Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]([Si:10]([CH3:38])([CH3:37])[O:11][C@H:12]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C@@H:28]([CH2:29][CH2:30][CH2:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH3:9])([CH3:8])[CH3:7].CN([CH:42]=[O:43])C>CCOCC>[C:6]([Si:10]([CH3:38])([CH3:37])[O:11][C@H:12]([C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C@@H:28]([CH2:29][CH2:30][CH2:31][C:32]3[S:33][C:34]([CH:42]=[O:43])=[CH:35][CH:36]=3)[CH2:27][CH2:26][CH:25]=2)=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH3:9])([CH3:7])[CH3:8]
Reactant: CN(C)C=O
Reactant: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(C2=CCC[C@@H]2CCCc2cccs2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(C2=CCC[C@@H]2CCCc2ccc(C=O)s2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
n-Butyllithium (0.14 mL, 0.22 mmol, 1.6 M/hexanes) was added to an ice cold solution of 41 (53 mg, 0.11 mmol) in 0.5 mL ether. After 1 h, DMF (85 μL, 1.1 mmol) was added and the reaction was allowed to stir for 40 min. At this time, the reaction was quenched by addition of 10 mL saturated NH4Cl solution. The mixture was extracted with ethyl acetate (2×20 mL) and the combined ethyl acetate solution was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography using a Combiflash unit by Teledyne Isco (12 g silica gel, 0%→15% ethyl acetate/hexanes) which gave the title compound (43 mg, 0.084 mmol, 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(Cl)Cl>[CH:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])=[CH:3][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Nc1ccc(C2CCCCCC2)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(C2CCCCCC2)cc1

Procedure:
6.81 g (36.0 mmol) of 4-aminophenyl-cycloheptane were dissolved in 60 ml of methylene chloride and treated with 3.13 g (39.6 mmol) of pyridine. The reaction mixture was treated dropwise at room temperature while stirring with a solution of 4.3 g (39.6 mmol) of ethyl chloroformate in 15 ml of methylene chloride. After 2 hours the mixture was washed with water and the organic phase was dried over sodium sulfate, filtered and evaporated. The ethyl 4-cycloheptylphenyl-carbamate distilled at 165°-170° and 0.3 mbar.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH3:11])=[CH:10][C:3]=12.C1C(=O)N([I:19])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH3:11])=[C:10]([I:19])[C:3]=12
Reactant: Cc1cc2c(Br)ccnc2[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Cc1[nH]c2nccc(Br)c2c1I
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a mixture of 4-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (D24) (1.65 g, 7.82 mmol) in DCM (70 mL) was added NIS (1.935 g, 8.60 mmol) at 0° C. and the mixture was stirred for 1.5 hour at 0° C. The mixture was evaporated in vacuo. DCM (ca. 20 mL) was added to the residue. The formed precipitate was filtered, rinsed with DCM to give the title compound (2.45 g). LCMS (A): m/z (M+H)+ 337/339, C8H6BrIN2 requires 336/338 (acidic).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1)[CH3:2].[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]>>[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20][NH:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCc1cccc(N)n1
Product: CCOC(=O)C(=CNc1cccc(CC)n1)C(=O)OCC
Temperature: 100 °C

Procedure:
The crude product from Example 8b was combined with 2-ethoxymethylene-malonic acid diethyl ester (6.6 mL, 0.032 mol) and the mixture heated under a N2 atmosphere in an oil bath at 100° C. for 2 h. Purified by flash chromatography on silica gel eluting with EtOAc/hexane giving the title compound (7.16 g, 98%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([CH3:24])=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]#[N:40]>CC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:38][C:39]#[N:40])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([CH3:24])=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cc(-c3ccc(OCC#N)cc3)ccc12

