Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([S:16]CC2C=CC(OC)=CC=2)([CH3:15])[CH3:14])[CH2:11][C@H:10]([CH2:26][S:27]CC2C=CC(OC)=CC=2)[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O>[CH2:1]([N:8]1[C@H:12]([C:13]([SH:16])([CH3:15])[CH3:14])[CH2:11][C@H:10]([CH2:26][SH:27])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CSC[C@H]2C[C@@H](C(C)(C)SCc3ccc(OC)cc3)N(Cc3ccccc3)C2=O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(S)[C@@H]1C[C@H](CS)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
To a stirred solution of cis-N-benzyl-4-[1-(4-methoxybenzylthio)-1-methylethyl]-2-(4-methoxybenzylthiomethyl )-4-butanelactam (compound No.14-1, 500 mg) in trifluoroacetic acid (4 ml), thioanisol (0.66 ml) and trifluoromethanesulfonic acid (0.50 ml) were added. After stirring for 2 hours at room temperature, the mixture was poured into a mixture of ice and saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and then saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was dissolved in ethanol (3 ml). To the solution sodium borohydride (20 mg) was added and the mixture was stirred for 30 minutes at room temperature. 1N hydrochloric acid was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 50 mg (18%) of the titled compound.
Reaction SMILES: [C:1]([CH:3]([OH:15])[C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1)#[N:2].B.CO.[ClH:19]>O1CCCC1>[ClH:19].[NH2:2][CH2:1][CH:3]([OH:15])[C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: COc1cc(F)c(C(O)C#N)cc1OC
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(F)c(C(O)CN)cc1OC

Procedure:
To a suspension of 3.24 g α-(cyano)-6-fluoro-3,4-dimethoxybenzyl alcohol obtained in Reference Example 1 in 20 ml tetrahydrofuran, was added dropwise 33 ml of 1M solution of borane in tetrahydrofuran with stirring in a methanol/ice bath under an argon gas atmosphere, and the resulting solution was heated under reflux for three hours. After cooling the reaction mixture in an ice bath, methanol was added until gas evolution was no longer observed, the resulting solution was stirred at room temperature for one hour, and hydrogen chloride gas was introduced until the pH fell below 1. The crystals which separated out were collected, affording 3.34 g of α-(aminomethyl)-6-fluoro-3,4-dimethoxybenzyl alcohol hydrochloride, m.p. 223°-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]([CH2:21][CH2:22][C:23]#[N:24])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2.[C:25]1(=[O:31])[NH:29][C:28](=[O:30])[CH:27]=[CH:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:27]2[C:28](=[O:30])[NH:29][C:25](=[O:31])[C:26]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:21][CH2:22][C:23]#[N:24])[C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)cc(/C=C/c1ccccc1Cl)n2CCC#N
Reactant: O=C1C=CC(=O)N1
Product: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCC#N)C(=O)NC3=O
Yield: 80.2 %

