Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][P:4]([O:9][CH2:10][CH3:11])([CH2:6][C:7]#[N:8])=[O:5].C(N(CC)CC)C.N1C=CC=CC=1.[SH2:25]>>[CH2:10]([O:9][P:4]([CH2:6][C:7]([NH2:8])=[S:25])(=[O:5])[O:3][CH2:2][CH3:1])[CH3:11]
Reactant: S
Reactant: CCOP(=O)(CC#N)OCC
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC(N)=S)OCC
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A 250-mL round-bottom flask equipped with a dry-ice condenser and drying tube filled with potassium hydroxide pellets, was charged with 50.0 g (0.2822 mol) of diethyl cyanomethyl phosphonate (Aldrich Lot HY0151136Y), 79.0 mL (0.5668 mol) of triethylamine and 53.0 mL (0.6553 mol) of pyridine. To the resulting solution was added 3.3 g (0.390 mol) of hydrogen sulfide via submerged tube. The reaction flask was stoppered and stirred overnight (small samples were withdrawn, evaporated at 55° C. and 10 torr, redissolved in CDCl3 and checked by NMR spectroscopy for completion of reaction). After about 16 hours, the reaction mixture was evaporated at 55° C. and 10 torr, the crystalline residue was taken up in 200 mL of dichloromethane and the resulting solution was washed with 200 mL of a 1:1 water-saturated sodium chloride solution. The aqueous phase was reextracted with 100 mL of dichloromethane. 50 mL of 1:1 water-saturated sodium chloride solution was used to wash the first extract and then the second. The extracts were combined, dried over sodium sulfate, and evaporated to yield 50.46 g of (2-amino-2-thioxoethyl)phosphonic acid diethyl ester as an off-white, crystalline material after drying at 45° C. and 10 tort, 85% yield.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:6][C:7](Cl)=[CH:8][CH:9]=1)(=[O:3])[NH2:2].[NH:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:35]1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[C:43]([O:42][C:41]([NH:40][C@@H:36]1[CH2:37][CH2:38][CH2:39][N:34]([C:7]2[N:6]=[C:5]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[C:4]([C:1](=[O:3])[NH2:2])=[CH:9][CH:8]=2)[CH2:35]1)=[O:47])([CH3:46])([CH3:44])[CH3:45]
Reactant: NC(=O)c1ccc(Cl)nc1Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(C(N)=O)c(Nc3ccc(N4CCN(C(=O)OCc5ccccc5)CC4)cc3)n2)C1
Temperature: 100 °C
Yield: 87.2 %

Procedure:
A mixture of benzyl 4-(4-(3-carbamoyl-6-chloropyridin-2-ylamino)phenyl)piperazine-1-carboxylate (4 g, 8.58 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (2.58 g, 12.88 mmol), and DIEA (3.00 mL, 17.17 mmol) in N-methyl-2-pyrrolidinone (6 mL) was placed in two capped scintillation vials and heated at 100° C. overnight. The reaction mixtures were quenched with water and filtered. The solid was purified by MPLC chromatography (ISCO, 6% NH4OH/MeOH/CH2Cl2, two 40 g stacked silica gel columns) to give 4.71 g of ((R)-benzyl 4-(4-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-carbamoylpyridin-2-ylamino)phenyl)piperazine-1-carboxylate).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](O)=[O:32]>N1C=CC=CC=1>[F:24][C:16]1[CH:15]=[C:14]([NH:13][C:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[O:32])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C(O)c1ccccn1
Reactant: COC(=O)c1ccc(N)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added to a pyridine (500 ml) solution of methyl 4-amino-2-fluorobenzoate (18.9 g) and picolinic acid (16.5 g), and stirred at room temperature for 2 hours. The solvent was evaporated away under reduced pressure, ethyl acetate (600 ml) was added to it, and the organic layer was washed with aqueous 0.25 N hydrochloric acid solution, aqueous 0.25 N sodium hydroxide solution and saturated saline water. After dried, this was concentrated under reduced pressure, and solidified from a mixed solvent of hexane/ethyl acetate, and taken out through filtration. After dried under reduced pressure, the entitled compound was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:3]=1.[F:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[C:35]([F:42])[N:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.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>[C:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[C:4]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:3][C:2]([C:38]2[C:33]([F:32])=[N:34][C:35]([F:42])=[CH:36][CH:37]=2)=[N:7][CH:6]=1)#[N:25]
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(Cl)cc1-c1ccncc1
Reactant: OB(O)c1ccc(F)nc1F
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: O
Solvent: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(-c2ccc(F)nc2F)cc1-c1ccncc1
Reaction time: 0.17 h
Yield: 18.2 %

