Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].[C:12](C1NC=CN=1)([C:14]1[NH:15]C=CN=1)=[O:13].[CH:24]1[CH:29]=[CH:28][C:27]([C@@H](N)CO)=[CH:26][CH:25]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:15]([C:27]1[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=1)[CH2:14][CH2:12][OH:13])=[O:8])#[N:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Product: N#Cc1cccc(C(=O)N(CCO)c2ccccc2)c1

Procedure:
By solution phase srategy: Typically 3-cyanobenzoic acid is activated with carbonyl-diimidazole and reacted with R-phenylglycinol to give 3-cyanobenzoylphenylglycinol. Reaction with a trichloroacetimidate and BF3 etherate, (4), gives an ether. Reaction of the cyano group with HCl in ethanol followed by ammonia in ethanol gives the amidino compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:19]=[C:18]2[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:19]=[C:18]3[CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCn1cc(Cc2cccnc2)c2cc(CCN)ccc21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCn1cc(Cc2cccnc2)c2cc(CCNS(=O)(=O)c3ccc(F)cc3)ccc21
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
4-Fluorobenzenesulphonyl chloride (0.346 g) was added portionwise to a stirred solution of methyl 5-(2-aminoethyl)-3-(3-pyridylmethyl)-1H-indole1-propanoate (0.50 g) and triethylamine (0.33 g) in dichloromethane (5 ml) at room temperature. The mixture was stirred for 30 minutes and then washed with water and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel using dichloromethane/methanol (50:1) as eluant. The product fractions were combined and evaporated to give the title compound as a gum (0.59 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[C:35]([Cl:39])=[CH:34][C:33]=1[S:40](Cl)(=[O:42])=[O:41].CO>C(#N)C.ClCCl>[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[C:35]([Cl:39])=[CH:34][C:33]=1[S:40]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1)(=[O:42])=[O:41]
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NS(=O)(=O)c3cc(Cl)c(Cl)cc3Cl)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.2 g; 0.547 mmole) and sodium hydrogen carbonate (0.05 g; 0.6 mmole) were mixed in acetonitrile (10 ml) and stirred at room temperature for 15 minutes. The mixture was then cooled in an ice-bath and 2,4,5-trichlorobenzenesulfonyl chloride (0.184 g; 0.657 mmole) was added. After addition, the ice-bath was removed and the reaction mixture was heated to reflux for 4 hours and then evaporated to dryness. Ethyl acetate and water were added to the residue and the phases were separated. The organic phase was dried with magnesium sulfate and the solvent was evaporated. Chromatography on silica gel (Isolute, SI) using dichloromethane and then methanol (2%) in dichloromethane as eluant gave 0.28 g (89% yield) of 3-(4-{2-[4-(2,4,5-trichlorobenzenesulfonylamino)phenyl]ethoxy}phenyl]-(S)-2-ethoxypropanoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1B(O)O.CCOC(C)=O.O>COCCOC.O.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>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][C:24]=2[Cl:26])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1OCc1ccccc1
Yield: 82 %

Procedure:
To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454, which is incorporated herein by reference)(5 g, 18.9 mmol) in DME/H2O, was added 2,4-dichlorophenylboronic acid (3.60 g, 18.9 mmol), Ba(OH)2 0.8H2O (5.96 g, 18.9 mmol), and Pd(PPh3)2Cl2 (0.77 g, 1.09 mmol) and the mixture was heated at reflux for 5 h. The reaction was cooled and poured into EtOAc and H2O (500 mL). The EtOAc layer was washed with H2O, brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification using flash chromatography (10% EtOAc-Hexane) gave 5.79 g (82%) of 2-benzyloxy-4-(2,4-dichloro-phenyl)-3-nitro-pyridine as a viscous oil: crude MS (AP) m/z 375.2 [(M+H)+, 100].
Reaction SMILES: C1(C)C=CC=CC=1NC1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][CH2:18]C(NC3C=CC([C@H](C)CC(O)=O)=CC=3)=O)[CH:14]=[CH:13][C:11]=2[N:12]=1.C([O-])=[O:36].[NH4+].[CH2:39]([OH:41])[CH3:40]>[Pd]>[NH2:12][C:11]1[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:41][CH2:39][CH3:40])=[O:36])=[CH:16][C:10]=1[OH:9]
Reactant: Cc1ccccc1Nc1nc2ccc(CCC(=O)Nc3ccc([C@H](C)CC(=O)O)cc3)cc2o1
Reactant: O=C[O-]
Reactant: CCO
Agent: [Pd]
Agent: [NH4+]
Product: CCOC(=O)Cc1ccc(N)c(O)c1
Temperature: 50 °C

