Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C)C=O.N1C=CN=C1.Cl[Si:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>O>[CH3:26][Si:21]([CH3:27])([C:22]([CH3:25])([CH3:24])[CH3:23])[O:9][CH2:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 6.2 parts of 2-amino-3-pyridinemethanol in 23.5 parts of N,N-dimethylformamide there were added 6.8 parts of 1H-imidazole and 7.5 parts of chlorodimethyl(1,1-dimethylethyl)silane. The whole was cooled for 10 min in an ice-bath and was stirred overnight at room temperature. The reaction mixture was diluted with 100 parts of water and the product was extracted with 1,1'-oxybisethane (2x). The combined extracts were washed with water and NaCl (sat.), dried, filtered and evaporated, yielding 11.1 parts (93.1% ) of 3-[[dimethyl(1,1-dimethylethyl)silyloxy]methyl]-2-pyridinamine (interm. 1).
Reaction SMILES: [CH3:1][C:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)([CH3:7])[C:3]([O:5]C)=[O:4].[OH-].[K+].O>O1CCOCC1>[CH3:7][C:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)c1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C(=O)O)c1cccs1
Temperature: 0 °C
Yield: 97.7 %

Procedure:
A solution containing 17.5 g of methyl 2-methyl-2-(2-thienyl)propionate [prepared as described in step (i) above], 12.6 g of potassium hydroxide, 72 ml of water, and 168 ml of 1,4-dioxane was heated under reflux for 2 hours. At the end of this time, it was diluted with ice-water, and extracted twice with diethyl ether. The aqueous layer was adjusted to a weakly acidic pH, extracted three times with diethyl ether, washed with water and with a saturated aqueous solution of sodium chloride, in that order, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure to give 15.8 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[N:17]=[C:18]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:19]2[S:24][C:23]([CH:25]=O)=[CH:22][C:20]=2[N:21]=1.COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:15][C:16]1[N:17]=[C:18]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[C:19]2[S:24][C:23]([CH2:25][N:11]3[CH2:10][CH2:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:14])[CH2:13][CH2:12]3)=[CH:22][C:20]=2[N:21]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: COC(OC)OC
Product: OC1(c2ccc(Cl)cc2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-(4-chlorophenyl)-4-hydroxypiperidine (368 mg, 1.74 mmol) in dichloroethane was added 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 (400 mg, 1.41 mmol) and trimethylorthoformate. After stirring for 1 hour at room temperature, sodium triacetoxyborohydride was added and the reaction mixture stirred overnight. The mixture was quenched with saturated aqueous Na2CO3. Chloroform/brine extraction gave crude material which was then triturated with hot ethyl acetate to give 1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-4-(4-chloro-phenyl)-piperidin-4-ol. (272 mg, 0.56 mmol).
Reaction SMILES: [CH3:1][C:2]([CH2:26][CH3:27])=[CH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[N:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:7](=[O:13])[NH:8]2.CC(=CC)CC1C=CC=C2C=1C(=NNC1C=CC(S(N)(=O)=O)=CC=1)C(=O)N2>>[CH3:1][CH:2]([CH2:26][CH3:27])[CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[N:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:7](=[O:13])[NH:8]2
Reactant: CCC(C)=Cc1cccc2c1C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Agent: CC=C(C)Cc1cccc2c1C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Product: CCC(C)Cc1cccc2c1C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 79 %

Procedure:
Reduction of the mixture of 4-{N′-[4-(2-methyl-1-butenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazino}-benzenesulfonamide and 4-{N′-[4-(2-methyl-2-butenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazino}-benzenesulfonamide according to Procedure M gave the title compound in 79% yield: 1H NMR (DMSO-d6): δ 0.87–0.90 (m, 6H), 1.21–1.25 (m, 2H), 1.47–1.63 (m, 1H), 2.82 (dd, J=12.6, 8.1 Hz, 1H), 2.95 (dd, J=12.6, 6.6 Hz, 1H), 6.77 (d, J=7.7 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 7.18 (t, J=7.7 Hz, 1H), 7.25 (s, 2H), 7.49 (d, J=8.6 Hz, 2H), 7.79 (d, J=8.6 Hz, 2H), 11.12 (s, 1H), 13.04 (s, 1H); APCI-MS m/z 385 (M−1)−.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH:11]=[C:12](O)[CH3:13])=[CH:5][CH:4]=1)[CH3:2].O.[NH2:17][NH2:18]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[C:12]([CH3:13])[NH:18][N:17]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CC(=O)C=C(C)O)cc1
Reactant: NN
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2cc(C)[nH]n2)cc1
Temperature: 100 °C