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1-benzyl-3-methyl-2-phenyl-1H-indol-6-yl)-phenol (0.291 g, 0.747 mmol) was reacted with K2CO3 (0.124 g, 0.896 mmol) and bromoacetonitrile (0.107 g, 0.896 mmol) in acetone (5 ml) to give the product (0.284 g, 0.663 mmol, 89%) as a white solid, mp 146-150° C. 1H NMR (DMSO-d6) δ 2.20 (s, 3H), 5.15 (s, 2H), 5.36 (s, 2H), 6.82 (d, J=7.0 Hz, 2H), 7.08-7.17 (m, 5H), 7.32-7.47 (m, 4H), 7.45 (t, J=6.7 Hz, 2H), 7.57-7.63 (m, 4H); [ESI(+)], m/z 429 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5](O)=[O:6].S(Cl)(Cl)=O.[NH4+:16].[OH-].[Na+].[Cl-]>C1COCC1>[F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5]([NH2:16])=[O:6]
Reactant: CC(C)(CC(=O)O)C(F)(F)F
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(CC(N)=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A solution of 4,4,4-trifluoro-3,3-dimethylbutanoic acid [See: US2010/0240663](0.6 g, 3.53 mmol) in thionyl chloride (6 mL, 82 mmol) was heated at 60° C. for 2 h, cooled to RT and concentrated to dryness. The residue was dissolved in DCM (2 mL), added drop-wise to a mixture of THF (8 mL) and NH4OH (˜15M, 8 mL, ˜120 mmol) and stirred at RT overnight. Solid NaCl was added until saturated, the mixture extracted with 4:1 DCM/THF (3×) and the combined organics were washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to dryness to afford 4,4,4-trifluoro-3,3-dimethylbutanamide (240 mg, 40%). 1H NMR (400 MHz, DMSO-d6): δ 7.46 (s, 1H), 6.93 (s, 1H), 2.20 (s, 2H), 1.18 (s, 6H).
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([OH:12])=[O:11])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42]O)[CH2:36][CH2:35]1>C(Cl)(Cl)Cl>[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][O:11][C:10]([C:4]23[CH2:5][CH:6]4[CH2:9][CH:2]([CH2:1][CH:8]2[CH2:7]4)[CH2:3]3)=[O:12])[CH2:36][CH2:35]1
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Reactant: OCCCN1CCN(c2ncccn2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Product: O=C(OCCCN1CCN(c2ncccn2)CC1)C12CC3CC(CC1C3)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To stirred solution of hexahydro-2,5-methanopentalene-3a[1H]-carboxylic acid (0.6 g, 3.6×10-3 mol) in 25 ml of chloroform under a dry nitrogen atmosphere was added carbonyldiimidazole (0.58 g, 3.6×10-3 mol). The resulting solution was stirred at ambient temperature for three hours, during which time a gas (CO2) was evolved. A solution of 3-[1-(2-pyrimidyl)-4-piperazinyl]propanol (0.80 g, 3.6×10-3 mol) in 25 ml of chloroform was then added, and the resulting reaction mixture was stirred under nitrogen at ambient temperature for two days. The mixture was diluted to 150 ml with chloroform, washed with three-one hundred ml portions of water, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator. The desired product (TLC on silica using a 30% methanol in ethyl acetate solvent system, Rf=0.48) was isolated by gravity chromatography on silica gel and converted to the hydrochloride salt with isopropanolic HCl (0.79 g, 51% yield), mp.=231°-232° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:4]([C:12]2[NH:11][CH:15]=[CH:14][CH:13]=2)=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: c1cc[nH]c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc[nH]1)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-chloronicotinoyl chloride (1 eq.) in dichloromethane (10 mL) was added slowly to a mixture of pyrrole (1.5 eq.) (Aldrich, Milwaukee, Wis.) and aluminum chloride (3.5 g, 1 eq.) in dichloromethane (8 mL) at 0° C. The mixture was stirred at 0° C. for 10 mins and at room temperature for 30 mins. The reaction was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 2.27 g of (2-chloro-pyridin-3-yl)-(1H-pyrrol-2-yl)-methanone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([CH2:17][C:18]1[CH:35]=[CH:34][C:21]2[N:22]([CH2:32][CH3:33])[C:23](=[O:31])[C:24]([CH3:30])([CH3:29])[C:25](=[O:28])[N:26]([CH3:27])[C:20]=2[CH:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:39]I.