Procedure:
A solution of ethyl 3-hydroxy4-nitrophenylacetate (5.0 g, Reference Example 6) was dissolved in ethanol (approximately 200 mL) was treated with ammonium formate (approximately 20 g). The mixture was warmed to 50° C. and then treated cautiously with palladium on charcoal (approximately 1 g, 5%)—effervescence was observed. After 30 minutes the mixture was filtered hot through a pad of filter-aid and the filtrate was concentrated to give the title compound (3.3 g) as a black solid.
Reaction SMILES: C(NCC)C.[CH2:6]([CH2:8][NH2:9])[OH:7].[C:10]1([C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)Cl)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)C>[C:16]([NH:9][CH2:8][CH2:6][OH:7])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Solvent: CC(C)O
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A mixture of isopropanol (750 ml), diethylamine (75 ml), ethanolamine (98%, 62.3 g, 1 mole) and triphenylchloromethane (97%, 143.7 g, 0.50 moles) was stirred at room temperature for 3 hours. The resulting solution was then poured into ice-cold water (4 l) under continuous stirring and the resulting precipitate was filtered off and dried. The crude product was digested in toluene (340 ml), then filtered off and dried in vacuo at 60° C. Thus 130 g (85%) of the pure desired compound were obtained.
Reaction SMILES: [CH3:1][C:2]1([O:8][C:9](=[O:23])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:24]1[CH2:28][CH2:27][O:26][CH:25]1[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:39])[CH:37]=[CH2:38])=[CH:31][CH:30]=1>CO.ClCCl.C(OCC)(=O)C>[O:24]1[CH2:28][CH2:27][O:26][CH:25]1[C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36]([CH2:37][CH2:38][N:5]2[CH2:6][CH2:7][C:2]([O:8][C:9](=[O:23])[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([CH3:1])[CH2:3][CH2:4]2)=[O:39])=[CH:33][CH:34]=1
Reactant: CC1(OC(=O)Nc2ccccc2-c2ccccc2)CCNCC1
Reactant: C=CC(=O)Nc1ccc(C2OCCO2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(OC(=O)Nc2ccccc2-c2ccccc2)CCN(CCC(=O)Nc2ccc(C3OCCO3)cc2)CC1

Procedure:
A mixture of biphenyl-2-ylcarbamic acid 4-methylpiperidin-4-yl ester (2.73 g, 8.79 mmol) and N-(4-[1,3]dioxolan-2-yl-phenyl)acrylamide (2.05 g, 8.80 mmol) were heated in 100 mL of 1:1 methanol/dichloromethane at 50° C. under nitrogen for 1 h. The solution was then diluted with ethyl acetate and the organic layer was washed with water, brine, dried (MgSO4) and concentrated under reduced pressure to give the title compound. MS m/z calcd for C31H35N3O5 (M+H)+ 530.6; found 530.4.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:31](ON1C(=O)CCC1=O)=[O:32])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26]C(C)(C)C)=[CH:22][CH:21]=1)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10]C(C)(C)C)=[CH:6][CH:5]=1.[NH2:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51].[CH3:57][N:58]1[C@@H:75]2[CH2:76][C:63]3[CH:64]=[CH:65][C:66]([O:77][CH3:78])=[C:67]4[O:68][C@H:69]5[C:70]([CH2:72][CH2:73][C@@H:74]2[C@:61]5([C:62]=34)[CH2:60][CH2:59]1)=[O:71]>>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:31]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:32])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:57][N:58]1[C@@H:75]2[CH2:76][C:63]3[CH:64]=[CH:65][C:66]([O:77][CH3:78])=[C:67]4[O:68][C@H:69]5[C:70]([CH2:72][CH2:73][C@@H:74]2[C@:61]5([C:62]=34)[CH2:60][CH2:59]1)=[O:71]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)ON1C(=O)CCC1=O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Product: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O