Procedure:
Diene (236) (1.30 g, 3.86 mmol) prepared as described in example 96 was reacted with maleimide (0.49 g) following The procedure described in example 68 and then aromatized according to the procedure described in example 70 to give crude material that was chromatographed on silica eluting with ethyl acetate/hexane (1:1). Trituration from methanol gave nitrile (237) (1.33 g, 80%) as a yellow powder, mp 287–288° C. 1H NMR δ [(CD3)2SO] 11.16 (br s, 1H), 8.53 (d, J=2.6 Hz, 1H), 8.02 (s, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.59 (m, 1H), 7.49 (m, 3H), 7.33 (dd, J=9.0, 2.6 Hz, 1H), 4.86 (t, J=6.7 Hz, 2H), 3.91 (s, 3H), 3.04 (t, J=6.7 Hz, 2H). Found: C, 65.32; H, 4.15; N, 9.60. C24H16ClN3O3.3/4H2O requires: C, 65.01; H, 3.98; N, 9.47.
Reaction SMILES: [CH2:1]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[H-].[Na+].Cl[CH2:33][CH:34]([OH:37])[CH2:35][OH:36]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:33][CH:34]([OH:37])[CH2:35][OH:36])=[O:26])=[CH:28][CH:29]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: OCC(O)CCl
Reactant: CCCCCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 8.05 g. of 4-(n-nonadecylamino)benzoic acid in 25 ml. of hexamethylphosphoramide is treated with sodium hydride and then 1-chloro-2,3-propanediol in the manner described in Example 2 to yield 2,3-dihydroxypropyl 4-(n-nonadecylamino)benzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH2:15])=[CH:4][CH:3]=1.[C:23]([NH:25][C:26](=[N:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:40]=1)OC1C=CC=CC=1)#[N:24]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][NH:15][C:26]([NH:25][C:23]#[N:24])=[N:34][CH2:35][CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)[CH:40]=2)[CH3:16])=[CH:4][CH:3]=1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: CN(CCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Solvent: CCOC(C)=O
Product: CN(CCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.5 g (1.57 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,3-propanediamine and 0.6 g (1.5 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography (eluant: ethyl acetate) analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=616 ([M+H]+, 1), 230 (100).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)=[CH:10]3)[C:6]=2[CH:21]=1.[C:22]([N:26]1[CH2:31][CH2:30][CH:29]([SH:32])[CH2:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([N:26]1[CH2:31][CH2:30][CH:29]([S:32][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[CH:10]=[C:9]([C:15]5[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=5)[N:8]=[C:7]4[C:6]=3[CH:21]=2)[CH2:28][CH2:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)N1CCC(S)CC1
Reactant: Brc1ccc2c(c1)-c1nc(-c3cccnc3)cn1CCO2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4cccnc4)cn2CCO3)CC1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of 9-bromo-2-pyridin-3-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (35 mg, 0.10 mmol), 1-tert-butylpiperidine-4-thiol (53 mg, 0.30 mmol), Pd2(dba)3 (9 mg, 10 mol %), XantPhos (12 mg, 20 mol %) and DIPEA (72 μL, 0.41 mmol) in dioxane (2 mL) was purged with argon and heated at 120° C. for 40 min, then 130° C. for 1 h and 140° C. for 1 h using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-20% 2M NH3/MeOH in EtOAc then C18, gradient 2-20% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 153 as an off-white solid (6 mg, 15%). LCMS: RT 2.42 min [M+H]+ 435.1. 1H NMR (CDCl3, 400 MHz): δ 9.03-9.02 (1H, m), 8.75-8.72 (1H, m), 8.51 (1H, dd, J=4.82, 1.67 Hz), 8.21 (1H, d, J=7.88 Hz), 7.35-7.33 (3H, m), 6.99 (1H, d, J=8.26 Hz), 4.52-4.50 (2H, m), 4.46-4.44 (2H, m), 3.03-2.98 (2H, br m), 2.20 (2H, br m), 2.06-1.94 (3H, br m), 1.66-1.62 (2H, br m), 1.06 (9H, br m)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]2[C:20]3=[C:21]4[C:26](=[CH:27][CH:28]=[C:19]3[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=3[O:10]2)[NH:25][C:24]([CH3:30])([CH3:29])[CH:23]=[C:22]4[CH3:31])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:37]1[O:38][CH:39]=[CH:40][CH:41]=1)CCC>CN1CCCC1=O.C(OCC)(=O)C.[F-].[K+]>[O:38]1[CH:39]=[CH:40][CH:41]=[C:37]1[C:2]1[CH:3]=[C:4]([CH:9]2[C:20]3=[C:21]4[C:26](=[CH:27][CH:28]=[C:19]3[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=3[O:10]2)[NH:25][C:24]([CH3:30])([CH3:29])[CH:23]=[C:22]4[CH3:31])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1cccc2c1-c1ccc3c(c1C(c1cc(C)cc(Br)c1)O2)C(C)=CC(C)(C)N3
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cccc2c1-c1ccc3c(c1C(c1cc(C)cc(-c4ccco4)c1)O2)C(C)=CC(C)(C)N3
Temperature: 85 °C
Reaction time: 3 h