Procedure:
A solution of the above 1-(4-ethylphenyl)-4-hydroxy-3-penten-2-one (3.98 g) and hydrazine hydrate (4.0 ml) in toluene (20 ml) was stirred under heating at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=2:1) to give 3-(4-ethylphenylmethyl)-5-methyl-1H-pyrazole (3.12 g) as yellow oil. APCI-Mass m/Z 201 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]1[C:24]([NH2:32])=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[CH:26]2.C1(C)C(C)=CC=CC=1.[Cl-].[Na+]>C(OCC)(=O)C>[F:16][C:13]([F:14])([F:15])[C:10]([CH:11]=[N:32][C:24]1[C:23]([CH3:22])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][NH:28]2)([OH:17])[CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[O:20][CH3:21])([CH3:19])[CH3:18]
Reactant: Cc1ccc2[nH]ncc2c1N
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: COc1c(F)cccc1C(C)(C)CC(O)(C=Nc1c(C)ccc2[nH]ncc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal (308 mg, 1.0 mmol) and 5-methyl-1H-indazol-4-ylamine (148 mg, 1.0 mmol) are introduced into 15.0 ml of xylene and mixed with titanium(IV)ethylate (0.42 ml, 2.0 mmol). After 3 hours under reflux, the reaction mixture is allowed to cool to room temperature. After ethyl acetate and saturated sodium chloride solution are added, it is stirred vigorously for 30 minutes at room temperature. The deposited precipitate is suctioned off, the aqueous phase is separated, and the organic phase is dried on sodium sulfate. The purification is carried out by means of chromatography on silica gel with hexane/ethyl acetate (30-40% ethyl acetate). 345 mg (79% of theory) of 1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-[(5-methyl-1H-indazol-4-ylimino)methyl]-pentan-2-ol is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH3:29])[CH:21]=2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([OH:7])[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH3:29])[CH:21]=2)=[CH:30][CH:31]=1
Reactant: CCCOc1cccc(-c2cc(=O)n(C)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1cccc(-c2cc(=O)n(C)c3ccc(C(O)c4ccc(Cl)cc4)cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
A solution of interm. (7-i) (3.55 g) in methanol (20 ml) and THF (20 ml) was cooled. Sodium borohydride (0.37 g) was added portionwise. The mixture was stirred at room temperature for 30 minutes, hydrolized and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 3.5 g (100%) of (±)-6-[(4-chlorophenyl)hydroxymethyl]-1-methyl-4-(3-propoxyphenyl)-2(1H)-quinolinone (interm. 7-j).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10](C(OC)=O)[C:11]([O:13]C)=[O:12].[OH-].[Na+].C(O)C>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(CCc1ccccc1F)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCc1ccccc1F

Procedure:
Dimethyl 2-[2-(2-fluorophenyl)ethyl]malonate, sodium hydroxide (22.7 g), ethanol (150 ml) and water (100 ml) were heated under reflux for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was acidified with hydrochloric acid, and extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-fluorophenyl)butanoic acid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-].[Li+:9].C[C:11](C)=[O:12]>CO>[C:4]([O:12][CH3:11])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O-:6])=[O:7].[Li+:9]
Reactant: CC(C)=O
Reactant: O=C1C=CC(=O)O1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)/C=C\C(=O)[O-]

Procedure:
Twenty grams of maleic anhydride is dissolved in 200 mls methanol, 4.8 grams (0.2 moles) of lithium hydroxide is added. The mixture is stirred until all the lithium hydroxide dissolves (at this point the pH reads 7.0). To the solution is added acetone and the solid is filtered and dried. 23 grams product is obtained.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[CH2:10][NH:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:13][CH2:14][C:15]([N:11]([OH:12])[CH2:10][C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: ONC[C@@H]1C[C@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N(O)C[C@@H]1C[C@H]1c1ccccc1
Reaction time: 5 h
Yield: 41.8 %