Procedure:
Tyr-Tyr-Ile-Hydrocodone was prepared by a similar method to Example 9 except the amino acid starting material was Boc-Tyr(tBu)-Tyr(tBu)-OSu and the conjugate starting material was Ile-Hydrocodone.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([OH:9])=O)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1>[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH:61][C:7](=[O:9])[C:6]3[CH:10]=[CH:11][N:12]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=3)=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1
Reactant: CC(C)c1cc(C(=O)O)ccn1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(C(C)C)c3)nc12

Procedure:
From 2-isopropyl-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 414 (M+H+, 100).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[CH2:22]([S:29][CH2:30][C@@H:31]([C:33]([NH:35][CH2:36][CH2:37][CH3:38])=[O:34])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[CH2:22]([S:29][CH2:30][C@H:31]([NH:32][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])[C:33](=[O:34])[NH:35][CH2:36][CH2:37][CH3:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CCCNC(=O)[C@@H](N)CSCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCNC(=O)[C@H](CSCc1ccccc1)NC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.34 g), S-benzyl-N-propyl-L-cysteinamide (0.27 g), 1H-1,2,3-benzotriazol-1-ol (0.22 g) and N,N-dimethylformamide (15 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.27 g) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-1:1), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (285 mg, yield 49%) as colorless crystals. melting point 124-125° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[C:1]([O:9][CH2:15][CH3:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
To a flask were added 6.1 g of benzoic acid and 40 ml of anhydrous ethanol, to which 2 ml of concentrated sulfuric acid was added slowly and dropwise with stirring, and the mixture was heated under reflux for 6 hours, and then cooled to room temperature. The solvent was distilled under reduced pressure, and the residue was diluted with 30 ml of ethyl acetate and 25 ml of water. The aqueous layer was extracted with ethyl acetate (30 ml×2) and the organic layers were combined, washed with saturated sodium bicarbonate solution to neutral and then with saturated NaCl, dried with anhydrous magnesium sulfate, and filtrated. The solvent was distilled under reduced pressure to give ethyl benzoate.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][OH:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])(=O)=O>CCOC(C)=O>[Si:42]([O:27][CH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:8]1[NH:9][C:10]2[C:15]([C:7]=1[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO)[nH]c2c1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO[Si](C)(C)C(C)(C)C)[nH]c2c1
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A solution (0.039 M) of methyl 3-cyclohexyl-2-[2-(hydroxymethyl)phenyl]-1H-indole-6-carboxylate was treated with 2,6-lutidine (2 eq) and then with tert-butyl(dimethyl)silyl trifluoromethanesulfonate (1.2 eq). The solution was stirred for 15 min. Removal of the volatiles in vacuo gave a residue that was diluted with EtOAc, washed with 1N HCl, saturated aqueous NaHCO3, brine, dried and concentrated in vacuo to afford the title compound (90%) as a solid. MS (ES+) m/z 478 (M+H+).
Reaction SMILES: [O:1]=[O+][O-].[CH:4]([CH:9]1[O:14][C:13]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:12][CH:11]([CH2:20][C:21]([OH:23])=[O:22])[CH2:10]1)=CC=CC>C(Cl)Cl>[CH:4]([CH:9]1[O:14][C:13]2([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[O:12][CH:11]([CH2:20][C:21]([OH:23])=[O:22])[CH2:10]1)=[O:1]
Reactant: CC=CC=CC1CC(CC(=O)O)OC2(CCCCC2)O1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: O=CC1CC(CC(=O)O)OC2(CCCCC2)O1

Procedure:
Ozone was passed through a solution of 4-(1,3-pentadienyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid (570 mg, 2.0 mmol) in methylene chloride (25 mL) at -78° C. After the solution had attained a blue color, nitrogen was passed through the solution to remove the excess ozone. Dimethyl sulfide (0.5 mL) was added and the solution was concentrated under reduced pressure to afford the title compound as a viscous oil which was used without further purification in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:14][C:15]1(C)[NH:20][C:19]2OCC[C:18]=2C=[N:16]1)=[S:13])(=[O:10])=[O:9].O([CH3:27])[Na].CO.CI.[O:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12]([S:13][CH3:27])[NH:14][C:15]1[N:20]=[C:19]([CH3:18])[C:34]2[CH2:35][CH2:36][O:32][C:33]=2[N:16]=1)(=[O:10])=[O:9]
Reactant: CC1(NC(=S)NS(=O)(=O)c2ccccc2Cl)N=CC2=C(N1)OCC2
Reactant: C1CCOC1
Reactant: CO[Na]
Solvent: CO
Solvent: CI
Product: CSC(=NS(=O)(=O)c1ccccc1Cl)Nc1nc(C)c2c(n1)OCC2
Reaction time: 12 h

