Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[CH:6]=[C:7]([CH:9]=[O:10])[S:8][C:4]=2[CH:3]=1.[F:13][C:14]([F:22])([F:21])[CH2:15][CH2:16][B-](F)(F)F.[K+]>>[F:13][C:14]([F:22])([F:21])[CH2:15][CH2:16][C:2]1[CH:12]=[CH:11][C:5]2[CH:6]=[C:7]([CH:9]=[O:10])[S:8][C:4]=2[CH:3]=1
Reactant: O=Cc1cc2ccc(Br)cc2s1
Reactant: F[B-](F)(F)CCC(F)(F)F
Agent: [K+]
Product: O=Cc1cc2ccc(CCC(F)(F)F)cc2s1
Yield: 79.3 %

Procedure:
The compound was synthesized as in Example 3.1 using 6-bromobenzothiophene-2-carbaldehyde (50 mg, 0.21 mmol) in place of 5-bromo-2-formylfuran and potassium (3,3,3-trifluoro)propyltrifluoroborate (63 mg, 0.31 mmol) in place of hexylboronic acid to give 6-(3,3,3-trifluoropropyl)benzothiophene-2-carbaldehyde (43 mg, 80%). Used without further characterization.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([CH2:11][CH2:12][CH2:13][CH3:14])=[C:6](Cl)[N:5]=1)(=[O:3])[NH2:2].C(C1C=C(Cl)C(CCCC)=C(N)N=1)(=O)N.[H][H]>CO.[Pd]>[C:1]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: CCCCc1c(N)cc(C(N)=O)nc1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: CCCCc1c(Cl)cc(C(N)=O)nc1N
Solvent: CO
Product: CCCCc1cnc(C(N)=O)cc1N

Procedure:
11.4 g (0.05 mol) of the isomer mixture of 2-carbamoyl-4-amino-5-n-butyl-6-chloro-pyridine and 2-carbamoyl-4-chloro-5-n-butyl-6-amino-pyridine, dissolved in 120 ml of pure methanol, are hydrogenated in the presence of 1.5 g of palladium on charcoal. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is rendered alkaline with 2 N sodium carbonate solution and extracted with ether. The crystalline product which is soluble in neither sodium carbonate solution nor in ether is filtered off and rinsed with water. The white crystals are dried for 20 hours at 70° in a high vacuum. 2-Carbamoyl-4-amino-5-n-butyl-pyridine of the formula ##STR33## and of melting point 186°-190° is thus obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1>C(O)CCCCCCC>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[C:6]([O:8][CH2:6][CH2:7][CH2:2][CH2:3][CH2:9][CH2:10][CH2:11][CH3:12])[CH:7]=1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ncc(O)cc3F)cc2)CC1
Solvent: CCCCCCCCO
Product: CCCCCCCCOc1cnc(-c2ccc([C@H]3CC[C@H](CCCCC)CC3)cc2)c(F)c1

