Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1.[C:16](Cl)(=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>N1C=CC=CC=1>[CH2:31]([O:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: OCCC#Cc1ccc(-c2cccs2)s1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCCC#Cc1ccc(-c2cccs2)s1
Reaction time: 8 h

Procedure:
5-(4-Hydroxy-1-butynyl)-2,2'-bithiophene (0.6 g) was dissolved in pyridine (10 ml). Palmitoyl chloride (1 ml) was added at room temperature, stirred for few minutes and kept overnight. The reaction mixture was treated as in example 21, and 1.2 g of light yellowish crystals were then obtained and the melting point thereof was 68°-69° C.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH2:10]([N:12]([CH2:28][CH3:29])[C:13](=[O:27])[C:14]1[C:19]([CH2:20]O)=[CH:18][CH:17]=[C:16]([F:22])[C:15]=1[Si:23]([CH3:26])([CH3:25])[CH3:24])[CH3:11]>C(Cl)Cl>[CH2:10]([N:12]([CH2:28][CH3:29])[C:13](=[O:27])[C:14]1[C:19]([CH2:20][F:7])=[CH:18][CH:17]=[C:16]([F:22])[C:15]=1[Si:23]([CH3:26])([CH3:25])[CH3:24])[CH3:11]
Reactant: CCN(CC)C(=O)c1c(CO)ccc(F)c1[Si](C)(C)C
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)c1c(CF)ccc(F)c1[Si](C)(C)C
Temperature: 0 °C
Yield: 83.5 %

Procedure:
A solution of DAST (400 mg, 2.5 mmol) and the compound of Example 54 (660 mg, 2.2 mmol) in CH2Cl2 (30 mL) was stirred for 2 h at 25° C. The solution was poured into ice water (50 mL) and extracted with CH2Cl2. The organic extracts were combined, washed with brine, dried (MgSO4), concentrated, and purified by RC with 1:9 ethyl acetate/hexanes to give 550 mg of the title compound as a yellow oil, an 83% yield.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[CH3:12][C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH3:17].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.O>C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:9]3[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]3[CH3:12])[S:8][C:4]=2[CH:3]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1nc2ccc(Br)cc2s1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(C)n1-c1nc2ccc(Br)cc2s1
Yield: 83.8 %

Procedure:
A solution 6-bromobenzo[d]thiazol-2-amine (5.75 g, 25.1 mmol), hexane-2,5-dione (2.95 mL, 25.1 mmol), and PPTS (0.95 g, 3.76 mmol) in benzene (100 ml) was refluxed for 16 h while water was removed with a Dean-Stark trap. The cooled mixture was poured into EtOAc (100 mL) and extracted with saturated aq. NaHCO3 (2×100 mL) and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 9:1 EtOAc:hexanes as the eluent to give the title compound as an orange oil (6.46 g, 84%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[N:18]4[C:13]([CH2:14][O:15][CH2:16][CH2:17]4)=[C:12]3[C:24]#[N:25])[CH:9]=2)[NH:4][N:3]=1.[F:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:27]1[N:32]=[CH:31][C:30]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH:11]4[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[N:18]5[C:13]([CH2:14][O:15][CH2:16][CH2:17]5)=[C:12]4[C:24]#[N:25])[CH:9]=3)[NH:4][N:3]=2)=[CH:29][CH:28]=1
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(Br)c3c2)C(C#N)=C2COCCN12
Reactant: OB(O)c1ccc(F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1=C(C#N)C(c2ccc3[nH]nc(-c4ccc(F)nc4)c3c2)C(C#N)=C2COCCN12
Temperature: 140 °C
Reaction time: 1.17 h
Yield: 49.3 %

Procedure:
To a degassed solution of 125 mg (0.315 mmol) 8-(3-bromo-1H-indazol-5-yl)-6-methyl-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-7,9-dicarbonitrile (Example 12A) and 53.3 mg (0.379 mmol) (6-fluoropyridin-3-yl)boronic acid in anhydrous 1,4-dioxane (2.2 ml) were added under inert gas atmosphere 36.5 mg (0.032 mmol) tetrakis(triphenylphosphine)palladium(0) and aqueous sodium bicarbonate solution (2 M, 0.56 ml). The resulting mixture was stirred at 140° C. for 70 min under microwave conditions. After cooling to room temperature and concentration under reduced pressure, the remaining solid was dissolved in ethyl acetate (20 ml). The solution was subsequently washed with water and with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient, final mixture 95:5 v/v) to yield the title compound as a white solid (64 mg, 49% of th.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1.[H-].[Na+].CI.[C:16](OCC)(=O)C>CN(C=O)C>[CH3:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2cccc(C=O)c21
Reaction time: 0.5 h

