Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15].[C-:16]#[N:17].[K+]>C(O)C.O>[C:16]([CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15])#[N:17]
Reactant: [C-]#N
Reactant: COc1cc2c(cc1OC)C(=O)C(Br)C2
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OC)C(=O)C(C#N)C2
Yield: 44.4 %

Procedure:
2-Bromo-5,6-dimethoxy-indan-1-one (69.1 g) was suspended in ethanol (1,200 ml) and added to a solution of potassium cyanide (70.4 g) in water (2,200 ml). The reaction mixture was heated at reflux for 1 hour and then the ethanol was distilled off. The dark solution was cooled, stirred and carefully neutralised with hydrochloric acid (5M, 120 ml) in a well ventilated hood. The organic extracts were combined, washed with brine, dried over magnesium sulphate, filtered, then concentrated to low volume under reduced pressure. The residual liquid was filtered through a column of coarse silica (0.2-0.5 mm, Merck, 300 g) and the column was eluted with dichloromethane. The appropriate fractions were combined and evaporated to dryness to give 2-Cyano-5,6-dimethoxy-indan-1-one (24.6 g). A portion crystallised from dichloromethane: ether; m.p. 177°-179° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1)=O.[CH3:11][C:12](=O)[CH2:13][C:14](=[O:16])[CH3:15].[F:18][C:19]([F:31])([F:30])[C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=1>O1CCCC1.CS(C)=O>[C:14]([C:13]1[CH:1]([C:3]2[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=2)[NH:29][C:27](=[O:28])[N:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:30])([F:31])[F:18])[CH:21]=2)[C:12]=1[CH3:11])(=[O:16])[CH3:15]
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)cn1
Reactant: CC(=O)CC(C)=O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)nc1

Procedure:
To a stirred solution of Example 3A (75 mg, 0.57 mmol) in tetrahydrofuran (5 ml) is given 2,4-pentandione (57 mg, 0.57 mmol), N-[3-(trifluoromethyl)phenyl]urea (116 mg, 0.57 mmol) and polyphosphoric acid ethyl ester (200 mg) [freshly prepared according to the procedure of Cava et al., J. Org. Chem. 34, 2665 (1969)]. The reaction mixture is refluxed for 24 hours after which time the solution is diluted with DMSO (2 ml) and purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([C:22]4[CH:23]=[N:24][N:25]([CH:27]([CH3:29])[CH3:28])[CH:26]=4)=O)[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl-:30].[NH4+]>CO>[ClH:30].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:22]4[CH:23]=[N:24][N:25]([CH:27]([CH3:29])[CH3:28])[CH:26]=4)[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)n1cc(C(=O)N2CCN(c3nccnc3-c3ccc(F)cc3)CC2)cn1
Reactant: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)n1cc(CN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)cn1
Product: Cl
Reaction time: 18 h
Yield: 98.5 %

Procedure:
Prepare the title compound using the methods of Example 135 starting with [3′-(4-fluorophenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]-(1-isopropyl-1H-pyrazol-4-yl)-methanone (94 mg, 47%). Dissolve the free base (0.087 g, 0.229 mmol) in methanol and add a solution of ammonium chloride (0.012 g, 0.229 mmol) in a minimal volume of methanol. Shake for 18 hr. at room temperature and concentrate to give the title compound (94 mg, 99%). MS (ES): m/z=381 [M+H]+.
Reaction SMILES: BrCC.Cl[CH:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.N1CCCCC1.[F:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[C:21]#N.[NH4+].[Cl-].[OH2:30]>O1CCCC1>[F:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[C:21]([CH:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1)=[O:30]
Reactant: O
Reactant: N#Cc1cc(F)ccc1F
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCBr
Solvent: C1CCNCC1
Product: CN1CCC(C(=O)c2cc(F)ccc2F)CC1
Reaction time: 65 h
Yield: 66.5 %