Procedure:
Octanol and 3-fluoro-5-hydroxy-2-[4-(trans-4-pentylcyclohexyl)phenyl]pyridine are reacted analogously to Example 2 to give 3-fluoro-5-octyloxy-2-[4-(trans-4pentylcyclohexyl)phenyl]pyridine. ##STR38##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:11]2)[CH:3]=1.[C:27]([C:29]1[C:34]([F:35])=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[F:39])#[N:28].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.O1CCOCC1>[C:27]([C:29]1[C:34]([F:35])=[CH:33][C:32]([C:2]2[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]3[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:11]3)[CH:3]=2)=[CH:31][C:30]=1[F:39])#[N:28]
Reactant: N#Cc1c(F)cc(B(O)O)cc1F
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide (500 mg, 1.34 mmol) and (4-cyano-3,5-difluorophenyl)boronic acid (318 mg, 1.74 mmol, 1.3 equiv), Pd2(dba)3 (92 mg, 0.10 mmol, 0.075 equiv), tricyclohexylphosphine (56 mg, 0.20 mmol, 0.15 equiv), and K3PO4 (483 mg, 2.27 mmol, 1.7 equiv) were charged to a 30 mL microwave vial, followed by addition of 1,4-dioxane (10 mL) and water (3.3 mL). The mixture was bubbled with argon for 10 minutes, and heated at 100° C. for 20 hours. After cooling to room temperature, the mixture was filtered through celite, and the filtrate was concentrated in vacuo. The resulting residue was partitioned between EtOAc (50 mL) and brine (15 mL), and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc afforded the title compound (470 mg) as a yellow/greenish gum. LC-MS (ES) m/z=477 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][NH:25][C:26](=[O:32])[CH:27]([CH3:31])[C:28](O)=[O:29])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][NH:25][C:26](=[O:32])[CH:27]([CH3:31])[C:28]([NH:1][CH:2]2[C:8](=[O:9])[N:7]([CH3:10])[C:6]3[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=3[C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]2=3)=[O:29])=[CH:22][CH:21]=1
Reactant: CC(C(=O)O)C(=O)NCc1ccc(F)cc1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: CC(C(=O)NCc1ccc(F)cc1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=446.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(4-fluoro-benzyl)-2-methyl-malonamic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.Cl[C:19]([O:21][CH3:22])=[O:20]>ClCCl>[CH3:22][O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:20]
Reactant: COC(=O)Cl
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 53.5 %

Procedure:
To a mixture of 6.0 mg (0.026 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.0 mg (.07 mMol) polyvinylpyridine in 3.0 mL dichloromethane were added 2.4 mg (0.0273 mMol) methyl chloroformate. The reaction mixture was mixed for 2 days at ambient temperature. To this mixture were then added 90 mg (0.073 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was then filtered and the volatiles evaporated to give 4.0 mg (53%) of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[F:14][C:15]([Si](C)(C)C)([F:17])[F:16]>O1CCCC1.CN(C)C=O>[F:14][C:15]([F:17])([F:16])[CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[OH:7]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OC(c1ccsc1)C(F)(F)F
Yield: 53 %

Procedure:
According to Reference Example 8-2, by use of thiophene-3-carbaldehyde (300 mg, 2.67 mmol) dissolved in tetrahydrofuran (4.5 mL) and N,N-dimethylformamide (1.5 mL), potassium carbonate (74 mg, 0.53 mmol) and (trifluoromethyl)trimethylsilane (0.772 mL, 5.34 mmol), the mixture was stirred and reacted at room temperature for 16 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=100/1) was performed to give 2,2,2-trifluoro-1-(thiophen-3-yl)ethanol (Compound DO) (258 mg, yield: 53%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([NH:14][C:15]3[CH:39]=[CH:38][C:18]([C:19]([N:21]([CH3:37])[C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=4[O:29]CC4C=CC=CC=4)=[O:20])=[CH:17][C:16]=3[O:40][CH3:41])=[O:13])[C:5]=2[N:4]=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH2:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([NH:14][C:15]3[CH:39]=[CH:38][C:18]([C:19]([N:21]([CH3:37])[C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=4[OH:29])=[O:20])=[CH:17][C:16]=3[O:40][CH3:41])=[O:13])[C:5]=2[N:4]=1
Reactant: [H][H]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCc2ccccc2)ccc1NC(=O)c1cccc2[nH]c(CN)nc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2O)ccc1NC(=O)c1cccc2[nH]c(CN)nc12
Yield: 84.7 %