Procedure:
To a solution of indole-7-carboxaldehyde (500 mg, 3.45 mmol) in DMF (8 mL) was added sodium hydride (152 mg of 60% dispersion in oil, 3.8 mmol). The mixture was stirred for 30 mins. Methyl iodide (0.98 g, 6.9 mmol) was then added and the mixture was stirred for 2 hrs. Ethyl acetate (200 mL) was added and solution was washed with H2O (3×20 mL) and brine (25 mL) dried over MgSO4 and concentrated to afford N-methylindole-7-carboxaldehyde as a brown oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:12]([CH:13]=O)=[CH:11][CH:10]=[C:9]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].Cl.[NH2:20]O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[C:12]([C:13]#[N:20])=[CH:11][CH:10]=[C:9]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(C=O)c1Cl
Reactant: NO
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCNC(=O)c1c([Si](C)(C)C)ccc(C#N)c1Cl
Temperature: 100 °C

Procedure:
A solution of the compound of Example 223 (0.28 g, 1.0 mmol) and hydroxylamine hydrochloride (0.12 g, 1.7 mmol) in pyridine (10 mL) was stirred at RT for 2 h. Acetic anhydride (0.75 mL, 8.0 mmol) was added and the solution was heated at 100° C. for 1.5 h. The mixture was concentrated, water added and the mixture extracted with ether. The organic layers were washed with 0.5 N HCl, sat NaHCO3, brine, dried (MgSO4) and concentrated to afford the title compound. The crude product was purified by recrystallization from ethyl acetate/hexanes to afford 0.21 g of white needles (74%). m.p. 111-112° C.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[N:15]([C:18]1[N:23]=[C:22]([O:24][CH3:25])[C:21]2[CH2:26][CH2:27][CH2:28][C:20]=2[N:19]=1)=[C:16]=[S:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:25][O:24][C:22]1[C:21]2[CH2:26][CH2:27][CH2:28][C:20]=2[N:19]=[C:18]([NH:15][C:16]([NH:1][S:2]([C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:3])=[O:4])=[S:17])[N:23]=1
Reactant: COC(=O)c1ccccc1S(N)(=O)=O
Reactant: COc1nc(N=C=S)nc2c1CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=S)Nc1nc2c(c(OC)n1)CCC2
Reaction time: 2 h
Yield: 49.8 %

Procedure:
A mixture of 4.3 g of methyl 2-(aminosulfonyl)-benzoate, 4.2 g of 6,7-dihydro-2-isothiocyanato-4-methoxy-5H-cyclopentapyrimidine and 2.2 g of anhydrous potassium carbonate in 70 ml of acetone was warmed to 40° with stirring. After 2 hours, a thick precipitate formed and stirring was continued for three more hours at ambient temperature. The precipitate was filtered, suspended in 150 ml of water, stirred and the pH adjusted to 2 by the addition of hydrochloric acid. The white solid was filtered, washed with cold water and dried to yield 4.2 g of product.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.[NH4+:12].[OH-]>CC(C)=O>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH2:12])(=[O:10])=[O:9])[CH:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Agent: [OH-]
Solvent: CC(C)=O
Product: NS(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-pyridinesulfonyl chloride hydrochloride (5.00 g) in acetone (8.5 ml) was added ammonia aqueous solution (28%, 8.5 ml) at 0° C. dropwise and stirred at room temperature for 3 hours. The solution was evaporated and poured into water (ca. 10 ml), ethyl acetate (100 ml) and tetrahydrofuran (100 ml). The organic layer was washed with brine twice and the aqueous layer was extracted with ethyl acetate (90 ml) and methanol (10 ml). The combined organic layer was dried over magnesium sulfate, evaporated and crystallized in hexane and ethyl acetate to give 3-pyridinesulfonamide (3.45 g).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]([C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO.O>[C:7]1([C:6]2[NH:2][NH:3][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:5]=2[CH3:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NN
Reactant: CC(=Cc1ccccc1)C(=O)c1ccccc1
Solvent: CO
Solvent: O
Product: CC1=C(c2ccccc2)NNC1c1ccccc1
Temperature: 68 °C
Yield: 88.9 %