Procedure:
A solution of Example 11 (0.253 g, 0.531 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was deoxygenated with nitrogen, treated with 2-(tributylstannyl)furan (0.33 mL, 1.06 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.045 g, 0.005 mmol), heated to 85° C. for 13 hours, cooled to room temperature, diluted with ethyl acetate and saturated KF, stirred for 3 hours, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5-10% ethyl acetate/hexanes to provide the desired compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11]Cl)[CH:5]=[CH:4][C:3]=1[OH:14].C([O-])(=O)C.[K+].C(Cl)(Cl)Cl>CO>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH:10]=[CH2:11])[CH:5]=[CH:4][C:3]=1[OH:14]
Reactant: O=C(CCCl)c1ccc(O)c(Cl)c1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=CC(=O)c1ccc(O)c(Cl)c1Cl
Yield: 83.8 %

Procedure:
A solution of 2,3-dichloro-4-(3-chloropropionyl)phenol (8.4 g, 0.033 mole) in methanol (30 ml) and potassium acetate (3.5 g, 0.033 mole) in methanol (30 ml) were united and refluxed for 20 minutes. The mixture was treated with chloroform (200 ml), washed with water, dried over MgSO4, filtered and the solvent removed from the filtrate by evaporation in vacuo. The residue was recrystallized from carbon tetrachloride to give 6 g of 2,3-dichloro-4-acryloylphenol, m.p. 135°-137° C.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH2:4]([O:6][C:7](OCC)=[CH:8][C:9]([O:11]CC)=O)[CH3:5].O.S(=O)(=O)(O)O>C(O)C.[Cl-].[Na+].O>[CH2:4]([O:6][C:7]1[CH2:8][C:9](=[O:11])[N:2]([CH3:1])[N:3]=1)[CH3:5]
Reactant: CCOC(=O)C=C(OCC)OCC
Reactant: CNN
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC1=NN(C)C(=O)C1
Yield: 42.5 %

Procedure:
Methylhydrazine (2.6 g, 0.056 mole) was added to a solution of ethyl 3,3-diethoxyacrylate (10.0 g, 0.053 mole) in ethanol (50 mL) and the mixture was heated and held at reflux for 18 hours. After cooling, water, saturated brine, and 3 mL of concentrated sulfuric acid were added; and the product was extracted with ethyl acetate. The combined extracts were dried with magnesium sulfate, filtered and concentrated in vacuo. Purification by chromatography on silica gel using ethyl acetate/cyclohexane gave 5-ethoxy-2,4-dihydro-2-methyl-3H-pyrazol-3-one (3.2 g, 42% yield) as a white solid, mp=79°-80° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([C:16]#[C:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13](/[CH:16]=[CH:17]\[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C#CC2CCCCC2)nc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(/C=C\C2CCCCC2)nc1
Yield: 30 %

Procedure:
Add 3-(tert-butoxycarbonylamino-methyl)-6-cyclohexylethynyl-pyridine (0.7 g, 2.21 mmol) and Lindlar's Catalyst (0.1 g) to EtOAc (20 mL). Bubble hydrogen (via balloon) through the mixture for 2 h and stir under static atmosphere of hydrogen overnight. Filter the catalyst through Celite® and concentrate the filtrate in vacuo. Purify the crude mixture by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 9:1 gradient over 1.25 h, 80 mL/min) to obtain the desired intermediate as a colorless oil (0.21 g, 30%) and starting material (0.42 g, 60%). Repeat the reaction on the recovered starting material to obtain the desired intermediate (242 mg, 57%; 452 mg total, 64% overall). MS (APCI+) m/z: 217 (M-Boc+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1F)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>CS(C)=O>[CH2:18]([S:25][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[F:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: SCc1ccccc1
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(SCc2ccccc2)c(F)c1
Temperature: 75 °C
Yield: 95.6 %

Procedure:
3,4-Difluorobenzoic acid (964 mg, 6.1 mmol, 1 eq), cesium carbonate (3.97 g, 12.1 mmol, 2 eq) and benzyl mercaptan (763 mg, 6.14 mmol, 1 eq) were combined in dimethyl sulphoxide (5 ml) and the reaction mixture heated at 75° C. for 4 hours. The reaction mixture was poured into ethyl acetate (10 ml) then extracted into water (10 ml). The aqueous phase was acidified with 2M HCl, extracted into ethyl acetate (10 ml), dried over sodium sulphate, filtered and evaporated to yield the title compound as a white solid (1.53 g, 5.83 mmol, 95%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)=[CH:14][C:12]=2[CH:13]=1.[O-:26][Mn](=O)(=O)=O.[K+].[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O.O>[CH3:1][C@@H:2]1[CH2:6][CH2:5][C:4](=[O:26])[N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=3)=[CH:14][C:12]=2[CH:13]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H]1CCC(=O)N1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Yield: 2 %