Procedure:
A solution of 4-(2-aminomethyl-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-(2-benzyloxy-4-methylphenyl)benzamide (120 mg) in methanol (15 ml) was stirred under atmospheric pressure of hydrogen in the presence of palladium hydroxide (20 mg) at ambient temperature overnight. After removal of the catalyst by filtration, the filtrate was evaporated in vacuo to give 4-(2-aminomethyl-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-(2-hydroxy-4-methylphenyl)benzamide (85 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[C:15]2[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)=[N:13][CH:12]=[N:11][C:10]=2[S:9][C:8]=1[CH3:28]>>[N:1]1([C:12]2[N:13]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:15]3[CH:7]=[C:8]([CH3:28])[S:9][C:10]=3[N:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1sc2ncnc(NCCc3ccc4c(c3)OCO4)c2c1Cl
Product: Cc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 5-chloro-6-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Li].[CH3:2][Si:3](Cl)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.II.[F:19][C:20](F)=[CH2:21]>O1CCCC1>[F:19][C:20]([Si:3]([CH3:2])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:21]
Reactant: C=C(F)F
Reactant: C[Si](Cl)(c1ccccc1)c1ccccc1
Agent: II
Agent: [Li]
Solvent: C1CCOC1
Product: C=C(F)[Si](C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of lithium wire (2.08 g, 300 mmol) in dry tetrahydrofuran (150 ml) was added methyldiphenylsilyl chloride (15.8 ml, 75 mmol) and a catalytic amount of iodine. The reaction mixture was sonicated for 40 min and then stirred overnight at room temperature. The reaction mixture was cooled to −78° C. and 1,1-difluoroethylene (approx. 225 mmol) was passed through the mixture for 30 min. The mixture was stirred at −78° C. for 2 h and then warmed to room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with cyclohexane (×2). The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, 1 kg) eluting with hexane, followed by cyclohexane. The appropriate fractions were combined and concentrated to give Preparation 83 (7 g) as a colourless oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:4]([N:6]1[CH2:14][C@H:13]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[CH2:30])[CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH2:12][C@H:7]1[C:8]([O:10][CH3:11])=[O:9])=[O:5]>ClCCCl.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:31]1([C@H:3]([NH:2][CH2:20][CH2:19][CH2:18][CH2:17][CH:22]=[CH2:21])[C:4]([N:6]2[CH2:14][C@H:13]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[CH2:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:12][C@H:7]2[C:8]([O:10][CH3:11])=[O:9])=[O:5])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: C=Cc1cccc(-c2cccc(CO[C@@H]3C[C@@H](C(=O)OC)N(C(=O)[C@@H](N)C4CCCCC4)C3)c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: C=CCCCCN[C@H](C(=O)N1C[C@H](OCc2cccc(-c3cccc(C=C)c3)c2)C[C@H]1C(=O)OC)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Et3N (2.0 eq.), hex-5-enal (1.0 eq.) (obtained from hex-5-en-1-ol via a PCC oxidation and sodium triacetoxyborohydride (1.3 eq.) were sequentially added to a 0.07 M solution of methyl (4R)-1-[(2S)-2-amino-2-cyclohexylacetyl]-4-[(3′-vinylbiphenyl-3-yl)methoxy]-L-prolinate hydrochloride 108 in DCE. The reaction mixture was stirred at RT for 2 h then it was diluted with DCM, saturated aqueous NaHCO3 and extracted. The collected organic layers were washed with brine, dried (Na2SO4) and evaporated under reduced pressure to yield a residue that was purified by flash chromatography (SiO2, PE:EtOAc=7:3) to afford the title compound 109 (67%) as a colourless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8]1.[CH3:17][O:18][NH:19][C:20](=O)[O:21]C1C=CC([N+]([O-])=O)=CC=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH3:17][O:18][NH:19][C:20]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:16][CH:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:21]
Reactant: CONC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(C2CCc3ccccc3N2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)N1c2ccccc2CCC1c1ccccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
A solution of 2-pyridin-2-yl-1,2,3,4-tetrahydroquinoline (0.723 g, 3.44 mmol) in methylene chloride (10.3 mL) was treated with 4-nitrophenyl methoxycarbamate (0.948 g, 4.47 mmol) (Org. Process Res. Dev. 2012, 16, 109-116) followed by the dropwise addition of N,N-diisopropylethylamine (1.20 mL, 6.88 mmol), and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was then poured over water (25 mL) and saturated sodium bicarbonate (25 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a crude oily solid. Purification by flash column chromatography (100% hexanes to 20% ethyl acetate/hexanes [the ethyl acetate contained 5% methanol]) gave the desired product (0.923 g, 95%) as a racemic mixture. LCMS calculated for C16H18N3O2 (M+H)+: m/z=284.1. found: 284.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[CH:8]=2)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2cc(Cl)cc(Cl)c2)sc1C(=O)NCc1ccccc1
Yield: 34 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3,5-dichlorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 34% yield; m.p. 104-105° C.; 1H NMR (CDCl3, 300 MHz) δ 7.69 (d, J=1.9 Hz, 2H), 7.52 (t, J=1.9, 1H), 7.35-7.31 (m, 5H), 6.04 (t, J=5.6 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 2.44 (s, 3H); MS (ES+) m/z 420 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[Cl-].[NH4+].[C:30]([O:33][CH2:34][CH3:35])(=[O:32])[CH3:31]>C(OCC)(=O)CC(OCC)=O.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(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[CH2:34]([O:33][C:30](=[O:32])[CH:31]([C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1)[C:30]([O:33][CH2:34][CH3:35])=[O:32])[CH3:35]
Reactant: CCOC(C)=O
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccccc2C)ccn1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)c1ccc([C@H](CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1
Temperature: 135 °C
Yield: 71 %