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[N:7]([CH2:17][C:18]1[CH:35]=[CH:34][C:21]2[N:22]([CH2:32][CH3:33])[C:23](=[O:31])[C:24]([CH3:29])([CH3:30])[C:25](=[O:28])[N:26]([CH3:27])[C:20]=2[CH:19]=1)[CH2:8][C:9]1[C:10]([CH3:16])=[N:11][C:12]([O:15][CH3:39])=[CH:13][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(Cc3ccc(=O)[nH]c3C)C(=O)OC(C)(C)C)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(Cc3ccc(OC)nc3C)C(=O)OC(C)(C)C)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methyl-6-oxo-1,6-dihydropyridin-3-ylmethyl)carbamic acid tert-butyl ester (536 mg) was dissolved in DMF(20 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 56.1 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (0.081 ml) was added thereto, and the mixture was stirred at 0° C. for 0.5 hours. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound(550 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1(C(C)C=O)C=CC=C[CH:26]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO.[Pd]>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([NH:15][CH2:14][CH:10]2[O:11][CH2:12][CH2:13][N:8]([CH2:1][CH2:2][CH2:7][C:6]3[CH:5]=[CH:4][CH:3]=[CH:26][CH:25]=3)[CH2:9]2)=[O:24])=[CH:22][CH:21]=1
Reactant: CC(C=O)c1ccccc1
Reactant: O=C(NCC1CN(Cc2ccccc2)CCO1)c1ccc(O)cc1
Agent: [Pd]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCC1CN(CCCc2ccccc2)CCO1)c1ccc(O)cc1
Reaction time: 0.25 h

Procedure:
A solution of N-(4-benzyl-morpholin-2-ylmethyl)-4-hydroxy-benzamide (EXAMPLE 202, Step 1) (55 mg) was dissolved in acetic acid (3 mL) and hydrogenated at 1 atm over 10% Pd/C (50 mg) for 18 h. The catalyst was removed by filtration, washed with acetic acid and the filtrate evaporated, to give an oil. A portion of this oil (21 mg) was dissolved in methanol (1 mL) and treated with phenylpropionaldehyde (24 mg) and sodium cyanoborohydride (25 mg). The resulting reaction was stirred for 15 min and the crude reaction mixture purified by preparative reverse phase IPLC to give the 4-Hydroxy-N-[4-(3-phenyl-propyl)-morpholin-2-ylmethyl]-benzamide compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[C:6]([C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=[C:10]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:9]=1)=[O:7])=O.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[BH3-]C#N.[Na+]>O1CCOCC1>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:1][C:3]2[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=2)[C:6]([C:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=[C:10]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[CH:24][CH:25]=3)[N:9]=2)=[O:7])[CH2:39][CH2:38]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1C(=O)c1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1C(=O)c1cccc(CN2CCN(C)CC2)c1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A solution of Example 215C (100 mg, 0.2 mmol) in dioxane (5 mL) was added 1-methylpiperazine (40 mg, 0.4 mmol) and NaCNBH3 (25 mg, 0.5 mmol). The reaction mixture was stirred at 70° C. for 2 days, and concentrated. The residue was purified by flash chromatography, eluted with 0-20% gradient methanol in methylene chloride to yield the title compound. MS (DCI/NH3) m/z 557 (M+H)+.
Reaction SMILES: P(=[S:5])([O-])([O-])[O-].[Na+].[Na+].[Na+].Cl.[C:10]([O:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C:19](=[NH:22])[CH2:20][Cl:21])[CH2:15]1)(=[O:12])[NH2:11].Cl>O>[ClH:21].[C:10]([O:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C:19](=[NH:22])[CH2:20][SH:5])[CH2:15]1)(=[O:12])[NH2:11]
Reactant: [O-]P([O-])([O-])=S
Reactant: N=C(CCl)N1CC[C@@H](OC(N)=O)C1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(CS)N1CC[C@@H](OC(N)=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.3 %

Procedure:
0.945 g of trisodium phosphorothioate were added to a solution of 1.21 g of 2-[(3R)-3-carbamoyloxypyrrolidin-1-yl]-2-iminoethylchloride hydrochloride in 8 ml of water, kept cooled in ice-water, and the mixture was stirred for about 3 hours at room temperature. After adding 6 ml of 1N hydrochloric acid, the mixture was heated to 50° C. for 30 minutes, and the solvent was then distilled off under reduced pressure. The concentrate was mixed with 8 ml of methanol, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was crystallized by adding ether, and the crystals were collected by filtration and washed with ether, giving 1.25 g of 2-[(3R)-3-carbamoyloxypyrrolidin-1-yl]-2-iminoethylmercaptan hydrochloride.
