Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:4]([CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][N:23]([C:20]3[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[CH2:5][CH2:6]1
Reactant: BrCCC1CCOc2ccccc21
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCN(CCC3CCOc4ccccc43)CC2)cc1
Yield: 45.7 %

Procedure:
The procedure of Example 1 is followed, but starting with 4-(2-bromoethyl)-3,4-dihydro-(2H)-benzopyran (5 g), 1-(4-nitrophenyl)piperazine (4.3 g) and from dry potassium carbonate (1.43 g), followed by potassium iodide (3.43 g) in 2-butanone (200 cc). The residue obtained is chromatographed on a column 4.4 cm in diameter, containing silica gel (100 g), using a dichloromethane-ethyl acetate mixture (50-50 by volume) as eluent, and collecting 20-cc fractions. The fractions between 100 and 300 cc are concentrated to dryness. The residue obtained is crystallized from isopropyl acetate (30 cc). 1-[2-(3,4-Dihydro-1(2H)-benzopyran-4-yl)ethyl]-4-(4-nitrophenyl)-piperazine (3.48 g) is thus obtained in the form of a yellow solid melting at 110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:21][NH:22][CH3:23]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:22]([CH3:23])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CNC
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reaction time: 3 h
Yield: 76.2 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.010 mole) 1,1'-carbonyldiimidazole (1.7 g, 0.010 mole) and dry tetrahydrofuran (150 ml) was stirred for 3 hrs. at room temperature with a stream of nitrogen bubbling through it. A solution of 1.0 g of dimethylamine in 25 ml of tetrahydrofuran was added and the reaction container was stoppered and the mixture was stirred overnight at room temperature. The tetrahydrofuran was evaporated and the residue triturated in water (50 ml) and filtered. The filter cake was recrystallized from isopropyl alcohol and then from ethanol, giving 2.4 g (32%) of white needles, mp 212°-213° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH:38]([CH3:40])[CH3:39])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])([CH3:40])[CH3:39]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-isopropyl-benzenesulfonamide [CAS 118837-66-4] according to general procedure II. Yellow solid. MS (ISP) 570.2 [(M−H)−]; mp 222° C.
Reaction SMILES: O[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.ClCCl>[CH3:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: O=c1c(CO)c[nH]c2c([N+](=O)[O-])cccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c[nH]c2c([N+](=O)[O-])cccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 1,4-dihydro-3-hydroxymethyl-8-nitro-4-oxoquinoline (3.1 g) in trifluoroacetic acid (10 ml) and dichloromethane (10 ml) was added triethylsilane (6.55 g), and the mixture was stirred at ambient temperature overnight. The mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give 1,4-dihydro-3-methyl-8-nitro-4-oxoquinoline (2.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1cccc(Cl)c1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(2-fluoro-6-chlorobenzyloxy)pyridine (3.46 g, 0.014 mol), 4chlorophenyl isothiocyanate (2.55 g, 0.015 mol) and toluene (10 ml) was refluxed for 2 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 4.64 g (73%), m.p. 162°-164 ° C.
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[C:3]=1N.C(ON=O)(C)(C)C.[ClH:21]>C(#N)C>[Cl:21][C:3]1[C:2]([Cl:1])=[C:8]([F:9])[C:7]([F:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1c([N+](=O)[O-])cc(F)c(F)c1Cl
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(F)c(Cl)c1Cl
Reaction time: 0.22 h

Procedure:
To a mixture of anhydrous cupric chloride (2.2 g) and 2-chloro-3,4-difluoro-6-nitroaniline (2.63 g) in anhydrous acetonitrile (20 ml) was added t-butylnitrite (2.0 g) dropwise at 46° to 55° C. during 9 minutes. After stirring for 13 minutes at the same temperature, the reaction mixture was poured into chilled 10% diluted hydrochloric acid (20 ml) and extracted with benzene. The organic layer was washed with diluted hydrochloric acid and with water successively, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography eluting with dichloromethane-n-hexane (1:5) to give the title compound (2.47 g), as yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[CH:26](Cl)[C:27](=[N:29][NH:30]S(C1C(C)=CC=CC=1)(=O)=O)[CH3:28]>CO>[I:15][C:12]1[CH:13]=[CH:14][C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][N:1]3[CH:26]=[C:27]([CH3:28])[N:29]=[N:30]3)[O:7][C:6]2=[O:8])=[CH:10][CH:11]=1
Reactant: NC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Reactant: CC(=NNS(=O)(=O)c1ccccc1C)C(Cl)Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(C[C@H]2CN(c3ccc(I)cc3)C(=O)O2)nn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(5S)-5-(Aminomethyl)-3-(4-iodophenyl)-1,3-oxazolidin-2-one (6.0 g, 18.9 mmol) was dissolved in methanol (150 ml, c=0.1M) and cooled to 0° C. Diisopropylethylamine (13.1 ml, 75.4 mmol) was added and the reaction stirred at 0° C. for 5 min; toluenesulfonic acid 2-(2,2-dichloro-1-methylethylidene)hydrazide was then added and the reaction stirred overnight. The volatiles were concentrated in vacuo, dichloromethane was added and some product crystallized from solution; the remaining residue was purified by flash chromatography on silica gel using 0-5% methanol in dichloromethane as the eluent. The relevant fractions were combined giving 5.5 g of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([S:23]([CH3:22])(=[O:25])=[O:24])[CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CNC1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C1CCN(C(=O)OC(C)(C)C)C1)S(C)(=O)=O
Reaction time: 24 h