Procedure:
To a stirred suspension of Mg (9.62 g, 0.40 moles) in tetrahydrofuran (THF) (45 ml) was added a few ml of bromoethane to initiate the reaction followed by dropwise addition of freshly distilled 4-chloro-N-methylpiperidine (42.3 g, 6.32 moles) in THF (140 ml). The reaction was initiated with a high intensity heat gun and controlled by the rate of addition of the piperidine. After the addition was complete, the reaction was refluxed for 1 hour. Next 2,5-difluorobenzonitrile (48.2 g, 0.318 moles) in THF (20 ml) was added and the reaction was refluxed for an additional 3 hours. The reaction was allowed to stand for 65 hours and was then poured into a solution of NH4Cl/H2O (120 g/400 ml). The mixture was heated on a steam bath for 2 hours, cooled and extracted with ether (500 ml.). Concentration produced an oil (50.6 g) which the product was distilled from (112° C.@0.5 mm) to yield 30.4 g (40%) of the product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][S:9]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:23]1[N:32]=[C:31]([NH2:33])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>C(O)CC(C)C>[NH2:33][C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][S:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:32]=1
Reactant: NCCCCCCNS(=O)(=O)c1cccc2ccccc12
Reactant: Nc1nc(Cl)nc2ccccc12
Solvent: CC(C)CCO
Product: Nc1nc(NCCCCCCNS(=O)(=O)c2cccc3ccccc23)nc2ccccc12

Procedure:
A solution of naphthalene-1-sulfonic acid (6-aminohexyl)-amide (0.450 g) and 2-chloro-quinazolin-4-ylamine (see: U.S. Pat. No. 3,956,495) (0.264 g) in 20 ml of isopentylalcohol is heated up to 120° C. for 15 h. Concentration of the reaction mixture followed by chromatography on silica gel (B1) yields naphthalene-1-sulfonic acid [6-(4-amino-quinazolin-2-ylamino)-hexyl]amide as a white powder, melting at 98-101° C. Rf(B1) 0.28, FAB-MS: (M+H)+ =450. Ananlytical C26H29N5O2S+HCl+H2O+0.6 1,4 dioxane. m.p. 98-101° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:10]3[CH:11]([OH:23])[CH2:12][CH2:13][CH2:14][C:9]=3[C:4]=2[CH:3]=1
Reactant: Oc1ccc(Br)cc1C1C=CCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: c1ccccc1
Product: OC1CCCc2c1oc1ccc(Br)cc21

Procedure:
A solution of the phenol and MCPBA in benzene is refluxed overnight. A solid is precipitated out and filtered. The filtrate is concentrated under vacuum and chromatographed (10% EtOAc in hexanes) to give 8-bromo-1,2,3,4-tetrahydro-dibenzofuran-4-ol 108 as clear oil, 0.66 g, 39%.
Reaction SMILES: C([Li])CCC.[CH2:6]([PH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:7]([CH3:9])[CH3:8].[CH3:17][C:18]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:19]=1[C:20](Cl)=[O:21].[OH:29]O>O1CCCC1>[CH3:17][C:18]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:19]=1[C:20]([P:10](=[O:29])([CH2:6][CH:7]([CH3:9])[CH3:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:21]
Reactant: CC(C)CPc1ccccc1
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(=O)P(=O)(CC(C)C)c2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
At −20° C., 40 ml (0.064 mol) of butyllithium 1.6 M are slowly added dropwise to 9.5 g (0.058 mol) of isobutylphenylphosphine in 100 ml of tetrahydrofuran (THF). At the same temperature, 11.7 g (0.064 mol) of 2,4,6-trimethylbenzoyl chloride are then added dropwise. After the mixture has been allowed to warm to room temperature, the orange reaction suspension is concentrated using a rotary evaporator (Rotavap). The residue is taken up in 150 ml of toluene, and is treated with 13.1 g (0.116 mol) of hydrogen peroxide 30%. After the mixture has been stirred for 2 hours between 20-30° C., the reaction is complete. The reaction emulsion is poured onto water and washed with aqueous saturated sodium hydrogencarbonate solution, then dried over magnesium sulfate and filtered. The filtrate is concentrated using the Rotavap. The residue is purified over silica gel and dried under a high vacuum. 11.8 g of the title compound are obtained as a yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(Cl)(Cl)Cl>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(Cl)c2c(c1)CCN2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(Cl)c2[nH]ccc2c1
Yield: 78.3 %