Procedure:
To a stirred solution of N-[(trans-2-phenylcyclopropyl)methyl]-N-hydroxylamine (3.26 g, 20 mM) in methylene chloride (50 ml) was added chloroacetyl chloride (4.52 g, 40 mM) and triethylamine (4.04 g, 40 ml) at room temperature. After stirring for 5 hours, it was poured into saturated aqueous sodium bicarbonate. The whole was extracted with chloroform (2×100 ml). The extracts were washed with water and brine, then were added and evaporated in vacuo. Chromatographic purification (eluent chloroform:ethanol=15:1) of the residue provided 2 g (41.8% yield) of the desired product as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:18])C=1.[OH-].[Na+].C[O-].[Na+].CO>ClCCl.CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:18])=[N:7][CH:8]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1ccc(C)nc1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc(C=O)nc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 20 %

Procedure:
In dichloromethane (25.0 ml), 5-ethyl-2-methyl-pyridine (2.31 g) was dissolved. The reaction solution was cooled to 0° C. and added with meta-chloroperbenzoic acid (4.43 g), followed by stirring at room temperature for 2.5 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. Subsequently, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off, followed by dissolving the resulting residue in dichloromethane (40.0 ml). The reaction solution was added with trifluoroacetic anhydride (5.6 ml) and subjected to thermal reflux for 3.5 hours. After the reaction solution had been cooled to room temperature, the solvent was distilled off. The residue obtained was dissolved in methanol (80.0 ml). After having been cooled to 0° C., the reaction solution was added with a 12.5% sodium methoxide/methanol solution and adjusted to pH 10, followed by stirring at room temperature for 16.5 hours. After the solvent had been distilled off, the residue was added with distilled water and extracted with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off, followed by dissolving the resulting residue in chloroform (50.0 ml). The reaction solution was added with manganese dioxide (chemically processed product) (7.44 g) and then stirred at room temperature for 18 hours. The reaction solution was filtrated through Celite. The solvent in the filtrate was distilled off and the residue obtained was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (515.6 mg) as a yellow oily substance.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:32]1([CH3:42])[C:33]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>C(OCC)(=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][S:38]([C:33]3[C:32]([CH3:42])=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:40])=[O:39])=[CH:19][CH:20]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(SCc2ccc(CCCCO)cc2)c(Cl)c1=O
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccccc1S(=O)(=O)OCCCCc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 2 h

Procedure:
To a 15 ml round bottom flask charged with 2-tert-butyl-4-chloro-5-(4-(4-hydroxybutyl)benzyl)thio-3(2H)-pyridazinone (0.15 g, 0.39 mmol) is added pyridine. Toluenesulfonyl chloride (88.9 mg, 0.42 mmol) is then added to it and the mixture stirred for 2 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using ethyl acetate-hexanes as the eluting mixture.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.I[CH:43]([CH3:49])[CH2:44][C:45]([F:48])([F:47])[F:46]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:49][CH2:43][CH2:44][C:45]([F:48])([F:47])[F:46])[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(I)CC(F)(F)F
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C(CCCC(F)(F)F)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 72.3 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.55 mL; 0.55 mmol), 3-iodo-1,1,1-trifluorobutane (0.127 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.172 g (72%) of the title compound as a yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[CH:2]=1.[F:12][C:13]([F:31])([F:30])[C:14]([C:17]1[CH:26]=[CH:25][C:24]2[CH2:23][C@H:22]([C:27](O)=[O:28])[CH2:21][CH2:20][C:19]=2[N:18]=1)([CH3:16])[CH3:15].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1C=NC2N(O)N=NC=2C=1>CN1CCCC1=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:27]([C@@H:22]2[CH2:21][CH2:20][C:19]3[N:18]=[C:17]([C:14]([CH3:16])([CH3:15])[C:13]([F:31])([F:30])[F:12])[CH:26]=[CH:25][C:24]=3[CH2:23]2)=[O:28])[CH:2]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)Nc1cnc3ccccc3c1)C2)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.03 h
Yield: 74.7 %