Procedure:
To a solution of 3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g) in dichloromethane (10 ml) was added triethylamine (0.38 ml) followed by methanesulfonyl chloride (0.21 ml). After stirring for 24 hours the reaction mixture was diluted with dichloromethane, washed with sodium bicarbonate solution, dried (Mg2SO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 3-(methanesulfonyl-methyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.52 g). Treatment of this compound with HCl in dichloromethane/methanol yielded N-Methyl-N-pyrrolidin-3-yl-methanesulfonamide hydrochloride salt (0.41 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][S:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(O)(C)C.Cl.O1CCOCC1>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[C:3]2[CH:17]=[CH:16][S:15][C:4]=2[N:5]=1
Reactant: Fc1ccccc1-c1nc(Cl)c2ccsc2n1
Reactant: Nc1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Fc1ccccc1-c1nc(Nc2ccncc2)c2ccsc2n1
Temperature: 80 °C
Yield: 87.8 %

Procedure:
4-Chloro-2-(2-fluoro-phenyl)-thieno[2,3-d]pyrimidine (110 mg, 0.41 mmole) and 4-aminopyridine (78 mg, 0.830 mmole) were combined in isopropanol (3 ml), then 4 drops of 4 M HCl/dioxane were added and the reaction mixture was heated to 80° C. for 7 hours. The reaction mixture was cooled and the product was isolated by filtration, washed with minimum cold methanol and dried under vacuum to give 116 mg of product (yield: 86%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20].N1CCCCC1>C(O)C>[NH2:22][C:21]1[O:1][C:2]2[C:11]3[N:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH:5]=[CH:4][C:3]=2[CH:17]([C:16]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:18]=1[C:19]#[N:20]
Reactant: COc1ccc(C=C(C#N)C#N)cc1OC
Reactant: Oc1cccc2cccnc12
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C2C(C#N)=C(N)Oc3c2ccc2cccnc32)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 8-hydroxyquinoline (2.90 g) and 3,4-dimethoxy benzylidenemalononitrile(4.28 g) in ethanol (15 ml) was treated with piperidine (1.70 g) and the suspension stirred at room temperature for one hour. This mixture was then heated at reflux for 90 minutes. The red solution was then allowed to cool to room temperature overnight. The precipitated orange solid was filtered off and washed with ethanol and ether and dried in vacuo at 60° C., yielding 2-amino-4-(3,4-dimethoxyphenyl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile as a tan solid, m.p. 118°-120° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:23]1[CH:24]=[N:25][N:26](C(OC(C)(C)C)=O)[CH:27]=1.[CH3:35][N:36]([C:38]1[C:39](B(O)O)=[N:40][CH:41]=[CH:42][CH:43]=1)[CH3:37].C(=O)([O-])[O-].[K+].[K+].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.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.O.CN(C=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([C:23]4[CH:27]=[N:26][NH:25][CH:24]=4)=[C:2]([C:42]4[CH:41]=[N:40][CH:39]=[C:38]([N:36]([CH3:37])[CH3:35])[CH:43]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)c1cccnc1B(O)O
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cnn(C(=O)OC(C)(C)C)c3)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cncc(N(C)C)c3)c(-c3cn[nH]c3)sc2n1
Temperature: 110 °C
Yield: 46.7 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(3-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methylthieno[2,3-b]pyridin-2-yl)-1H-pyrazole-1-carboxylate (Description 75) (150 mg, 0.257 mmol), dimethylamino pyridine boronic acid (85 mg, 0.514 mmol), potassium carbonate (107 mg, 0.771 mmol), tetrakis(triphenylphosphine)palladium(0) (7.42 mg, 6.42 μmol) and bis(triphenylphosphine)palladium(II) chloride (4.51 mg, 6.42 μmol) were weighed into a microwave vial. 1,4-Dioxane (2.0 mL), DMF (1.0 mL) and water (0.5 mL) were added and the mixture heated in a microwave at 110° C. for 30 min. At this point, both reaction mixtures were combined and concentrated. The residue was passed through an SCX cartridge, eluting with MeOH (100 mL) and then with 2M NH3 in MeOH (150 mL). The basic methanolic solution was concentrated and purified by MDAP (acidic conditions) and then further purified by normal phase chromatography, eluting with a gradient of 0-10% MeOH in DCM, to give the title compound (63 mg). LCMS (A) m/z: 523 [M−1]−, Rt 0.78 min (acidic).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].Cl.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33]Cl.[I-].[Na+].C(N(CC)CC)C>C(#N)C>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:33][CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:27]
Reactant: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCNCC2)cc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCN(CCCN(C)C)CC2)cc1
Yield: 25.2 %