Procedure:
To a solution of (S)-3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (600 mg) in diethyl malonate (11 mL) were added sodium hydride (124 mg), tris(dibenzylideneacetone)dipalladium(0) (81.4 mg) and 2-(di-tert-butylphosphino)biphenyl (26.5 mg) at room temperature. The reaction mixture was stirred at 135° C. for 1½ h. A saturated aq. solution of ammonium chloride and ethyl acetate were added, the phases were separated and the inorganic one was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10% to 70% ethyl acetate in n-heptane) to yield the title compound as a light yellow oil (514 mg, 71%), MS (ESI+): m/z=474.3 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14]/[CH:15]=[C:16](\[CH3:22])/[CH2:17][CH2:18][CH2:19][C:20]#N.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.[OH:39]S(O)(=O)=O>CC(OC)(C)C.O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14]/[CH:15]=[C:16](\[CH3:22])/[CH2:17][CH2:18][CH2:19][CH:20]=[O:39]
Reactant: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCC#N)c1C
Reactant: O=S(=O)(O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: COC(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCC=O)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enenitrile (178 mg, 0.59 mmol) was dried azeotropically with toluene in vacuo (3×2 mL), redissolved into toluene (3 mL) and cooled to 0° C. DIBALH (1.0 M in heptane, 0.9 mmol) was added over 3 minutes dropwise. After 1 h, H2O (2 ml) and aqueous H2SO4 (6 mL 2.5 M) were added and the mixture let warm to room temperature for 2.5 h. MTBE (5 mL) was added, the layers separated and the aqueous phase extracted 3×5 mL MTBE. The combined organics were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated to give (E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enal as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][N:34]=2)[CH2:13][C:14](=[O:32])[N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH2:17][CH2:16]2)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[BH-](O[C:51]([CH3:53])=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.N1CCCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([C:33]2[CH:40]=[CH:39][C:36]([CH2:37][N:8]3[CH2:53][CH2:51][CH2:5][CH2:6][CH2:7]3)=[CH:35][N:34]=2)[CH2:13][C:14]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH2:17][CH2:16]2)=[O:32])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: Cc1cc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2ccc(C=O)cn2)cc2cn[nH]c12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CC(Cl)Cl
Product: Cc1cc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2ccc(CN3CCCCC3)cn2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of (±)-6-(1-(7-methyl-1H-indazol-5-yl)-4-oxo-4-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)butan-2-yl)nicotinaldehyde (previous example, 8 mg, 0.015 mmol, 1.0 equiv.) in dichloroethane (1 mL) was treated with by 2 drops of piperidine. Excess Na(OAc)3BH was added and the reaction mixture was stirred at room temperature overnight. The mixture was directly purified by flash column chromatography (10% of 2M ammonia in methanol in methylene chloride) afforded the desired product (10.1 mg, 72% for two steps).
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[CH:10]\[CH3:11])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:40]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[F:18][C:14]1[CH:13]=[C:12]([C:9](=[O:8])[C@H:10]([OH:40])[CH3:11])[CH:17]=[CH:16][CH:15]=1
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(F)c1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@@H](O)C(=O)c1cccc(F)c1
Yield: 87.2 %