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[SH-:21].[Na+].Cl>C(O)C>[SH:21][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: [SH-]
Reactant: O=C(O)C(Cl)CCc1ccc(-c2ccccc2Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(S)CCc1ccc(-c2ccccc2Cl)cc1

Procedure:
A mixture of 0.05 moles of α-chloro-γ-(2'-chloro-4-biphenylyl) butyric acid and 5 g. of sodium hydrosulfide in 100 ml. of absolute ethanol and under a nitrogen atmosphere is stirred for 15 hours. The mixture is then acidified with 6 N hydrochloric acid. The solvent is removed in vacuo and the residue is extracted into ether, washed with water, saturated sodium chloride solution, dried and evaporated to dryness to obtain α-mercapto-γ-(2'-chloro-4-biphenylyl)butyric acid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5](=O)[C:4]1=[O:14])[CH3:2].O.NN.Cl>CCOC(C)=O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:14])[CH3:2]
Reactant: CCN1C(=O)C(=O)c2cc(C)ccc21
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1C(=O)Cc2cc(C)ccc21
Temperature: 110 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
A mixture of 1-ethyl-5-methyl-1H-indole-2,3-dione (ix-a, 1.53 g, 8.09 mmol) and hydrazine monohydrate (30 mL, 618 mmol) was heated to 110° C. After 5 h, the reaction was cooled to RT and conc. HCl was added to adjust the reaction mixture to approximately pH 3. The mixture was stirred overnight, and poured into a separatory funnel containing EtOAc (150 mL). The mixture was shaken and the layers were separated. The aqueous layer was extracted with EtOAc (2×150 mL) and the combined organic layers were dried, filtered and concentrated to give 1-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one (i-a, 1.03 g, 72.5%). NH4OAc QC conditions. DAD Retention time=1.48 min. M+H=176.
Reaction SMILES: [Mg].Br[C:3]1[CH:11]=[CH:10][C:6]2[CH2:7][CH2:8][O:9][C:5]=2[CH:4]=1.II.CON(C)[C:17](=[O:28])[C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19].C([Mg]Cl)(C)C>O1CCCC1>[O:9]1[C:5]2[CH:4]=[C:3]([C:17](=[O:28])[C@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH3:19])[CH:11]=[CH:10][C:6]=2[CH2:7][CH2:8]1
Reactant: Brc1ccc2c(c1)OCC2
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)c1ccc2c(c1)OCC2
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 36.3 %

Procedure:
Magnesium (711 mg, 29.3 mmol) was placed in a screw-cap reaction tube, and a solution of 6-bromo-2,3-dihydrobenzofuran (4.16 g, 20.9 mmol) in tetrahydrofuran (30 mL) was added, followed by a small crystal of iodine. The tube was sealed and flushed with argon. The mixture was heated at 60° C. for 1 h, and then the reaction mixture was allowed to cool to r.t. A slurry of (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (4.85 g, 20.9 mmol) in THF (20 ml) was cooled on a acetone/ice bath to −10° C., and a solution isopropylmagnesium chloride (2 M in THF, 10.5 mL, 21 mmol) was slowly added. The mixture was stirred for 15 min, the cooling bath was removed. Stirring was continued for 10 min. Then the preformed Grignard reagent was added in small portions with stirring. After the addition the mixture was allowed to reach r.t. and stirred for 2 h. The solvent was evaporated, and the mixture was poured into an ice-cold ethyl acetate (150 ml) and aq. HCl (1M, 35 ml) mixture. The organic layer was separated, washed with water and brine, filtered, and evaporated. The product was purified by flash chromatography on silica with ethyl acetate/n-heptane (3:7) to give 2.21 g (36%) of the subtitle compound.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[N:13]S(C(C)(C)C)=O)=[CH:5][CH:4]=1>O1CCOCC1>[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[NH:13])=[CH:5][CH:4]=1