Procedure:
To a solution of N,N-diethyl-4-[benzyl(piperidin-4-yl)amino]benzamide (Compound 8) (0.29 g, 0.793 mmole) in 25 mL of acetonitrile was added 3-(dimethylamino)propyl chloride hydrochloride (0.013 g, 0.793 mmol), sodium iodide (0.02 g, 0.119 mmol), and triethylamine (0.32 g, 3.18 mmol). The reaction mixture was refluxed for 20 hours under Argon and then was cooled and concentrated in vacuo. To the residue was added, aqueous sodium hydroxide (1 N) solution (30 mL), and the resulting solution was extracted three times with chloroform (25 mL). The organic extracts were combined, washed with sodium carbonate solution, dried (Na2SO4), and concentrated to provide a brown oil. This material was purified on a flash silica gel column (10% methanol-chloroform to 17.5% methanol-chloroform) to provide 0.09 g (25%) of N,N-diethyl-4-[benzyl(1-(3-dimethylaminopropyl)piperidin-4-yl)amino]benzamide as a pale rose glass. MS (ES), m/z 451 (MH+). 300 MHz 1H NMR (CDCl3) δ1.17 (t, J=7.0 Hz, 6H), 1.69-1.89 (m, 4H), 2.14 (br t, 2H), 2.18-2.38 (br m, 2H), 2.42 (s, 4H), 2.47 (t, J=7.1 Hz, 2H), 2.59 (t, J=6.9 Hz, 2H), 3.06 (br d, J=11.6 Hz, 2H), 3.30-3.49 (m, 4H), 3.72-3.90 (br m, 1H), 4.52 (s, 2H), 6.65 (d, J=8.7 Hz, 2H), 7.10-7.30 (m, 7H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.Cl[CH2:22][C:23]([OH:25])=[O:24].C(O)C.[OH-].[K+].Cl>C(O)C>[C:23]([CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:6][CH:7]=1)([OH:25])=[O:24]
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccc(O)cc2)N1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(C2(c3ccccc3)NC(=O)NC2=O)cc1

Procedure:
400 mg of 5-(p-hydroxyphenyl)-5-phenylhydantoin in 4 ml of absolute ethanol was mixed with 140 mg of chloroacetic acid in 3.5 ml of 1 N-potassium hydroxide ethanol solution and then the mixture was refluxed for 22 hours. After cooled, the mixture was acidified with 0.33 ml of 5 N-hydrochloric acid, followed by distillation to remove the ethanol. Then 20 ml of distilled water was added and the pH value was adjusted to 1.0-2.0 with 5 N-hydrochloric acid. The solution obtained was extracted four times with 5 ml of ethyl acetate and dried with anhydrous sodium sulfate. Then it was dissolved in 2 ml of chloroform-methanol (2:1, v/v) solution and the solution was fractionated through a 2.0×40 cm silica gel column. The second fraction was collected. 5-(p-carboxymethoxyphenyl)-5-phenylhydantoin (CMPPH) was obtained by evaporating the second fraction and dried on calcium chloride under vacuo.
Reaction SMILES: CS(O[CH2:6][C@H:7]([CH3:15])[CH2:8][CH2:9]OS(C)(=O)=O)(=O)=O.[NH2:16][CH2:17][CH2:18][OH:19].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C(#N)C.O>[CH3:15][C@@H:7]1[CH2:8][CH2:9][N:16]([CH2:17][CH2:18][OH:19])[CH2:6]1
Reactant: C[C@H](CCOS(C)(=O)=O)COS(C)(=O)=O
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CCN(CCO)C1
Temperature: 25 °C
Yield: 28.2 %