Procedure:
The mono-(L)-tartaric acid salt of the product of Example 1D (96 mg, 0.20 mmol) was suspended in acetone (10 mL) and treated with a solution of KMnO4 (158 mg, 1.0 mmol) and MgSO4 (120 mg, 1.0 mmol) in water (5 mL) over 30 minutes. After the purple color had disappeared, the solids were filtered off. The filtrate was diluted with EtOAc, washed with aqueous potassium dihydrogen phosphate, concentrated, and purified by HPLC [Waters Nova-Pak HR C18 column (25 mm×100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN/0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL/min.] to provide the title compound (2% yield). MS (ESI APCI) m/z 345 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.22 (d, 3 H), 1.55-1.64 (m, 1 H), 2.15-2.32 (m, 2 H), 2.34-2.42 (m, 1 H), 2.99-3.13 (m, 2 H), 3.39-3.46 (m, 1 H), 3.68-3.76 (m, 1 H), 3.89-3.97 (m, 1 H), 6.65 (s, 1 H), 7.51-7.56 (m, 2 H), 7.76-7.84 (m, 5 H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][C:3]=1[CH:21]=[CH2:22].[H][H]>CO.[Pd]>[CH2:21]([C:3]1[CH:4]=[C:5]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH:6]=[N:7][C:2]=1[CH3:1])[CH3:22]
Reactant: C=Cc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1C
Reaction time: 24 h
Yield: 45.5 %

