Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH:17]=[O:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.S([CH2:37][N+:38]#[C-:39])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CO.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]4[O:18][CH:39]=[N:38][CH:37]=4)=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3nc(C=O)ccn23)ccc1F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(-c4cnco4)ccn23)ccc1F
Yield: 35.9 %

Procedure:
2′-Fluoro-5′-(7-formylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile (100 mg), tosylmethyl isocyanide (60 mg) and potassium carbonate (40 mg) were suspended in methanol (10 ml) and heated at reflux for 90 min. The reaction was cooled, diluted with dichloromethane and filtered. The filtrate was evaporated to dryness and the residue partitioned between dichloromethane and water. The organic phase was dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by flash column chromatography on silica gel eluting with dichloromethane with 1% ammonia on a gradient of methanol (1-5%) gave a solid. Trituration with diethyl ether afforded 2′-fluoro-5′-[7-(oxazol-5-yl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as a yellow solid (40 mg, 34%): δH (360 MHz, DMSO) 7.53 (1H, d, J 7), 7.65 (1H, s), 7.70 (1H, s), 7.81 (1H, s), 7.87-7.95 (3H, m), 8.06 (1H, d, J 8), 8.11 (1H, s), 8.20 (1H, s), 8.70 (1H, s), 9.19 (1H, d, J 7); m/z (ES+) 382 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH:19][C:20]2[C:21](=[O:32])[N:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:23]=[CH:24][N:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH:19][C:20]2[C:21](=[O:32])[N:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:23]([Cl:33])=[CH:24][N:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cn1ccnc(N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccccn2)c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1c(Cl)cnc(N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccccn2)c1=O
Reaction time: 12 h

Procedure:
A stirred solution of 3-(1-tert-butyloxycarbonyl-trans-4-(2-pyridyl)-pyrrolidin-3-ylamino)-1-ethoxycarbonylmethylpyrazinone from step 8 above (2.0 g, 4.5 mmol) and N-chlorosuccinimide (0.67 g, 5.0 mmol) in CHCl3 was heated to reflux for 6 h. More N-chlorosuccinimide (0.20 g, 1.5 mmol) was added and refluxing was continued for 12 h. The reaction was diluted with CHCl3 and washed with aqueous NaHCO3. The organic phase was separated, dried over Mg SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using a gradient elution of 25-50% EtOAc:hexanes to give the title compound as an amorphous solid (1.5 g, TLC Rf=0.5, 1:1 EtOAc:hexanes; HPLC RT=7.17 min, method A).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][NH:9][C:10]([CH:12]2[CH2:15][CH2:14][CH2:13]2)=O)=[N:6][N:5]=[CH:4][NH:3]1>P(Cl)(Cl)(Cl)=O>[CH:12]1([C:10]2[N:6]3[C:7]([C:2](=[O:1])[NH:3][CH:4]=[N:5]3)=[CH:8][N:9]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: O=C(NCc1nnc[nH]c1=O)C1CCC1
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1[nH]cnn2c(C3CCC3)ncc12
Temperature: 0 °C

Procedure:
A crude solution of cyclobutanecarboxylic acid (5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)amide (1.33 g, 6.39 mmol) in phosphorus oxychloride (POCl3) (10 mL) was heated to 55° C. The reaction was heated for 2 h then concentrated in vacuo and the crude oil was cooled to 0° C. in an ice-bath and quenched with 2M NH3 in ispropanol (IPA) until slightly basic. This crude reaction mixture was concentrated in vacuo and was partitioned between DCM and H2O and separated. The aqueous layer was extracted with DCM (3×) and the combined organic fractions were dried over sodium sulfate (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 5% MeOH in DCM], resulting in the title compound as an off-white solid; 1H NMR (DMSO-d6, 400 MHz) δ 1.86-1.96 (m, 1H), 2.00-2.13 (m, 1H); 2.26-2.46 (m, 4H); 3.87-4.00 (m, 1H); 7.71 (s, 1H); 7.87 (d, J=3.6 Hz, 1H); 11.7 (brs, 1H); MS (ES+): m/z 191.27 (100) [MH+], HPLC: tR=2.06 min (MicromassZQ, polar—5 min).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([CH3:15])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2
Reactant: O=c1[nH]ccc2cc(F)ccc12
Reactant: CNC
Solvent: CCO
Product: CN(C)c1ccc2c(=O)[nH]ccc2c1
Temperature: 150 °C