Procedure:
10 mg (0.02 mmol) of 4-((6-chloro-[4,4′-bipyridin]-3-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 5 mg (0.03 mmol) of (2,6-difluoropyridin-3-yl)boronic acid was added thereto, and then 2.4 mg (10 mol %) of Pd(PPh3)4, 6.7 mg (0.6 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 2 mg (19% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.COC(=O)/C=C/C1C=CC(O)=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: COC(=O)/C=C/c1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.215 g, 1.15 mmol) in THF at 0° C., triphenylphosphine (0.316 g, 1.21 mmol), diisopropyl azodicarboxylate (236 μL, 1.21 mmol) and E-3-(4-hydroxy-phenyl)-acrylic acid methyl ester (0.215 g, 1.21 mmol) were added. The reaction mixture was stirred for 2 h at 0° C., followed by 4 h at room temperature and then the solvent was evaporated in vacuo. The residue was purified by flash column chromatography, using 20%-30% EtOAc in hexane, to give crude (S)-3-[4-(E)-2-methoxycarbonylvinyl)phenoxy]pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow solid.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16](S(N4CCC(O)CC4)(=O)=O)=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1.NC1C=C2C(=CC=1)[N:39]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:38](=[O:49])[CH2:37][CH2:36]2>>[CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[C:17]4[C:16](=[CH:15][CH:14]=3)[N:39]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:38](=[O:49])[CH2:37][CH2:36]4)[N:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1)N1CCC(O)CC1
Reactant: CCOC(=O)CN1C(=O)CCc2cc(N)ccc21
Product: CCOC(=O)CN1C(=O)CCc2cc(Nc3nc(NC4CCC4)c4cc[nH]c4n3)ccc21

Procedure:
According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, ethyl 2-(6-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate and 2-chloro-N-cylclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave Ethyl 2-(6-(4-(cyclobutyamino)-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (MS calcd for C23H26N6O3 434.2, found [MH] 435.2; UV 209.8, 304.5 nm).
Reaction SMILES: [CH:1]([N:4]([CH2:8][CH2:9][NH2:10])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[OH:11][C:12]1[CH:27]=[CH:26][C:15]([C:16](=O)[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=O)=[CH:14][CH:13]=1>C(O)(=O)C.O.Cl>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[CH2:8][CH2:9][N:10]1[C:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=2[CH:17]=[C:16]1[C:15]1[CH:14]=[CH:13][C:12]([OH:11])=[CH:27][CH:26]=1)([CH3:3])[CH3:2]
Reactant: O=C(CC1CCCCC1=O)c1ccc(O)cc1
Reactant: CC(C)N(CCN)C(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)N(CCn1c(-c2ccc(O)cc2)cc2c1CCCC2)C(C)C
Temperature: 25 °C