Procedure:
A mixture of (R)-2-methylbutane-1,4-diyl dimethanesulfonate (30 g, 0.115 mol), 2-aminoethanol (7.0 g, 0.115 mol), and K2CO3 (31.7 g, 0.23 mol) in acetonitrile (0.9 L) was refluxed for 20 h. The mixture was cooled to room temperature and concentrated under vacuum to afford a residue (a mixture of oil and solid). DCM (300 mL) and sat'd K2CO3 solution (300 mL) were added and just enough water was added to dissolve all solid. The organic layer was separated, and aqueous phase was further extracted with DCM (2×300 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography [EA/Hex/MeOH/TEA=10:7:2:1] gave (R)-2-(3-methylpyrrolidin-1-yl)ethanol (4.19 g, 28%). 1H NMR (CDCl3): δ 3.61 (t, 2H), 2.84 (dd, 1H), 2.70 (m, 1H), 2.65 (m, 1H), 2.62 (m, 1H), 2.54 (m, 1H), 2.25 (m, 1H), 2.11 (dd, 1H), 2.03 (m, 1H), 1.36 (m, 1H), 1.03 (d, 3H); MS: 130.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH2:7]O)=[CH:4][CH:3]=1.[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Cl)(Cl)(Cl)[Cl:29]>>[Br:1][C:2]1[O:6][C:5]([CH2:7][Cl:29])=[CH:4][CH:3]=1.[C:22]1([P:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1ccc(Br)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1ccc(Br)o1
Temperature: 75 °C

Procedure:
To a solution of (5-bromo-2-furanyl)methanol (Example 310A) (144 mmol) in dry carbon tetrachloride (30 mL) was added triphenylphosphine (6.0 g, 228 mmol) at rt. The reaction is heated at 75° C. for 1 h. Concentration and purification by radial chromatography (0-10% EtOAc-hexanes gradient) afforded the title compound with contamination of triphenylphosphine. The product is used without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[OH:38][CH2:39][CH2:40][C:41]#[CH:42]>C1(C)C=CC=CC=1.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>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:42]#[C:41][CH2:40][CH2:39][OH:38])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CCCO)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A suspension of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 729 mg, 1.5 mmol) in toluene (8 mL) was treated with N,N-diisopropylethylamine (2 mL), 4-hydroxybutyne (210 mg, 3.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (60 mg), and copper(I) iodide (30 mg). The mixture was stirred at 25° C. overnight, and an oily black precipitate was obtained. The top clear solution was decanted, and the oily precipitate was rinsed first with toluene (5 mL) and then with hexanes (5 mL). The residue was dissolved in methylene chloride and extracted with methylene chloride and a 0.2N aqueous hydrochloric acid solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, elution with 1/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxy-but-1-ynyl)-pyrazin-2-yl]-propionamide (650 mg, 88.4%) as a fluffy solid: (ES)+-HRMS m/e calcd for C23H26ClN3O4S (M+H)+ 476.1406, found 476.1395.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]([CH3:20])[C:7]2[C:12]([C:13]=1[CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2].CO.ClCCl.[OH-].[Na+]>C(O)(=O)C>[C:1]([NH:4][C:5]1[N:6]([CH3:20])[C:7]2[C:12]([C:13]=1[CH2:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1c(NC(C)=O)n(C)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1c(CC(=O)O)c2ccccc2n1C
Reaction time: 8 h

Procedure:
To a solution of 3.7 g. of 2-acetamido-3-carbethoxymethyl-1-methylindole in 37 ml. of methanol and 5 ml. of dichloromethane, 15.5 ml. of 1N sodium hydroxide are added at 0° C. The mixture is allowed to stand overnight and then it is neutralized with acetic acid and then evaporated to dryness. The oily residue is taken up with diluted hydrochloric acid and the solid which forms is washed with water. The product is purified by crystallization from ethanol. Yield 3.07 g., m.p. 200°-206° C.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[C:11]([O:18][CH3:19])[CH:10]=1)=[O:8].[OH-].[NH4+]>C(O)(=O)C.O>[CH3:5][O:6][C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][NH:15]2)=[C:11]([O:18][CH3:19])[CH:10]=1)=[O:8]
Reactant: COC(=O)c1cc(OC)c2cc[nH]c2c1
Agent: [BH3-]C#N
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc2c(c(OC)c1)CCN2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Sodium cyanoborohydride (3.6 g, 57.8 mmol, 3 equiv.) was added to a stirred solution of 4-methoxy-1H-indole-6-carboxylic acid methyl ester (3.96 g, 19.3 mmol, 1 equiv.) in acetic acid (40 mL) at room temperature over 5 minutes. The mixture was stirred for 30 minutes, then cooled to 0° C. and slowly poured onto concentrated ammonium hydroxide (78 mL, d=0.880) at 0° C. The mixture was diluted with water (20 mL) extracted with dichloromethane (4×25 mL). The organic layers were combined, dried over Na2SO4 and the solvent was removed under vacuum. The crude mixture was purified by flash column chromatography (SiO2, dichloromethane) and the fractions combined to afford 4-methoxy-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester, 2.8 g (70% yield). LC @215 nm; Rt 0.85: 97%, m/z (ES+): 208 (M+H+.); δH (400 MHz; d6-DMSO) 6.90 (1H, s), 6.86 (1H, s), 3.80 (3H, s), 3.79 (3H, s), 3.49 (2H, t), 2.89 (2H, t).