Procedure:
To a solution of 7-chloro-5-nitroindoline (0.23 g, 1.2 mmol) in 20 mL of acetone was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone until color of the solution turns to dark green. Reaction mixture was concentrated in vacuo providing a dark residue which was subjected to column chromatography (CHCl3, neat) to yield 0.18 g (0.94 mmol, 79%) of the indole.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][NH:9][CH3:10])[O:3]1.[CH3:11][N:12]([CH3:24])[S:13]([C:16]1[S:20][C:19]([N:21]=[C:22]=[O:23])=[N:18][N:17]=1)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[CH3:11][N:12]([CH3:24])[S:13]([C:16]1[S:20][C:19]([NH:21][C:22]([N:9]([CH2:8][CH:4]2[O:3][CH:2]([CH3:1])[CH2:7][CH2:6][O:5]2)[CH3:10])=[O:23])=[N:18][N:17]=1)(=[O:15])=[O:14]
Reactant: CN(C)S(=O)(=O)c1nnc(N=C=O)s1
Reactant: CNCC1OCCC(C)O1
Solvent: ClC(Cl)Cl
Product: CC1CCOC(CN(C)C(=O)Nc2nnc(S(=O)(=O)N(C)C)s2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(4-methyl-1,3-dioxan-2-ylmethyl)-methylamine (6 grams), 5-(N,N-dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl isocyanate dimer (6 grams) and chloroform (20 ml) were charged into a glass reaction vessel and stirred at room temperature for a period of about 2 hours. The solvent was then stripped off on a rotary evaporator and the residue treated with a mixture of diethyl ethyl (100 ml)/water (50 ml). The ether, layer was isolated and dried. Ether was stripped off an a rotary evaporator to yield the desired product N-[5-(N,N-dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl]-N'-(4-methyl-1,3-dioxan-2-ylmethyl)-N'-methylurea as the residue. Melting point 131° C.-133° C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:27]=3[CH3:26])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Cl)ccc1C(=O)Cl
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1C(=O)OC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Methyl-4-chlorobenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro- 1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(2-methyl- 4-chlorobenzoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[C:7]2=[N:6][C:5]1=[O:17])([CH3:3])[CH3:2].[CH2:19]([SH:22])[CH:20]=[CH2:21].C(N(CC)CC)C.C(O)=O>O1CCCC1>[CH2:19]([S:22][C:7]12[NH:6][C:5](=[O:17])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:18])[N:8]1[C:9](=[O:16])[C:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=1)[CH:20]=[CH2:21]
Reactant: C=CCS
Reactant: CC(C)C1(C)C(=O)N=C2c3ncccc3C(=O)N21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: C=CCSC12NC(=O)C(C)(C(C)C)N1C(=O)c1cccnc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under a nitrogen atmosphere, 7.8 g of 3-isopropyl-3-methyl-3H-imidazo[1',2':1,2]pyrrolo[3,4-b]pyridine-2,5-dione in 50 ml of tetrahydrofuran are stirred together with 3.5 ml of allylmercaptan and 4.9 ml of triethylamine. The mixture is stirred further for 15 hours at room temperature. In order to work up the reaction mixture, 1.2 ml of formic acid are added and most of the solvent is evaporated off. The residue is chromatographed through a column of silica gel eluted with a 1:1 mixture of ethyl acetate and hexane. The eluant is evaporated off off, leaving a residue which crystallises. Yield: 3.2 g of the title product; m.p.: 126°-138° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:20][C:21](Cl)=[O:22].O1CCCC1.[H-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([N:8]1[CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH2:20][C:21]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(O)c(CNCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CN(Cc1ccccc1)C(=O)CO2
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A mixture of 2.43 g of 2-(benzylamino-methyl)-4-methoxy-phenol and 20 mL of toluene was cooled to 5° C. and a solution of chloroacetyl chloride (0.88 mL) in 5 mL of toluene slowly added while stirring. Stirring was continued for 2 hours at room temperature. Dry tetrahydrofuran (25 mL) was added and 3.4 g of sodium hydride (95%; dispersion in mineral oil) were added in small portions under a nitrogen atmosphere. The mixture was allowed to stir at room temperature for 24 h. Water was added and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and the solvent removed in vacuo yielding 2.0 g of 4-benzyl-7-methoxy-4,5-dihydro-benzo[f][1,4]oxazepin-3-one as an oil. EI-MS: 283 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2([CH2:23][OH:24])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]2=[O:22])[CH:7]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:24][CH2:23][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22])[C:6]=2[CH:7]=1
Reactant: CCCCCN1C(=O)C(CO)(c2cc(F)ccc2O)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C2(COc3ccc(F)cc32)c2ccccc21
Yield: 3 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 3-(5-fluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 3% yield: 1H NMR (300 MHz, CDCl3) δ 7.37-7.28 (m, 1H), 7.18-7.11 (m, 1H), 7.09-7.01 (m, 1H), 6.98-6.82 (m, 3H), 6.45-6.37 (m, 1H), 4.95 (d, 1H), 4.69 (d, 1H), 3.89-3.63 (m, 2H), 1.81-1.65 (m, 2H), 1.48-1.28 (m, 4H), 0.92 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.7, 159.4, 156.6, 132.2, 130.1, 129.3, 124.1, 123.4, 116.3, 110.8, 110.5, 108.9, 80.4, 58.4, 40.6, 29.2, 27.3, 22.5, 14.1; MS (ES+) m/z 326 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[C:12](O)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:22]2[N:27]=[N:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C([O-])(O)=O.[Na+]>[C:16]1([C:22]2[CH:23]=[CH:24][C:25]3[N:26]([C:12]([CH:11]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH3:15])=[N:29][N:28]=3)[N:27]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: CC(C(=O)O)c1ccc2ncccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(c1ccc2ncccc2c1)c1nnc2ccc(-c3ccccc3)nn12
Temperature: 160 °C
Yield: 54.5 %