Procedure:
Compound 10c was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(3-fluorophenyl)prop-1-enyloxy)dimethylsilane, (9c, 8.0 g, 0.030 mol), AD-mix-β (42.1 g), and CH3SO2NH2 (2.90 g, 0.0301 mol) in tert-butyl alcohol-water (120 mL:120 mL). The reaction was quenched with sodium sulfite (30.1 g). After purification, 4.4 g (87%) of the desired product 10c was isolated: [α]20D +58.1° (c 3.2, CHCl3); 1H NMR (CDCl3) δ 7.74-7.59 (m, 2H), 7.54-7.45 (m, 1H), 7.37-7.28 (m, 1H), 5.19-5.07 (m, 1H), 1.76 (d, 1H, J=6.3 Hz), 1.46 (d, 3H, J=6.9 Hz); 13C NMR (CDCl3) δ 201.6, 164.9, 131.0, (d), 124.7, 121.3 (d), 115.8 (d), 69.9, 22.4. C9H9FO2.
Reaction SMILES: [O:1]1[CH:5]([CH2:6][NH2:7])[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[C:2]1=2.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].CC1C=CC(S(OC)(=O)=O)=CC=1>>[O:1]1[CH:5]([CH2:6][NH:7][C:26](=[O:27])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[C:2]1=2
Reactant: NCC1Cc2ccc3c(c2O1)CCCC3
Reactant: O=C(Cl)OCc1ccccc1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2ccc3c(c2O1)CCCC3)OCc1ccccc1
Yield: 79.1 %

Procedure:
Treatment of (±)-1-(2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-yl)methanamine (0.846 g, 4.16 mmol) with diisopropylethylamine (0.592 g, 4.58 mmol) followed by benzyl chloroformate (0.745 g, 4.37 mmol) generally according to the procedure described for Intermediate 7 provided 1.11 g (79%) of (±)-benzyl 2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-ylmethylcarbamate as a white solid. Rf=0.39 (silica, ethyl acetate:hexanes 1:4); mp 88-90° C.; 1H NMR (DMSO-d6) δH 7.49 (t, 1H); 7.33 (m, 4H); 6.87 (d, 1H); 6.50 (d, 1H); 5.02 (s, 2H); 4.76 (m, 1H); 3.20 (m, 3H); 2.83 (dd, 1H); 2.62 (s, 2H); 2.49 (m, 2H); 1.67 (m, 4H). Chiral HPLC separation of (±)-benzyl 2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-ylmethylcarbamate (Chiralcel OJ, isopropanol:hexane 9:1) provided two fractions. Fraction 1 (Rt=11.576 min, Chiralcel OD, isopropanol:hexanes 1:9); Fraction 2 (Rt=14.729 min, Chiralcel OD, isopropanol:hexanes 1:9).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[I:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.O>CN(C=O)C>[I:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][C:8]1[S:9][CH:10]=[CH:11][N:12]=1
Reactant: Brc1nccs1
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1cccc(Oc2nccs2)c1
Temperature: 135 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
Cesium carbonate (4.52 g, 13.87 mmol) was added to 2-bromo-1,3-thiazole (1.90 g, 11.6 mmol) and 3-iodophenol (2.54 g, 11.5 mmol) in anhydrous DMF (30 mL). The reaction was heated to 135° C. and stirred at this temperature overnight. The reaction was allowed to cool, then was poured into water (100 mL), and extracted with EtOAc (3×100 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated. The crude product was purified via flash chromatography using a Varian SF15-24 g column and an eluent of EtOAc in hexanes (0-10%) to afford the title compound as a yellow oil (2.52 g, 71.8%). MS (LCMS) m/z 304.1 (M+1).