Procedure:
To a suspension of 3.85 g 2-chloro-N-[(5,6-dihydro-2-methylfuro[2,3-d]pyrimidine-2-yl)aminothioxomethyl]benzenesulfonamide in 150 ml of anhydrous tetrahydrofuran was added 4.3 ml of 3 M NaOCH3 /CH3OH solution. The reaction reaction mixture was refluxed for 1.25 hour, whereupon 1.85 g of methyl iodide in 10 ml of anhydrous tetrahydrofuran was added. After refluxing and stirring for an additional 12 hours, the reaction mixture was cooled, solvent was removed under vacuum and the residue was recrystallized from acetonitrile to yield 1 g of the product.
Reaction SMILES: O[C:2]([CH:6]1[NH:10][C:9](=[O:11])[CH2:8][CH2:7]1)([CH3:5])[C:3]#[CH:4].N1C=CC=CC=1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH3:5][C:2]([CH:6]1[NH:10][C:9](=[O:11])[CH2:8][CH2:7]1)=[C:3]=[CH:4][Cl:20].[CH2:5]=[C:2]([CH:6]1[NH:10][C:9](=[O:11])[CH2:8][CH2:7]1)[C:3]#[CH:4]
Reactant: O=S(Cl)Cl
Reactant: C#CC(C)(O)C1CCC(=O)N1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C#CC(=C)C1CCC(=O)N1
Product: CC(=C=CCl)C1CCC(=O)N1
Reaction time: 96 h

Procedure:
To a toluene solution of 5-(1-hydroxy-1-methylprop-2-yn-1-yl)-2-pyrrolidone at room temperature was added 4.0 equivalents of pyridine and 1.5 equivalents of thionyl chloride. The reaction mixture was left for four days. It was then quenched with cold water, extracted repeatedly with ethyl acetate and the organic extract washed once with water, brine, dried over anh. MgSO4 and concentrated to give an oil. Purification by chromatography over silica gel gave a 1:1 ratio of 5-(1-methyl-3-chloro-1,2-propadien-1-yl)-2-pyrrolidone (IR 1960 cm-1) and 5-(1-methyleneprop-2-yne-1-yl)-2-pyrrolidone (IR 2100 cm-1). The mixture was then refluxed in a 1:1 solution of THF: 20% HCl for 2 days, diluted with water, and washed with ether. The aqueous phase was passed through an ion-exchange column (Ag 50 W×8) eluting with 20% pyridine-water. The concentrate was then chromatographed on HPLC (RP-18) giving two diasteromeric allenes which separated under the HPLC conditions. 4-Amino-5-methyl-7-chloro-5,6-heptadienoic acid; IR (KBr): 1962, 1545 cm-1, 'H NMR (δD2O): 1.93 (d, 3H, J=2.2 Hz, CH3), 1.9-2.5 (m, 4H, CH2CH2), 3.9 (m, 1H, CHN), 6.49 (m, 1H, CH=C), mass spectrum (M+Cl 154), 102, 84; and 4-amino-5-methylene-6-heptynoic acid IR: 3165, 2130, 1610, 1540 cm-1 ; 'H NMR (δD2O): 1.9-2.5 (m-4H, CH2CH2), 2.58 (s, 1H, C=CH), 2.96 (m, 1H, HCN), 5.8 (d, 2H, J=7.3 Hz, H2C=C).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([Br:15])[CH:5]=[CH:4][C:3]=1[OH:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25](Br)=[O:26]>C(#N)C.O>[Br:15][C:6]1[CH:5]=[CH:4][C:3]2[O:16][CH2:24][C:25](=[O:26])[NH:1][C:2]=2[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Br)CBr
Reactant: Nc1c(O)ccc(Br)c1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1COc2ccc(Br)c(Oc3ccccc3)c2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A solution of 2-amino-4-bromo-3-phenoxyphenol (0.060 g, 0.214 mmol) in acetonitrile (3.88 mL) and water (1.21 mL) was treated with potassium carbonate (0.118 g, 0.857 mmol), followed by the addition of bromoacetyl bromide (0.0279 mL, 0.321 mmol), and the resultant reaction mixture was stirred at RT for 30 min, after which time additional bromoacetyl bromide (0.0186 mL, 0.214 mmol) was added dropwise and the reaction mixture was stirred at RT for 1 h, then warmed to 75° C. and stirred at that temperature for 30 min. The reaction mixture was concentrated and diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo the yield a crude product. Purification by flash column chromatography (100% hexanes to 50% EtOAc/hexanes) gave the desired product (59.5 mg, 87%) as a white solid. LCMS calculated for C14H11BrNO3 (M+H)+: m/z=320.0, 322.0. found: 319.9, 321.9.
Reaction SMILES: C1COCC1.[C:6]1([Mg]Br)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26].[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C>CCCCCC.C1(C)C=CC=CC=1>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccccc1Cl
Reactant: Br[Mg]c1cccc2ccccc12
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1ccccc1-c1cccc2ccccc12
Reaction time: 48 h
Yield: 92 %