Procedure:
Isolated α-methylchalcone, 1.5 g (85% pure product by gas liquid chromatography) (0.00578 mole) is reacted with 0.55 g (0.008 mole) of 75% hydrazine hydrate in 7.5 ml of methanol and 1 ml of water under N2 at reflux (68° C) for 1 hour. Gas liquid chromatography shows the α-methylchalcone had reacted to form 3,5-diphenyl-4-methylpyrazoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11](O)[CH2:10][CH2:9]1)=[O:7].[CH2:24]([N:31]1[CH2:36][CH2:35][C:34]2([C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][CH2:37]2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[CH2:36][CH2:35][C:34]2([C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]([CH:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:8]([C:6](=[O:7])[C:5]4[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:9][CH2:10]3)[CH2:37]2)[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(CN2CCC3(CC2)CNc2ccccc23)cc1
Reactant: COc1ccc(C(=O)N2CCC(O)c3ccccc32)cc1OC
Product: COc1ccc(C(=O)N2CCC(N3CC4(CCN(Cc5ccccc5)CC4)c4ccccc43)c3ccccc32)cc1OC
Yield: 48.4 %

Procedure:
Starting with 1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-4-quinolinol (250 mg, 0.76 mmol) prepared in Reference Example 2 and 1′-benzylspiro[indoline-3,4′-piperidine] (532 mg, 1.91 mmol), the same procedure as shown in Example 1 was repeated to give the product of interest, i.e., 4-(1′-benzylspiro[indoline-3,4′-piperidin]-1-yl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinoline (211 mg, yield: 48%) as a white crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)C(C)C)C.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CCOC(=O)CCCCCBr
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCNc1ccccc1-c1ccccc1
Yield: 98.1 %

Procedure:
20.0 g of 2-aminobiphenyl, 15.3 g of ethyldiisopropylamine and 26.3 g of ethyl 6-bromocaproate are reacted, analogously to Example 47a), to obtain 36.0 g of ethyl 6-(biphenyl-2-yl)aminocaproate as a non-crystallizing oil. 18.0 g of this ester are reacted, analogously to Example 47b), with 7.5 g of ethyldiisopropylamine and 10.1 g of p-chlorobenzoyl chloride in 70 ml of benzene. The resulting reaction product is purified chromatographically over a silica gel column (eluent: methylene chloride) to obtain 11.5 g (44.2% of theory) of ethyl 6-[p-chloro-N-(biphenyl-2-yl)benzamido]caproate as a viscous non-distillable oil. Saponification of this ester yields 8.1 g (75.1% of theory) of 6-[p-chloro-N-(biphenyl-2-yl)benzamido]caproic acid, MP 93° to 95°.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][Zn]Cl>C1COCC1>[C:1]1([C:7]2[C:8]([C:16]3[CH:17]=[CH:18][C:19]([CH:20]([OH:21])[CH3:24])=[CH:22][CH:23]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Zn]Cl
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Temperature: 100 °C

Procedure:
100 mg 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde (prepared as described for example 1) were dissolved in 2 mL THF and 1 mL of a 2M solution of MeZnCl was added. The mixture was heated (100° C., microwave) for 2 h, cooled to room temperature and extracted with a mixture of dichloromethane and water. The organic layers were dried over sodium sulphate and the solvent was evaporated. The crude product was purified by chromatography on silica gel (dichloromethane/ethyl acetate)
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(Cl)(Cl)=O>CCOCC>[CH2:10]([O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[NH2:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCC[C@H](N)C(=O)O
Reactant: OCc1ccccc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCCC[C@H](N)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
According to the general procedure outlined in J. Med. Chem. 1986, Vol. 30, p. 3575, 15.0 g norleucine (Nle) was mixed with 200 ml benzyl alcohol and cooled to 0° C. Thionyl chloride (25 ml) was added dropwise over 15 minutes and the mixture was slowly heated to 90° C. with a fierce evolution of SO2 occurring at about 50° C. After 2 hours at 90° C. the mixture was cooled to 0° C. and 25 ml more thionyl chloride was added. The mixture was then heated again at 90° C. for 2 hours, cooled, diluted with 1.6 liters ether and stored overnight at 0° C. The crystals which formed were filtered, washed with ether and dried to give 23.1 g of a damp solid which was recrystallized from 1:10 ethanol-ether, using 23 ml ethanol. The filtered and dried solid weighed 17.1 g, TLC Rf 0.25 in System C (the spotted plate was exposed to ammonia vapor and dried prior to elution).
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[C:3]#[CH:4].Br[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2>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.CN(C=O)C.CCN(CC)CC>[OH:6][C:2]([CH3:5])([CH3:1])[C:3]#[C:4][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(C)(C)O)c21