Reactant: CC(C)(C)S(=O)N=C1CCCc2ccc(Br)cc21
Agent: Cl
Solvent: C1COCCO1
Product: N=C1CCCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HCl (4M in 1,4-dioxane) (6.75 mL, 222.07 mmol) was added to a suspension of N-(7-bromo-3,4-dihydronaphthalen-1(2 H)-ylidene)-2-methylpropane-2-sulfinamide (Example 51 Step 1, 7.29 g, 22.2 mmol) in anhydrous 1,4-dioxane (50 mL). The resulting mixture was stirred under a nitrogen atmosphere at r.t. for 1 h. The formed precipitate was filtered off and washed with Et2O. The solid was then dissolved in DCM and sat. aq. NaHCO3. The mixture was poured into a phase separator, the organic layer was collected and concentrated. The product was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[C@@H:17]12[C:26](=[O:27])[O:25][C:23](=[O:24])[C@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22]2>COCCOC>[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:26]([C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[C:23]([OH:25])=[O:24])=[O:27])[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[OH:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Solvent: COCCOC
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCC[C@H]2C(=O)O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A solution containing 4.00 g (0.022 mole) of 4-amino-2,6-di-t-butylphenol in 50 ml of 1,2-dimethoxyethane was added dropwise over a period of ten minutes to a solution of 3.35 g (0.022 mole) of trans-1,2-cyclohexanedicarboxylic anhydride in 50 ml of 1,2-dimethoxyethane. The reaction mixture was stirred at room temperature for about seventy-two hours. The solvent was removed under vacuum and the residual solid was triturated with a mixture of diethyl ether and hexane. The resulting solid was recrystallized from a mixture of ethyl acetate and hexane to give 4.4 g of white solid 2-[N-(3,5-di-t-butyl-4-hydroxyphenyl) carbamoyl]-trans-cyclohexanecarboxylic acid, m.p. 247°-252° C. Analysis: Calculated for C22H33NO4 : %C, 70.4; %H, 8.9; %N, 3.7; Found: %C, 70.4; %H, 8.9; %N, 3.6.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([Cl:21])=[CH:19][C:18]([F:22])=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[N:3]=[C:4]([CH3:7])[S:5][CH:6]=3)=[N:16][C:15]=2[CH:17]=[C:18]([F:22])[CH:19]=1
Reactant: Cc1nc(I)cs1
Reactant: C#CCCc1nc2cc(F)cc(Cl)c2o1
Product: Cc1nc(C#CCCc2nc3cc(F)cc(Cl)c3o2)cs1
Yield: 55.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 4-iodo-2-methylthiazole (200 mg, 0.89 mmol) and 2-(but-3-ynyl)-7-chloro-5-fluorobenzo[d]oxazole (199 mg, 0.89 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 85:15) to yield 157 mg (0.49 mmol, 55%) of 7-chloro-5-fluoro-2-(4-(2-methylthiazol-4-yl)but-3-ynyl)benzo[d]oxazole as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]([C:10]#[N:11])=[CH:8][CH:9]=1)=[O:20]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(C#N)c(OS(=O)(=O)C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#N)c(-c2ccccc2)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
4-Cyano-3-(trifluoromethanesulfonyloxy)-benzoic acid methyl ester from step 1 (2.5 g, 8.1 mmol) and phenylboronic acid (2 g, 16.2 mmol) were dissolved in DMF (33 ml) and treated with Et3N (3.1 ml, 17.8 mmol). Argon was bubbled into the solution for 20 min. and then a catalytic amount of PdCl2 (PPh3)2 (285 mg, 0.405 mmol) was added. The reaction mixture was warmed to 90° C. and stirred for 3 hours under argon atmosphere. The reaction was quenched with satd. NaHCO3 (20 mL) and extracted with EtOAc (2×20 mL). The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (10% EtOAc/Hexane) to yield the desired product. FAB MS: 238 m/z (M+ +H)