Procedure:
Using a THF solution of 1-naphthylmagnesium bromide (4.62 mL, 0.26 M, 1.2 mmol), 1-chloro-2-methoxybenzene (142.6 mg, 1.0 mmol), FeF3.3H2O (8.34 mg, 0.05 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (64.1 mg, 0.15 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 70° C. for 48 hours in the same manner as in Example 2. After performing silica gel column chromatography (toluene=10, 20 and 40% in hexane), the above compound was obtained as a white solid (0.215 g, yield=92%, purity=>99% (GC analysis)).
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:55]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:54][C:53]4[C:52]5=[N:62][N:63]=[C:64]([C:65]6[N:66]=[CH:67][N:68]([CH3:70])[CH:69]=6)[N:51]5[CH2:50][CH2:49][C:48]=4[N:47]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[CH3:70][N:68]1[CH:69]=[C:65]([C:64]2[N:51]3[C:52]([C:53]4[CH:54]=[C:55]([C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)[C:46]([C:43]5[CH:42]=[CH:41][C:40]([C:36]6([NH2:35])[CH2:37][CH2:38][CH2:39]6)=[CH:45][CH:44]=5)=[N:47][C:48]=4[CH2:49][CH2:50]3)=[N:62][N:63]=2)[N:66]=[CH:67]1
Reactant: Cn1cnc(-c2nnc3n2CCc2nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)cc2-3)c1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: Cn1cnc(-c2nnc3n2CCc2nc(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)cc2-3)c1
Yield: 105.6 %

Procedure:
Following the procedure for 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(3-(1-methyl-1H-imidazol-4-yl)-9-phenyl-5,6-dihydro-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-8-yl)phenyl)cyclobutyl)carbamate (9 mg, 0.02 mmol) was reacted to afford the title compound (10 mg, quantitative). LCMS (Method A): RT=3.53 min, M-NH2=377. 1H NMR (500 MHz, MeOD): 8.43 (1H, s), 7.99 (1H, br s), 7.91 (1H, br s), 7.52 (2H, d), 7.44 (2H, d), 7.33-7.27 (5H, m), 3.89 (3H, s), 3.54 (2H, t), 3.32 (2H, t), 2.79-2.73 (2H, m), 2.61-2.55 (2H, m), 2.27-2.20 (1H, m), 2.00-1.92 (1H, m).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)C=C.[C:14]1(C)[C:15](C)=CC=C[CH:19]=1>>[CH2:15]([C:10]1[CH:9]=[C:8]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[OH:4])[CH:14]=[CH2:19]
Reactant: C=CCOc1ccc(C(C)=O)cc1
Reactant: Cc1ccccc1C
Product: C=CCc1cc(C(C)=O)ccc1O

Procedure:
A solution of 4′-allyloxyacetophenone (6.0 g, 34.1 mmol) in 10 mL xylene is introduced into a thick walled pyrex tube, which is sealed with a teflon cap. After heating to 230° for 5 hours, the solution is cooled to 0°. The precipitated white solid is filtered and the solid is washed with cold toluene and hexane to yield 3′-allyl-4′-hydroxyacetophenone.