8.3 Hz, 1H), 7.72 (s, 1H), 7.76 (dd, J=8.3, 2.2 Hz, 1H), 7.85 (s, 1H), 8.95-8.96 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7].[I:42]I>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][C:19]([I:42])=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7]
Reactant: II
Reactant: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1ccccc1
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3cc(I)sc3c12)c1ccccc1

Procedure:
By lithiation of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-phenyl-amide and reaction with iodine.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[C:1]([N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)Cl
Reactant: C1CCCNCC1
Product: CCCCCCCC(=O)N1CCCCCC1
Yield: 67.9 %

Procedure:
In a manner similar to that described in Example 1, octanoyl chloride (16.26 g, 0.1M) was treated with hexahydro-1H-azepine (9.92 g, 0.1M). Work up and distillation of the residue gave 15.3 g (68%) of product, b.p. 122/0.8 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:20][CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH:27]([C:30](=O)[CH3:31])[CH2:26][CH2:25]3)=[O:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:4][CH:3]=1.[Cl-].[F:34][C:35]1([F:40])[CH2:39][CH2:38][NH2+:37][CH2:36]1.CC([O-])=O.[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:20][CH2:21][C:22]([N:24]3[CH2:25][CH2:26][CH:27]([CH:30]([N:37]4[CH2:38][CH2:39][C:35]([F:40])([F:34])[CH2:36]4)[CH3:31])[CH2:28][CH2:29]3)=[O:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:6][CH:7]=1
Reactant: FC1(F)CC[NH2+]C1
Reactant: CC(=O)C1CCN(C(=O)CCC2(c3ccc(Cl)cc3)c3ccccc3-c3nccn32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C1CCN(C(=O)CCC2(c3ccc(Cl)cc3)c3ccccc3-c3nccn32)CC1)N1CCC(F)(F)C1
Reaction time: 8 h

Procedure:
To a mixture of 1-(1-{3-[5-(4-chlorophenyl)-5H-imidazo[2,1-a]isoindol-5-yl]propanoyl}piperidin-4-yl)ethanone (27 mg), 3,3-difluoropyrrolidinium chloride (17 mg) and NaOAc (15 mg) in CH2Cl2 was added AcOH (0.01 mL). After stirring the resulting mixture for 30 minutes NaBH(OAc)3 (26 mg) was added and allowed to stir overnight. The reaction mixture was then partitioned between saturated aqueous NaHCO3 and CH2Cl2. Aqueous layer was extracted with CH2Cl2 (2×). Combined organic layers were dried over Na2SO4 and concentrated. Purification by reversed phase HPLC (21×100 mm Phenomenex Gemini, 15-95% MeCN/water containing 0.05% NH4OH over 20 min at 20 mL/min) afforded title compound as a white solid. HRMS. Found, 539.2387; calcd for (M+H)+, 539.2384. 1H NMR (500 MHz, CDCl3): δ 7.86 (d, J=7.62 Hz, 1 H); 7.43-7.38 (m, 1 H); 7.35-7.26 (m, 4 H); 7.25-7.19 (m, 1 H); 7.11 (d, J=8.36 Hz, 2 H); 6.96 (d, J=9.03 Hz, 1 H); 4.54 (d, J=13.34 Hz, 1 H); 3.31 (d, J=13.41 Hz, 1 H); 3.11-3.03 (m, 1 H); 2.91-2.80 (m, 3 H); 2.76-2.61 (m, 3 H); 2.38-2.13 (m, 4 H); 1.69-1.50 (m, 6 H); 0.90-0.83 (m, 4 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1cc(NCc2ccccc2)ccc1Sc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
A solution of the product of Example 62A (0.63 g, 2.4 mmol), benzaldehyde (0.24 g, 2.3 mmol) and sodium cyanoborohydride (0.15 g, 2.4 mmol) in methanol (10 mL) containing 1% acetic acid was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (20 mL) and the resultant solution was concentrated under vacuum to a yellow solid. The solid was dissolved in ethyl acetate (50 mL), and washed with water, 10% sodium bicarbonate and 10% sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and solvent removed under vacuum leaving a light yellow oil. The oil was purified by silica gel chromatography eluting with 1% methanol in methylene chloride to provide the title compound (0.63 g, 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:11].C[O-].[Na+].C[CH2:16][O:17]C(C)=O>CO>[CH3:16][O:17][C:6]1[CH:5]=[CH:4][N+:3]([O-:11])=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc[n+]([O-])c(C)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-methyl-4-nitropyridine 1-oxide (24 g, 0.155 mol) in MeOH (100 mL). Sodium methoxide (10 g, 0.187 mol, Aldrich) was added, and the reaction mixture was stirred for 2 h at 80° C. Reaction progress was monitored by TLC (50% EtOAc in petroleum ether). The reaction mixture was concentrated and water (50 mL) was added and the aqueous solution was extracted with EtOAc (4×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the title compound as a brown liquid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (d, J=7.2 Hz, 1H), 7.14 (d, J=3.3 Hz, 1H), 6.91 (dd, J=3.6, 7.2 Hz, 1H), 3.80 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[C:13]([O:14][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(c1ccc(F)cc1)c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccnc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
A mixture of give 2-(4-fluorobenzoyl)-3-hydroxypyridine (2.2 g, 11.3 mmol), ethyl bromoacetate (1.6 ml, 14.15 mmol) and potassium carbonate (4.34 g, 31.4 mmol) in acetone (40 ml) was heated at reflux. After 3 h, the reaction was cooled to room temperature, filtered and concentrated in vacuo to give ethyl 2-[2-(4-fluorobenzoyl)pyridin-3-yloxy]acetate (3.5 g) which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[C:19]([CH2:34][CH3:35])=[C:20]([CH2:24][CH2:25][N:26]4[CH2:29][CH:28]([C:30]([O:32]C)=[O:31])[CH2:27]4)[CH:21]=[CH:22][CH:23]=3)=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+].Cl>C(O)(C)C.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[C:19]([CH2:34][CH3:35])=[C:20]([CH2:24][CH2:25][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)[CH:21]=[CH:22][CH:23]=3)=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1c(CCN2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of methyl 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)ethyl]-3-azetidinecarboxylate (D32) (59 mg) in isopropanol (3 mL) and water (3 mL) was added sodium hydroxide (50 mg). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with 1 M HCl solution. The solvent was removed in vacuo. The residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)ethyl]-3-azetidinecarboxylic acid (E10) (17 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 0.93 (6H, d), 1.11 (3H, t), 1.99 (1H, m), 2.85 (6H, m), 3.38 (2H, m), 3.61 (1H, m), 4.27 (4H, m), 7.40 (1H, m), 7.51 (2H, t), 7.68 (1H, d), 8.31 (1H, dd), 8.46 (1H, d), 13.04 (1H, br s). MS (ES): C27H30N4O2S requires 474. found 475.2 (M+H+).