Procedure:
A solution of 5.77 g (0.04 mole) of diisopropylaminoethylamine and 9.3 g (0.04 mole) of 2-(p-hydroxyphenacyl) cyclohexanone in glacial acetic acid is refluxed under nitrogen for 14 hours, then cooled to ambient temperature and diluted with water and dilute hydrochloric acid. The aqueous solution is washed with ether, basified with 10% sodium carbonate and extracted with ether. After drying the ether solution over magnesium sulfate, the ether is removed to give a pale yellow solid. The solid is recrystallized from an ether-petroleum ether mixture to give pale yellow crystals of 1-(2-diisopropylaminoethyl)-2-(p-hydroxyphenyl)-4,5,6,7-tetrahydroindole as pale yellow crystals, m.p. 112°-114.5° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+].[CH:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O-:24])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[Na+].COCCOCCN(CCOCCOC)CCOCCOC>[Cu]Cl.COCCOCCOC>[CH:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: [O-]c1ccccc1C1CCCCC1
Reactant: O=C([O-])c1ccccc1Cl
Agent: Cl[Cu]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Na+]
Solvent: COCCOCCOC
Product: O=C(O)c1ccccc1Oc1ccccc1C1CCCCC1
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A mixture of 21.4 g (0.12 mol) of sodium 2-chlorobenzoate, 26.1 g (0.132 mol) of sodium 2-cyclohexylphenolate, 4.95 g (0.05 mol) of copper(I) chloride and 16.17 g (0.05 mol) of tris[2-(2-methoxyethoxy)-ethyl]amine (TDA) in 1.5 1 of diethylene glycol dimethyl ether ("diglyme") is kept at 140° C. for 8 hours. The solvent is then concentrated on a vacuum rotary evaporator and the residue is diluted with water and acidified with concentrated hydrochloric acid. The product is extracted with ethyl acetate. The organic phases are washed with water, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. 22.2 g (68%) of 2-(2-cyclohexylphenoxy)benzoic acid, melting point 109°-123° C., result as a beige powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:14][CH3:15])[N:3]=1.[CH2:22]([O:26][C:27](Cl)=[O:28])[CH:23]([CH3:25])[CH3:24]>>[CH3:9][C:6]1[C:7]([O:8][C:27]([O:26][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:28])=[C:2]([CH3:1])[N:3]=[C:4]([NH:10][CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][CH2:14][CH3:15])[N:5]=1
Reactant: CC(C)COC(=O)Cl
Reactant: CCCC(CNc1nc(C)c(O)c(C)n1)c1ccccc1
Product: CCCC(CNc1nc(C)c(OC(=O)OCC(C)C)c(C)n1)c1ccccc1

Procedure:
In a manner similar to that of the method of Example 2, the title compound was prepared from 0.5 g (1.8 mmol) of 4,6-dimethyl-5-hydroxy-2-phenylpentylaminopyrimidine and isobutylchoroformate (0.23 ml, 1.8 mmol) to afford 0.45 g of product. Mass spectrum m/e=385. NMR (CDCl3) delta: 7.27-7.16 (m, 5H): 5.00 (bs, 1H); 4.06 (d, 5 Hz, 2H); 3.00-3.60 (m, 2H); 2.61 (t, 4 Hz, 2H); 2.23 (s, 6H): 1.65-1.36 (m, 6H): 0.99 (d, 4 Hz, 6H). IR (CHCl3) 1760, 1580 cm-1. Anal. Calc'd for C22H31O3N3 : C, 68.54: H, 8.10: N, 10.90. Found: C, 68.14; H, 7.85; N, 10.69.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[S:6][C@@H:5]2[C@H:7](N)[C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=[O:12].C(N(C(C)C)CC)(C)C.N1(C=O)CCCCC1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[S:6][CH:5]2[N:4]([C:8](=[O:9])[CH2:7]2)[CH:3]1[C:11]([OH:13])=[O:12]
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: O=CN1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC1(C)SC2CC(=O)N2C1C(=O)O
Reaction time: 1 h
Yield: 22371.5 %