Procedure:
Using Method D above, 3-methyl-1-butyn-3-ol (150 mg, 1.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (101 mg, 0.32 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and CuI (16 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-butynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 43 mg, 38%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[C:25]([C@H:29]1[CH2:38][CH2:37][C@H:36]2[C@@:39]3([CH:59]=[CH2:60])[C@H:48]([C@@H:49]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]O)[CH2:50][C@:30]12[CH2:31][O:32][SiH:33]([CH3:35])[CH3:34])[C:47]1[CH:46]=[CH:45][C:44]([O:57][CH3:58])=[CH:43][C:42]=1[CH2:41][CH2:40]3)([CH3:28])([CH3:27])[CH3:26].[Br:61]C(Br)(Br)Br>ClCCl>[Br:61][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][C@H:49]1[CH2:50][C@@:30]2([CH2:31][O:32][SiH:33]([CH3:35])[CH3:34])[C@@H:36]([CH2:37][CH2:38][C@@H:29]2[C:25]([CH3:26])([CH3:28])[CH3:27])[C@@:39]2([CH:59]=[CH2:60])[C@H:48]1[C:47]1[CH:46]=[CH:45][C:44]([O:57][CH3:58])=[CH:43][C:42]=1[CH2:41][CH2:40]2
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCO)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21
Reactant: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCBr)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21
Temperature: 0 °C
Yield: 97.1 %

Procedure:
1.62 g of triphenylphosphine and 420 mg of imidazole are added in succession to a solution of 2.11 g of alcohol 8 in 41 ml of dichloromethane. The solution is cooled to 0° C., and 2.05 g of tetrabromomethane is added. The reaction mixture is heated to room temperature and stirred until the reaction is completed. For working-up, it is diluted with dichloromethane, the organic phase is washed with water and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. Column-chromatographic purification (cyclohexane/ethyl acetate) yields 2.3 g of bromide 10 as a colorless, viscous mass (GC-MS: m/z theor.: 574, pract.: 574).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([N:42]([CH2:46][CH2:47][CH3:48])[CH2:43][CH2:44][CH3:45])=[O:41])[CH:39]=1)[C:6]([NH:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:10]([OH:29])[CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)C(=O)OC(C)(C)C)=[O:7])#[N:2].[Cl:49]CCl.Cl>CO>[ClH:49].[CH2:30]([C@H:9]([NH:8][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:39]=[C:38]([C:40]([N:42]([CH2:43][CH2:44][CH3:45])[CH2:46][CH2:47][CH3:48])=[O:41])[CH:37]=1)[C@H:10]([OH:29])[CH2:11][NH:12][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: ClCCl
Reactant: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN(Cc2cccc(OC)c2)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Product: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(OC)c2)c1
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (2R,3S)-3-({3-cyano-5-[(dipropylamino)carbonyl]benzoyl}amino)-2-hydroxy-4-phenylbutyl(3-methoxybenzyl)carbamate (XXXVI, EXAMPLE 585, 0.080 g, 0.122 mmol), dichloromethane (1 mL), and methanol saturated with hydrochloric acid (1 mL) is stirred for 8 hours, after which time the solvents are removed under reduced pressure. A few drops of methanol, followed by ether, gives the title compound, MS (ESI+) for C33H40N4O4 m/z (M+H)+=557.5
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[CH2:18])[CH:16]=[CH2:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20](=[CH2:23])[CH:21]=[O:22].B(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH2:18][CH2:19][C:20]([CH3:23])([CH:21]=[O:22])[CH2:17][CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C=O
Reactant: C=CC(=C)c1ccc(OCc2ccccc2)cc1
Agent: FB(F)F
Solvent: ClCCl
Product: CC1(C=O)CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Reaction time: 3 h