Procedure:
6-Fluoro-2H-isoquinolin-1-one (54 mg, 0.33 mmol) was deposited in a sealed tube with 5 mL 33% dimethylamine in ethanol. This was heated at 150° C. for 3.5 hours. This was concentrated in vacuo and purified by flash chromatography (gradient elution 50 to 100% ethyl acetate/hexanes) to yield 6-Dimethylamino-2H-isoquinolin-1-one (39 mg, 0.21 mmol). MS (ESI) 189.1 (M+H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[N:10]=1)=[O:5])[CH3:2].[Br:14]Br>CO>[CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11](=[O:13])[CH2:12][Br:14])[N:10]=1)=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)c1nc(C(C)=O)cs1
Solvent: CO
Product: CCOC(=O)c1nc(C(=O)CBr)cs1

Procedure:
A solution of 4-acetylthiazole-2-carboxylic acid ethyl ester (1.5 g) and bromine (1.4 g) in methanol (50 ml) was stirred for 8 hours at room temperature. The solvent was removed under reduced pressure to give 4-bromoacetylthiazole-2-carboxylic acid ethyl ester. A suspension of the above residue and diaminomethylenethiourea (800 mg) in ethanol (50 ml) was refluxed for 4 hours. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and diisopropyl ether afforded 4-[2-(diaminomethyleneamino)thiazol-4-yl]thiazole-2-carboxylic acid ethyl ester hydrobromide (800 mg).
Reaction SMILES: C([Li:5])CCC.[CH2:6]([C:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH:8]=[CH2:9]>C1COCC1>[CH2:6]([C:10]1([Li:5])[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH2:7][CH:8]=[CH2:9]
Reactant: [Li]CCCC
Reactant: C=CCCC1=CC=CC1
Solvent: C1CCOC1
Product: [Li]C1(CCC=C)C=CC=C1
Reaction time: 1 h

Procedure:
47.5 millimoles of butyllithium mixed with a C6 alkane are added slowly to 47.5 millimoles of the γ-butenylcyclopentadiene prepared in the preceding stage (b), in 50 ml of THF at 0° C. and are stirred for 1 hours. The γ-butenylcyclopentadienyllithium solution thus produced is added to 19 millimoles of hafnium tetrachloride in 50 ml of THF at 0° C. and is stirred for 65 hours. The volatile compounds are removed under vacuum and the residue is extracted with ether and filtered. The product is precipitated in the form of a white solid by slowly cooling the solution to −50° C. and recrystallizing from ether at −12° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][O:20]1>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][O:20]3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncnc2ccn(CC3CCCO3)c12
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150 mg) in N,N-dimethylformamide (1.0 mL) was added cesium carbonate (478 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 2-(bromomethyl)tetrahydrofuran (242 mg), and the mixture was stirred at room temperature for 26 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (200 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[CH:10]=[N:9]2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[N:9]2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=1
Reactant: CCOC(=O)c1cnn(Cc2cc(-c3cccc(C(F)(F)F)c3)c(C)s2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc(Cn2cc(C(=O)O)cn2)cc1-c1cccc(C(F)(F)F)c1
Yield: 86.1 %

Procedure:
The compound (0.20 g) obtained in Example 126e was dissolved in ethanol (2 mL), and 6N aqueous sodium hydroxide solution (0.83 mL) was added. The reaction mixture was heated under reflux for 2 hr, cooled in an ice bath, adjusted to pH 2 with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was washed with ether to give the title compound (0.16 g) as a colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1.O.[OH-].[Li+].CO.Cl>O1CCCC1.O.C(OCC)(=O)C.CCCCCCC>[O:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=[C:5]1[CH2:4][C:3]([OH:14])=[O:2]
Reactant: COC(=O)Cc1cc2ccccc2o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=C(O)Cc1cc2ccccc2o1
Reaction time: 8 h