Procedure:
A mixture of 4-[3-(1H-imidazol-1-yl)propyl]-piperidine (1.5 g, 0.0078M) and dimethylformamide dimethylacetal (10 ml) was heated at 100° C. for 16 hrs. The excess of dimethylformamide dimethylacetal was removed to give 4-[3-(1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde dimethylacetal. To the mixture of 6-aminopenicillanic acid (1.16 g, 0.0053M) and diisopropylethylamine (1.03 ml) in dry CHCl3 (9 ml) was added the above piperidinecarboxaldehyde in CHCl3 (5 ml) at 0° C. and stirred at that temperature for 1 hr, then at room temperature for 3 hrs. After the reaction, the solvent was removed and the residue dissolved in water (40 ml). The aqueous solution, washed with diethyl ether, was adjusted to pH 3 with dilute aqueous HCl and purified on Sephadex LH 20 column to give [2S-(2alpha,5alpha,6beta)]-6-[[4-[3-(1 H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 1.2 mole hydrochloride monohydrate (0.87 g, 39% yield).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N+:5]([O-])=[C:4]([CH3:11])[CH:3]=1.P(Br)(Br)Br>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: COc1c[n+]([O-])c(C)cc1Br
Agent: BrP(Br)Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cnc(C)cc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-bromo-5-methoxy-2-methyl-pyridine 1-oxide (Step AL4) (150 mg, 0.7 mmol) in CHCl3 (2 mL) at 10° C. was added dropwise PBr3 (78 μL, 0.826 mmol). The mixture was stirred at rt for 4 h, then at 50° C. for 1 h. The reaction mixture was dissolved in CH2Cl2 and extracted with a saturated aqueous solution of NaHCO3, washed with brine, dried (Na2SO4), filtered and concentrated. The product was crystallised (CH2Cl2/TBME). ESI-MS: tR=0.69 min, [M+H]+ 202.0/204.0 (LC-MS 1).
Reaction SMILES: [C:1]([C:3]1(C(OCC)=O)[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:4]1([CH3:13])[CH3:12])#[N:2].C(=O)(O)[O-].[Na+].O>C(O)CCO>[CH3:12][C:4]1([CH3:13])[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]1[C:1]#[N:2]
Reactant: CCOC(=O)C1(C#N)C(c2ccccc2)C1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCCO
Solvent: O
Product: CC1(C)C(C#N)C1c1ccccc1
Reaction time: 0.75 h
Yield: 95.5 %

Procedure:
A mixture of 234 mg (0.96 mmole) of cyclopropanoid cyanoester 10 (produced in accordance with Example VIII), 174 mg (2.1 mmoles) of sodium bicarbonate, and 35 mg of water in 2.0 mL of 1,3-propanediol was heated at reflux, protected from atmospheric moisture, for 45 minutes. The product was isolated by diluting the cooled mixture with 25 mL of saturated brine and extraction with ether. The ether extracts were washed in successive order with 20 mL of 1:1 (v/v) 1M aqueous NaOH:saturated brine and 20 mL of 10% aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. Removal of the ether by evaporation at reduced pressure afforded 157 mg (95% yield) of nitrile 17 as a mixture of cis and trans stereoisomers, subsequently shown by NMR analysis (vinyl H absorption at approximately 5.0δ) to be accompanied by a minor amount (~10-15%) of ring-opened by-product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:14]=1.S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13][CH2:20][CH3:21])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:14]=1
Reactant: CCO
Reactant: O=C(O)C1CCc2cc(O)ccc2O1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2cc(O)ccc2O1
Reaction time: 3 h
Yield: 70 %

Procedure:
A mixture of 60 parts of 3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-carboxylic acid, 800 parts of ethanol and 5.52 parts of concentrate sulfuric acid was stirred for 3 hours at reflux temperature. The reaction mixture was evaporated. Water was added and the product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was solidified in petroleumether. The product was filtered off and dried, yielding 48 parts (70%) of ethyl 3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-carboxylate as a residue (intermediate 21).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:11]=[CH:10][NH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35](Cl)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17]>C1COCC1>[CH:1]1([NH:4][C:5]([C:7]2[CH:11]=[CH:10][N:9]([S:35]([C:33]3[CH:32]=[CH:31][C:22]4[N:23]([CH2:24][CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)[C:19]([C:15]([CH3:18])([CH3:14])[CH2:16][CH3:17])=[N:20][C:21]=4[CH:34]=3)(=[O:37])=[O:36])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1cc[nH]c1
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NC4CC4)c3)ccc2n1CC1CCOCC1
Yield: 83.3 %