Procedure:
6-Methyl-5-vinyl-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (0.26 g, 0.86 mmol, from Example 35 above) was dissolved in MeOH (15 mL) and treated with 10% Pd/C (50 mg) and 1 atm hydrogen gas. After 1 day, the catalyst was removed, the solvent evaporated, and the residue was chromatographed (silica gel; hexanes-EtOAc, 1:1) to provide 5-ethyl-6-methyl-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)pyridine (0.12 g, 45%): MS (CI/NH3) m/z: 307 (M+H)+; 1H NMR (300 MHz, CDCl3) δ1.23 (t, J=7 Hz, 3H), 1.42 (s, 9H), 2.23-2.38 (m, 2H), 2.47 (s, 3H), 2.60 (q, J=7 Hz, 2H), 3.86-3.93 (m, 2H), 4.12 (dd, J=3, 9 Hz, 1H), 4.29 (dd, J=5,10 Hz, 1H), 4.43-4.53 (m, 1H), 7.04 (d, J=3 Hz, 1H), 8.05 (d, J=3 Hz, 1H). The product from above (0.26 g, 0.85 mmol) was treated with 10 mL of 1:1 TFA-methylene chloride at 0° C. for 1 hour. The residue was diluted with saturated sodium bicarbonate and extracted into CHCl3. The organic layer was washed with water, dried over MgSO4, and evaporated to provide of the free base of the title compound (132 mg, 75%). This was dissolved in ether and treated with 1 M HCl in ether and the resulting salt collected by filtration to provide the title compound (52 mg, 25%). The mother liquor was evaporated to further provide 73 mg of the title compound: mp 150-153° C.; [α]D −7.6 (c 0.62, MeOH); 1H NMR (300 MHz, CD3OD) δ1.34 (t, J=7 Hz, 3H), 2.63-2.76 (m, 2H), 2.72 (s, 3H), 4.04-4.19 (m, 2H), 4.49-4.63 (m, 2H), 4.88-4.97 (m, 1H), 8.14 (d, J=2 Hz, 1H), 8.40 (d, J=2 Hz, 1H); MS (CI/NH3): m/z 207 (M+H+). Anal. Calcd for C12H18N2O.2HCl.0.1 H2O: C, 51.29; H, 7.25; N, 9.97. Found: C, 51.21; H, 7.14; N, 9.77.
Reaction SMILES: [S:1]1[C:5]([CH:6]=[CH:7][C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.O1CCCC1.C1([Li])C=CC=CC=1.[Br:29][CH2:30][CH2:31][CH2:32]Br>C1CCCCC1>[S:1]1[C:5]([CH:6]=[CH:7][C:8]2[S:9][C:10]([CH2:32][CH2:31][CH2:30][Br:29])=[CH:11][CH:12]=2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2
Reactant: BrCCCBr
Reactant: C(=Cc1cc2ccccc2s1)c1cccs1
Agent: [Li]c1ccccc1
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: BrCCCc1ccc(C=Cc2cc3ccccc3s2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a stirred, chilled (-65° C.) solution of 2-[2-(benzo[b]thiophen-2-yl)-ethenyl]thiophene (8.1 g) and tetrahydrofuran (100 ml) was added over 15 mins phenyl lithium (18 ml of a 2.0M solution in cyclohexane). The mixture was stirred for 1 hr, and 1,3-dibromopropane (40.5 g) was added. The solution was allowed to warm to room temperature, and was refluxed overnight. The reaction mixture was quenched with methanol (30 ml) and water (100 ml). The organic phase was evaporated in vacuo, and the residue was extracted with dichloromethane. The combined, dried over anhydrous sodium sulfate organic phase was concentrated. The residue was purified by high pressure liquid chromatography (silica gel, eluted with 7:1 hexane: dichloromethane). The appropriate fractions were combined and evaporated to yield 2.15 g (18%) of product, mp 109°-111° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:44][C:45]1[N:50]=[CH:49][C:48](O)=[CH:47][N:46]=1>O1CCCC1.C(OCC)(=O)C>[Cl:44][C:45]1[N:50]=[CH:49][C:48]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)=[CH:47][N:46]=1
Reactant: CN1CCC(O)CC1
Reactant: Oc1cnc(Cl)nc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(Oc2cnc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 100 mg (0.766 mmol) of 4-hydroxy-1-methyl piperidine in 1.5 ml of tetrahydrofuran, 155 mg (1.53 mmol) of di-tert-butyl azocarboxylic acid, 402 mg (1.53 mmol) of triphenylphosphine and 0.170 ml (1.53 mmol) of 2-chloro-5-hydroxypyrimidine were added, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate was added to the reaction solution and the reaction solution was extracted with 1 N hydrochloric acid. 1 N sodium hydroxide aqueous solution was added to the aqueous layer to make its pH 10 and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to provide 152 mg of the title compound as a white solid (yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.C(C1NC(C=O)=C(C)N=1)C.[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:37][C:36](=[O:38])[CH2:35][C:34](=[O:39])[O:33]2)[CH:27]=[CH:26][C:25]=1[C:45]([CH3:49])([CH3:48])[C:46]#[N:47].C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=CC(=O)O2)CCCC1>>[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44]3)[CH2:37][C:36]([OH:38])=[C:35]([CH2:11][C:9]3[N:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)[C:34](=[O:39])[O:33]2)[CH:27]=[CH:26][C:25]=1[C:45]([CH3:49])([CH3:48])[C:46]#[N:47]
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Agent: CCc1nc(C)c(C=O)[nH]1
Product: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(Cl)cn4n3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example A(97) where 6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde and 2-{2-Chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrile from Example A(147) (was substituted in place of 2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile. 1H NMR (400 MHz, CDCl3) δ: 1.17-1.59 (m, 8H), 1.56-1.6 (m, 2H)), 1.82 (s, 6H), 1.88-2.01 (m, 2H), 2.31-2.79 (m, 3H), 3.79 (d, J=16 Hz, 1H), 3.89 (d, J=16 Hz, 1H), 7.34-7.52 (m. 3H), 8.91 (d, J=2.5 Hz, 1H), 9.63 (d, J=2.5 Hz, 1H), 10.9 (s, 1H). C28H29Cl2N5O3: C, 60.65; H, 5.27; N, 12.63. Found: C, 60.45; H, 5.19; N, 12.40. MS (ESI): 555.2(M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[NH:22][CH3:23]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:22]([C:21]4[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=4[Cl:19])[CH3:23])=[O:17])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1
Reactant: CNc1ccccc1Cl
Reactant: O=C(O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl

Procedure:
Following Example 10 and General Procedure C, 150 is prepared from 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid 11 and 2-chloro-N-methylaniline. MS: (ESI+) 449.9.