Procedure:
A solution of Example 8 (5.32 g, 28 mmol) and lithium hydroxide monohydrate (1.24 g, 30 mmol) in tetrahydrofuran (45 mL), water (30 mL), and methanol (12 mL) was stirred for 5 hours at room temperature. Water (60 mL) was added, and the reaction mixture was acidified to pH 4 using 2 M HCl and extracted with dichloromethane (5×150 mL). The organics were dried (MgSO4) and the solvent removed in vacuo. Column chromatography (ethyl acetate:heptane 4:1→ethyl acetate:methanol) gave a brown solid. This was dissolved in ethyl acetate, heptane was added, and the mixture was stirred overnight. Solvent was removed by syringe to give product as a pale brown solid, 17 mmol, 61%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[CH3:32][N:33]([C@H:43]([CH3:47])[C:44](O)=[O:45])[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:44](=[O:45])[C@H:43]([N:33]([CH3:32])[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35])[CH3:47]
Reactant: C[C@H](C(=O)O)N(C)S(=O)(=O)c1ccccc1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@H](C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)N(C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (397 mg, 0.945 mmol), EDC (362 mg, 1.891 mmol), and DMAP (289 mg, 2.364 mmol) in 10 ml of dry DCM was stirred for 15 minutes at room temperature, then (R)-2-(N-methylphenyl-sulfonamido)propanoic acid (345 mg, 1.418 mmol) was added. After stirring overnight at room temperature, the reaction was complete. The mixture was washed twice with 1N HCl, then with aq. NaHCO3, with brine and finally dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (AcOEt) to obtain 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((R)-2-(N-methylphenylsulfonamido)propanoyloxy)-ethyl)pyridine 1-oxide (430 mg, 0.666 mmol, 70.5% yield, MS/ESI+ 645.05 [MH]+, [αD]=+6.6, c=0.483, DCM).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[CH:25]=3)[C:20]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)=[C:19]2[CH2:47][C:48]([CH3:54])([CH3:53])[C:49]([O:51]C)=[O:50])(=O)=O)C=CC=CC=1.[Na]>O>[CH2:1]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH:25]=2)[C:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[C:19]1[CH2:47][C:48]([CH3:54])([CH3:53])[C:49]([OH:51])=[O:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1S(=O)(=O)c1ccccc1
Reactant: ClCc1ccccc1
Agent: [Na]
Solvent: O
Product: CC(C)(Cc1c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1Cc1ccccc1)C(=O)O

Procedure:
The title compound was prepared under the conditions described in Step A and Step B of Example 38, but substituting benzyl chloride for the benzenesulfonyl chloride from Example 38 (Step A). Anal. C, H, N for sodium salt 1/2 H2O Calc. C 71.66; H 5.36; N 4.52 Found. C 71.65; H 5.49; N 4.44.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([O:26][CH3:27])[CH2:21]3)=[CH:16][C:15]=2[CH:28]2[CH2:33][CH2:32][C:31]([CH2:36][CH3:37])([CH2:34][CH3:35])[CH2:30][CH2:29]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH2:36]([C:31]1([CH2:34][CH3:35])[CH2:30][CH2:29][CH:28]([C:15]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([O:26][CH3:27])[CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:33][CH2:32]1)[CH3:37]
Reactant: CCC1(CC)CCC(c2cc(N3CCC[C@H](OC)C3)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCC1(CC)CCC(c2cc(N3CCC[C@H](OC)C3)ccc2N2CCNCC2)CC1
Reaction time: 0.33 h

Procedure:
(S)-4-[2-(4,4-Diethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazine-1-carboxylic acid t-butyl ester (59 mg, 0.1148 mmol) produced in Example (50b) was dissolved in a mixed solvent of dichloromethane (0.7 mL)-water (1 drop). Trifluoroacetic acid (0.177 mL, 2.296 mmol) was added thereto followed by stirring for 15 hours and 20 minutes under the same conditions. Aqueous solution of potassium carbonate was added to the reaction mixture to make the mixture basic. The mixture was then extracted with ethyl acetate. The separated organic layer was concentrated under reduced pressure to give a crude product of (S)-1-[2-(4,4-diethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazine as a brown oil. This was directly used without purification for the following reaction.
Reaction SMILES: [N+:1]([C:4]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.Cl[Sn]Cl.O>C(O)(=O)C.Cl>[NH2:1][C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1cccc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a suspension of 2 g (9.4 mmol) of 2,3-di-nitrobenzoic acid in 20 mL of acetic acid at 0° C. was added a solution of 14.8 g (65 mmol) SnCl2. 2 H2O in 7 mL of concentrated HCl. After stirring for 2 h at rt, the reaction mixture was concentrated. The residue was dissolved in 30 mL of H2O and the pH was adjusted to pH=12-13 with 6N NaOH. The mixture was filtered and the solid was washed with 0.1N HCl. The combined aqueous fractions were concentrated to give 1.4 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14]Br)=[CH:9][CH:8]=1.C(N(CC)CC)C.O>CCOCC>[C:7]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:8]=[CH:9][C:10]([C:13](=[O:16])[CH2:14][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Reactant: C1COCCN1
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Morpholine (1.67 g, 19.1 mmol) in anhydrous ether (20 mL) was added dropwise to a solution of 1-(4-biphenylyl)-2-bromoethanone (2.63 g, 9.56 mmol) and triethylamine (TEA) (2.90 g, 28.68 mmol) in anhydrous ether (50 mL) at 0° C. over 30 min. The reaction mixture was then warmed to room temperature. After stirring for 2 h, water (80 mL) was added and the aqueous layer was extracted with ethyl acetate (2×60 mL). The combined organic layer was dried over MgSO4 and concentrated to yield the title compound as a light yellow solid (2.52 g, 93%), which was used without further purification. MS (ES) m/e 281[M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[OH:25])[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[C:28]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[OH:25])[C:9]2=[O:27])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)c(O)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)c(O)c1
Yield: 27.5 %