Procedure:
Following the same procedure in Example 29, using N-cyclopropyl-1H-pyrrole-3-carboxamide (49 mg, 0.33 mmol) (see the step B in example 32 for preparation), sodium hydride (110 mg, 60%, 2.75 mmol) and 2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (354 mg, 0.92 mmol) in THF (10 mL). The crude product was purified by MPLC using Hex/EtOAc (3:7) on silica gel to give 137 mg (83%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.50-0.57 (m, 2 H), 0.69-0.75 (m, 2 H), 0.78 (t, J=7.42 Hz, 3 H), 1.42-1.56 (m, 4 H), 1.60 (s, 6 H), 1.95 (q, J=7.62 Hz, 2 H), 2.21-2.37 (m, 1 H), 2.67-2.75 (m, 1 H), 3.23-3.35 (m, 2 H), 3.84-3.93 (m, 2 H), 4.43 (d, J=7.42 Hz, 2 H), 6.65 (dd, J=3.32, 1.76 Hz, 1 H), 7.28 (dd, J=3.32, 2.15 Hz, 1 H), 7.77-7.84 (m, 1 H), 7.90-8.01 (m, 2 H), 8.26 (d, J=0.78 Hz, 1 H); MS (ESI) (M+H)+=499.0; Anal. Calcd for C26H34N4O4S+1.2 TFA (635.48): C, 53.68; H, 5.58; N, 8.82. Found: C, 53.65; H, 5.61; N, 8.56.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:41][CH2:40][CH2:39][N:38]([CH3:42])[CH3:37])=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CN(C)CCN
Reactant: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12
Agent: CCOP(=O)(C#N)OCC
Product: CN(C)CCNC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-[2-[(5chloro-1H-indol-3-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and N,N-dimethylethane-1,2-diamine using diethyl cyanophosphonate as a coupling reagent Mass: 577.31 (M+H).
Reaction SMILES: C([O:4]CC=C)C=C.[CH2:8]([C:11]1[CH:16]=[C:15]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:14]=[C:13]([Br:22])[C:12]=1[OH:23])[CH:9]=[CH2:10].ClC1C=C(C=CC=1)C(OO)=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=C(C)C=C(C)C=1>[Br:22][C:13]1[C:12]2[O:23][CH:9]([CH2:10][OH:4])[CH2:8][C:11]=2[CH:16]=[C:15]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:14]=1
Reactant: C=CCOCC=C
Reactant: C=CCc1cc(C2CCCC2)cc(Br)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1cc(C)cc(C)c1
Product: OCC1Cc2cc(C3CCCC3)cc(Br)c2O1
Yield: 53 %

Procedure:
To a solution of 4-cyclopentylphenol (3.0 g, 18.0 mmol) in acetonitrile (30 mL) cooled to 0° C. was slowly added N-bromosuccinimide (3.29 g, 18 mmol) generally according to the procedure described for Example 309 afforded 3.75 g (84%) of 2-bromo-4-cyclopentylphenol Treatment of 2-bromo-4-cyclopentylphenol (3.75 g, 16.0 mmol) with potassium carbonate (5.4.0 g, 40 mmol) and allyl bromide (2.38 g, 20.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-cyclopentylphenol. Treatment of 2-allyl-6-bromo-4-cyclopentylphenol (3.0 g, 10.0 mmol) with 3-chloroperoxybenzoic acid (3.49 g, 12.0 mmol, 77%) followed by potassium carbonate (3.7 g, 25.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.68 g, (53%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.68 g, 4.6 mmol) with p-toluenesulfonyl chloride (0.96 g, 5.0 mmol) generally according to the procedure described for Intermediate 10 gave 1.78 g (70%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.1 mmol) and 2-methylphenylboronic acid (0.45 g, 3.3 mmol) generally according to the procedure described for Intermediate 35 afforded 0.51 g, (99%) of (5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.239 g, 3.67 mmol) generally according to the procedure described for Intermediate 98 afforded 0.16 g (65%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.24 g, 0.48 mmol) according to the procedure described in Example 154 afforded 0.126 g (50%) of (±)-[(5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 190-193° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>>[CH3:19][C:20]([CH3:25])([CH3:24])[C:21]([NH:12][C:10]1[S:11][C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[C:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]=1)=[O:22]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Product: Cc1nc(-c2sc(NC(=O)C(C)(C)C)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and 2,2-dimethyl-propionyl chloride.