Procedure:
To a 2-5 ml Personal Chemistry microwave vial was added 2-(quinolin-6-yl)propanoic acid (0.25 g, 1.2 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.42 g, 2.2 mmol) and conc. HCl (2 mL). The mixture was heated in the microwave at 160° C. for 8 h. After cooling to rt, the mixture was poured into sat. NaHCO3 (100 mL) and then extracted with EtOAc (4×75 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (1.0 to 4.5% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as an off-white solid (0.23 g, 53% yield). MS (ESI, pos. ion) m/z: 352 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]([C@H:24]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:34]=[C:33]([C:35]#[N:36])[S:32][CH:31]=2)[C:25]1=[O:37])[S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:35]([C:33]1[S:32][CH:31]=[C:30]([CH2:29][N:26]2[CH2:27][CH2:28][C@H:24]([N:8]([S:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][CH:18]=4)[CH:13]=3)(=[O:11])=[O:10])[CH2:7][C:6]([OH:38])=[O:5])[C:25]2=[O:37])[CH:34]=1)#[N:36]
Reactant: COc1ccc2ccc(S(=O)(=O)N(CC(=O)OC(C)(C)C)[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N(CC(=O)O)[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Reaction time: 2 h

Procedure:
To a solution of 2-[[1-(5-cyanothiophene-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-(7-methoxynaphthalene-2-sulfonyl)amino]acetic acid tert-butyl ester (0.40 g, 0.72 mmol) in 15 mL of CH2Cl2 is added 5 mL of TFA. After 2 hours, the solution is concentrated to give the title compound as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH3:19])[CH:5]=1.FC(F)(F)S(O[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH:28]=1)(=O)=O>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:28][CH:29]=2)=[C:6]([CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: O=S(=O)(OC1=CCCc2ccccc21)C(F)(F)F
Product: COC(=O)c1ccc(C2=CCCc3ccccc32)c(C)c1
Yield: 97.3 %