Procedure:
To a mixture of 3-quinolinamine (26 mg, 0.18 mmol), (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (40 mg, 0.14) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (79 mg, 0.21 mmol) in N-methylpyrrolidinone (0.7 mL), followed by N,N-diisopropylethylamine (73 μL, 0.42 mmol) was added. Aliquot after 2 min: LCMS showed formation of the HOAt and Me ester, and some amide. After 1.3 h, the reaction was heated at 60° C. Aliquot after 25 h: LCMS showed the reaction was complete—all HOAt ester had been consumed. The material was filtered and purified by reverse-phase HPLC (20-80% ACN in 10 mM Et2NH/H2O; 3 injections of 400 μL, each) to afford the amide (43 mg, 75%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.95 (d, J=2.4 Hz, 1H), 8.76 (d, J=2.4 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.92 (dd, J=1.1, 8.0 Hz, 1H), 7.68-7.54 (m, 3H), 7.40 (d, J=8.0 Hz, 1H), 3.08-3.00 (m, 2H), 2.99-2.87 (m, 3H), 2.29-2.20 (m, 1H), 2.03-1.91 (m, 1H), 1.56 (s, 6H); m/z=414.1 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])#[CH:21].C(N(CC)CC)C>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]#[C:21][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccccc2F)c1)c1ccccc1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A mixture of (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (105 mg, 0.31 mmol) and 1-ethynyl-2-fluorobenzene (75 mg, 0.62 mmol) in 2.0 mL EtOAc was degassed with argon at 70° C. Upon cooling to room temperature the reaction mixture was treated with triethylamine (0.16 mL, 1.1 mmol), dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol) and copper(I) iodide (2 mg, 0.012 mmol). The reaction was heated at 70° C. for 20 hours then partitioned between EtOAc and H2O. The EtOAc layer was washed with acetic acid solution, saturated NaHCO3, brine, dried with anhydrous Na2SO4 and concentrated. The dark film obtained was purified by chromatography (silica gel, hexane/EtOAc) to give the title compound as a tan foam (110 mg, 94%).
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[C:26]([O:30][C:31](=[O:34])[CH2:32]Br)([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>O>[C:26]([O:30][C:31](=[O:34])[CH2:32][N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: c1ccc(Cc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 60 °C
Yield: 64.3 %

Procedure:
(S)-2-(4-Benzyl-phenoxymethyl)-pyrrolidine (200 mg, 0.658 mmol) was taken into DMF (2 mL), and t-butylbromoacetate (141 mg, 0.724 mmol) was added, followed by potassium carbonate (182 mg, 1.317 mmol). The mixture was heated to 60° C. and left to react overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, and concentrated to dryness. The compound was then purified by flash chromatography (eluted with 0.5% methanol in dichloromethane with a 40:1 silica ratio) to obtain the title product (161 mg, 0.423 mmol, 64% yield); LCMS; m/z 381.52, found 381 (M); 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 1.66-1.73 (m, 2H), 1.79-1.85 (m, 2H), 1.99-2.06 (m, 1H), 2.63-2.69 (m, 1H), 3.18-3.22 (m, 2H), 3.40 (d, J=17.2, 1H), 3.59 (d, J 16.8, 1H), 3.79-3.83 (m, 1H), 3.91-3.95 (m, 2H), 6.82 (d, J 8.88, 2H), 7.08 (d, J8.8, 2H), 7.15-7.27 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Sn](C)(C)C>CN1CCCC1=O.C(OCC)(=O)C.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:19])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Agent: [Cu]I
Agent: C[Sn](C)(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Lit. Tetrahedron Lett. 1999, 40, 2719-2722. To a stirred suspension of 1.58 mmol 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) in 3 ml N-methylpyrolidone were added 0.05 mmol tris(dibenzylideneacetone)dipalladium chloroform complex and 0.32 mmol triphenylphosphine and the mixture was stirred at 50° C. for 10 min. 0.16 mmol copper(I) iodide was then added and the mixture stirred at 50° C. for a further 10 min. Finally, 3.48 mmol tetramethyl tin was added and the reaction mixture was stirred at 80° C. for 16 h. The mixture was then cooled to room temperature, diluted with ethyl acetate and washed twice with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a yellow solid. MS (m/e): 214.1 ({37Cl}[M+H− Me2C═CH2]+, 35%), 212.0 ({35Cl}[M+H− Me2C═CH2]+, 100%).