Procedure:
To a solution of 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one (27.9 g, 63.8 mmol) in dichloromethane (200 mL) were added trifluoroacetic acid (2 mL) and triethylsilane (1.5 mL) at ambient temperature. The reaction mixture was refluxed for 15 h. The mixture was concentrated in vacuo to dryness. The residue was purified by flash chromatograph using 25% ethyl acetate in hexane to afford 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one (7.40 g, 27%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.40-7.18 (m, 11H), 7.13-7.06 (m, 2H), 6.97 (s, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.67-6.64 (m, 1H), 6.57-6.52 (m, 1H), 6.41 (dd, J=8.4, 2.4 Hz, 1H), 5.11 (s, 1H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[N:29]1>CO.N1CCCCC1>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]\[CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:29]1
Reactant: COc1ccc2c(c1/C=C\C1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1/C=C\C1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
A solution of tert-butyl (Z)-4-[2-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)vinyl]piperidine-1-carboxylate (0.0374 g, 0.100 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0146 g, 0.100 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((Z)-2-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}vinyl)piperidine-1-carboxylate (0.0387 g, 77%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=2)=[C:11]([CH3:24])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[C:26]1[CH:39]=[CH:38][C:29]2[C@H:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:31][O:32][C:28]=2[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:26]3[CH:39]=[CH:38][C:29]4[C@H:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:31][O:32][C:28]=4[CH:27]=3)[CH:17]=2)=[C:11]([CH3:24])[CH:10]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1-c1cccc(CO)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[Si](C)(C)C(C)(C)C)cc4C)c3)ccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 177.6 %

Procedure:
(4′-((tert-Butyldimethylsilyl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methanol 3f (1.19 g, 3.48 mmol), methyl (S)-2-(6-hydroxyl-2,3-dihydrobenzofuran-3-yl)acetate (660 mg, 3.17 mmol) and triphenylphosphine (1.34 g, 4.75 mmol) were dissolved in 10 mL of dichloromethane. The reaction solution was cooled down to 0° C., followed by addition of diisopropyl azodicarboxylate (960 mg, 4.75 mmol), then warmed up to room temperature and stirred for 4 hours. The resulting solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound (S)-methyl 2-(6-((4′-((tert-butyldimethylsilyl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3 g (1.28 g, yield 76.0%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][CH:6]([C:15]([OH:17])=[O:16])[C:5]2=1.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][CH:6]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[C:5]2=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(C(=O)O)CCC3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]c3c(c2c1)C(C(=O)OCc1ccccc1)CCC3

Procedure:
Following a procedure similar to that of 34C but using 8.2 g. of 6-methyl-1,2,3,4-tetrahydrocarbazole-4-carboxylic acid, 4.6 g. of benzyl chloride and 4 g. of sodium carbonate in 50 ml. dry dimethylformamide there was obtained 9.1 g. of the title compound; m.p. 115°-117°C. (ethyl alcohol-pentane).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([O:16]CC)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:20][NH2:21]>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([NH:20][NH2:21])=[O:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C1CC1c1ccc(C(C)(C)C)cc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(C2CC2C(=O)NN)cc1
Temperature: 95 °C
Yield: 83.9 %

Procedure:
To a room temperature solution of ethyl 2-(4-tert-butylphenyl)cyclopropanecarboxylate (1.0 g, 0.004 mol) in ethanol (10 mL) was added hydrazine hydrate (2 g, 0.04 mol) and the reaction mixture was then heated at 95° C. for 16 h. The mixture was then concentrated in vacuo and the solid that was obtained was washed with hexanes to afford 2-(4-tert-butylphenyl)cyclopropanecarbohydrazide (0.78 g, 82%) as a white solid.