Procedure:
1-benzyloxy-4-(1-methylene-allyl)-benzene (0.40 g, 1.694 mmol) and 2-methyl-propenal (0.355 mL) in DCM (10 mL) was cooled to −10° C. BF3.OCH2CH3 (0.322 mL, 1.778 mmol) was added and the reaction mixture stirred for 3 h. The mixture was then quenched by aqueous saturated NaHCO3 solution. After extraction with ethyl acetate (2×100 mL), the reaction mixture was dried over MgSO4 and purified on SiO2 to yield 4-(4-benzyloxy-phenyl)-1-methyl-cyclohex-3-ene carbaldehyde.
Reaction SMILES: [P:1]([O:19][C:20]1[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][C:23]2[C:24](=S)[N:25]([C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[CH2:34][CH2:33][CH2:32]4)[C:26](=[O:28])[O:27][C:22]=2[CH:21]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O.[NH2:45][NH2:46]>C(O)C>[P:1]([O:19][C:20]1[CH:21]=[C:22]([OH:27])[C:23]([C:24]2[N:25]([C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[CH2:34][CH2:33][CH2:32]4)[C:26]([OH:28])=[N:46][N:45]=2)=[CH:39][C:40]=1[CH:41]([CH3:43])[CH3:42])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:2]
Reactant: CC(C)c1cc2c(=S)n(-c3ccc4c(c3)CCC4)c(=O)oc2cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(c2)CCC3)c(O)cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
To a stirred solution of 0.52 g (0.84 mmols) of 7 in 15 mL of anhydrous ethanol was added 63 mg (1.27 mmols) of hydrazine hydrate and the mixture stirred at 80° C. for 30 min. The mixture was concentrated and chromatographed on silica gel using 1:1 hexane:ethylacetate to afford 0.16 g of the product 8 as off-white foam.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[O:11][CH2:12][C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[CH:15]([C:16]([OH:18])=O)[C:9]=2[CH:8]=[C:7]([CH3:23])[CH:6]=1)=[O:4].[CH:24]([C:27]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:28]=1[NH2:29])([CH3:26])[CH3:25]>>[CH:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:27]([CH:24]([CH3:26])[CH3:25])[C:28]=1[NH:29][C:16]([CH:15]1[C:14]2[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=2[CH2:12][O:11][C:10]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]([CH3:23])=[CH:8][C:9]1=2)=[O:18])([CH3:36])[CH3:35]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: COC(=O)c1cc(C)cc2c1OCc1ccccc1C2C(=O)O
Product: COC(=O)c1cc(C)cc2c1OCc1ccccc1C2C(=O)Nc1c(C(C)C)cccc1C(C)C
Yield: 8.5 %

Procedure:
The similar procedures as in Example 1 were repeated except using 6.73 g of 6,11-dihydro-4-methoxycarbonyl-2-methyldibenz[b,e]oxepin-11-carboxylic acid obtained in Example 65 (Compound AD) in place of Compound A and 3.82 g of 2,6-diisopropylaniline in place of aniline to obtain 0.86 g of Compound 51.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].O>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
To a sealed tube was added 2,4-dichloropyrimidine (100 mg, 0.671 mmol), 4-(trifluoromethoxy)phenylboronic acid (138 mg, 0.671 mmol), tetrakis(triphenylphosphine)palladium0) (78 mg, 0.067 mmol), acetonitrile (2 mL) and 2M Na2CO3 in H2O (1.007 mL, 2.014 mmol). Argon was bubbled through the reaction mixture for 1 min. The reaction mixture was then sealed and stirred at 90° C. for 16 hrs. The reaction was cooled to rt and diluted with EtOAc (30 ml). The resulting organic solution was washed with water (30 ml) and saturated aqueous NaCl (30 ml). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-40% EtOAc/Hex to give the product, 2-chloro-4-(4-(trifluoromethoxy)phenyl)pyrimidine, (62 mg, 0.226 mmol, 33.6% yield) as a white solid. Anal. Calcd. for C11H6ClF3N2O m/z 273.9, found: 275.0 (M+H)+.