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Example 28, Step A (5.00 g, 18.1 mmol) and 3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate (5.54 g, 19.9 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with 10% ethyl acetate in hexane, afforded the title compound (4.90 g) as a light yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[CH:4][N:3]=1.[C:14]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>C(O)C.C(OCC)(=O)C>[CH3:17][C:14]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][NH:23][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[CH:4][N:3]=2)=[CH:24][CH:25]=1)([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(F)cnc1NCc1ccc(C(C)(C)C)cc1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
A solution of ethyl 2-chloro-5-fluoro-3-pyridinecarboxylate (0.490 g, 2.41 mmol) in ethanol (10.0 mL) was treated with 4-tert-butylbenzylamine (0.450 mL, 2.55 mmol). The mixture was heated to 150° C. for 0.5 h and then to 160° C. for 20 min. in a Biotage Initiator microwave synthesizer. The solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The combined organic portions were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography (20-40% ethyl acetate in hexanes) afforded a mixture of the title compound and starting material as a clear yellow oil (0.326 g, 41%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.39 (d, J=3.0 Hz, 1H), 8.20 (d, J=3.3 Hz, 1H), 8.14 (t, J=5.1 Hz, 1H), 7.91 (dd, J=6.9, 3.2 Hz, 2H), 7.89 (dd, J=8.1, 3.0 Hz, 2H), 4.69 (d, J=5.3 Hz, 2H), 4.44 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H), 1.32 (s, 9H). MS(ES+) m/e 331 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[NH4+].[Zn]>[CH2:1]([C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Product: O=C(O)c1ccc(Cl)cc1Cc1ccccc1

Procedure:
To a solution of 5.0 g of cupric sulfate in 3 liters of concentrated ammonium hydroxide was added 300 g (4.6 mole) of activated zinc dust and 100 g (0.42 mole) of 2-benzoyl-4-chlorobenzoic acid. The mixture was refluxed for 3 days, during which the volume was maintained by the addition of concentrated ammonium hydroxide. The mixture was cooled, and the excess zinc was removed by filtration. The filtrate was acidified by the addition of concentrated hydrochloric acid to a pH of 3. The resulting percipitate was collected by filtration, and dried to constant weight to give a white solid with mp 142°-144°.
Reaction SMILES: [C:1]([CH2:6][CH:7]1[O:14][CH:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[CH:8]1/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(OCC)=[O:2].CCCCCCC.[H-].C([Al+]CC(C)C)C(C)C.Cl>CCCCCC>[CH:1]([CH2:6][CH:7]1[O:14][CH:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[CH:8]1/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:2]
Reactant: CCCCCC/C=C/C1C(CC(=O)OCC)OC2CCCC21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCCC
Solvent: CCCCCC
Product: CCCCCC/C=C/C1C(CC=O)OC2CCCC21
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1.00 g. (0.00308 mole) of 2-(carbethoxymethyl)-3-(1-trans-octenyl)-1,1-dioxolano cyclopentane in 5 ml. of heptane at -78°C. and under nitrogen is added dropwise 2.60 ml. of a solution of 25% diisobutylaluminum hydride in hexane. The resulting solution is stirred at -78°C. for 2.5 hours and then poured into cold dilute hydrochloric acid. The organic phase is washed with saturated brine, dried (Na2SO4), and evaporated to yield 0.863 g. of a colorless oil. IR 2695, 1723, 1045, 970 cm-1.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([NH:28][C@H:29]([B:46]2[O:54]C3C(C)(C4CC(C3)C4(C)C)[O:47]2)[CH2:30][C:31]2[C:32](OC)=[C:33]([CH:41]=[CH:42][CH:43]=2)[C:34]([O:36]C(C)(C)C)=[O:35])=[O:27])[CH:13]=[CH:14][C:15]=1[CH2:16][NH:17]C(OC(C)(C)C)=O)=O)(C)(C)C.B(Cl)(Cl)Cl>>[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([NH:28][C@H:29]2[CH2:30][C:31]3[CH:43]=[CH:42][CH:41]=[C:33]([C:34]([OH:36])=[O:35])[C:32]=3[O:54][B:46]2[OH:47])=[O:27])[CH:13]=[CH:14][C:15]=1[CH2:16][NH2:17]
Reactant: COc1c(C[C@H](NC(=O)Cc2ccc(CNC(=O)OC(C)(C)C)c(CNC(=O)OC(C)(C)C)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: NCc1ccc(CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)cc1CN

Procedure:
Prepared from tert-butyl 3-((2R)-2-(2-(3,4-bis((tert-butoxycarbonylamino)methyl)phenyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate and BCl3 following the procedure described in Step 2 of Example 3. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 384 (MH)+.