Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[F:20])(=[O:29])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1F)n1ccc2c(OCc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
To a magnetically stirred mixture of 4-benzyloxyindole (13.80 g, 0.062 mol), tetrabutylammonium hydrogen sulfate (1.05 g, 0.0031 mol) and finely ground sodium hydroxide (2.72 g, 0.068 mol) in 100 mL of dichloromethane at 0° C., was added 2-fluorobenzenesulfonyl chloride (13.25 g, 0.068 mol). After 18 hours stirring at ambient temperature, 2-fluorobenzenesulfonyl chloride (3.96 g, 0.020 mol) and finely ground sodium hydroxide (0.82 g, 0.020) were added. One hour later, the reaction mixture was washed sequentially with water (2×100 ML) and an aqueous K2CO3 solution (2 M, 100 mL). The aqueous fractions were combined and extracted with CH2Cl2 (2×45 mL). The organic fractions were combined, dried over MgSO4 and concentrated in vacuo. The resulting solid was recrystallized from 10:2 ethyl acetate/hexanes (100 mL) to give 4-benzyloxy-1-(2-fluorobenzenesulfonyl)-1H-indole as an off-white powder (21.48 g, 91%). MP 117-120° C.
Reaction SMILES: N(C[C@H]1CCC[C@@H](CN=C=O)C1)=C=O.N(C[C@H]1CCC[C@H](CN=C=O)C1)=C=O.[N:29]([CH2:32][C@H:33]1[CH2:38][CH2:37][C@@H:36]([CH2:39][N:40]=[C:41]=[O:42])[CH2:35][CH2:34]1)=[C:30]=[O:31]>>[N:29]([CH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([CH2:39][N:40]=[C:41]=[O:42])[CH2:35][CH2:34]1)=[C:30]=[O:31]
Reactant: O=C=NC[C@H]1CC[C@@H](CN=C=O)CC1
Agent: O=C=NC[C@H]1CCC[C@@H](CN=C=O)C1
Agent: O=C=NC[C@H]1CCC[C@H](CN=C=O)C1
Product: O=C=NC[C@H]1CC[C@H](CN=C=O)CC1

Procedure:
A mixture of consisting essentially of 36% cis-1,3-bis(isocyanatomethyl)cyclohexane, 18% trans-1,3-bis(isocyanatomethyl)cyclohexane, 13% cis-1,4-bis(isocyanatomethyl)cyclohexane, and 33% trans-1,4-bis(isocyanatomethyl)cyclohexane is produced by The Dow Chemical Company.
Reaction SMILES: Cl[C@:2]1([O:9][C@@H:8]([CH3:10])[C@@:6]([O:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])([OH:7])[C@@H:5]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:4]1)O.C1C=CC=CC=1.[Hg](C#N)C#N>O1CCOCC1>[F:23][C:20]([F:21])([F:22])[C:19]([NH:18][C@@H:5]1[C@:6]([O:11][C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])([OH:7])[C@H:8]([CH3:10])[O:9][CH:2]=[CH:4]1)=[O:24]
Reactant: C[C@@H]1O[C@](O)(Cl)C[C@H](NC(=O)C(F)(F)F)[C@@]1(O)OC(=O)C(F)(F)F
Agent: N#C[Hg]C#N
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H]1OC=C[C@H](NC(=O)C(F)(F)F)[C@@]1(O)OC(=O)C(F)(F)F
Yield: 93.9 %

Procedure:
To a solution of 800 mg of 1-chloro-2,3,6-trideoxy-3-trifluoroacetamido-4-trifluoroacetoxy-alpha-L-lyxohexopyranose (I)* in 25 ml of a 4:1 (by volume) mixture of benzene and dioxane there were added 500 mg of Hg(CN)2. The resulting suspension was heated under reflux for 3 1/2 hours. After cooling, the reaction mixture was filtered to give a clear solution, which was then evaporated to a residue. The residue was extracted with benzene and, upon evaporation of the benzene solution, there were obtained 650 mg of 1,2,3,6-tetradeoxy-3-trifluoroacetamido-4-trifluoroacetoxy-L-lyxo-hex-1-enopyranose (II) in crystalline form melting at 73°-74° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[C:14]([CH2:5][N:10]([CH3:14])[CH3:11])=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(Br)cc2C#N)c1CN(C)C

Procedure:
A solution of 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile (11.0 g, 42.0 mmol) and N,N-dimethylmethyleneiminium chloride (5.0 g, 53.4 mmol) in DMF (75 mL) was stirred at 90° C. for 16 h. The solvent was evaporated and the oily residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and chromatographed (SiO2, dichloromethane:methanol=1000:0 to 965:35) to afford the title compound as an oil that solidifies on standing (10.62 g, 79%). MS: m/e=321.3/319.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:11][S:12]([C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:19][CH:20]=1)(=[NH:14])=[O:13].Cl.CN(C)CCCN=C=NCC.CCOC(C)=O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([N:14]=[S:12]([C:15]2[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:19][CH:20]=2)([CH3:11])=[O:13])=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: COC(=O)Cc1cccc(S(C)(=N)=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of 5-bromonicotinic acid (648 mg, 3.21 mmol), methyl [3-(S-methylsulfonimidoyl)phenyl]acetate (802 mg, 3.53 mmol), and catalytic DMAP in 15.0 ml DMF at room temperature was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (738 mg, 3.85 mmol). The reaction was stirred 1 hour at room temperature then added to EtOAc. The EtOAc solution was washed with dilute brine, NaHCO3 solution, brine, dilute HCl/brine mixture, brine/NaHCO3 solution, dried with anhydrous Na2SO4 and rotary evaporated. The oil was chromatographed eluting with CHCl3/EtOAc to give viscous clear oil (994 mg, 75%).
Reaction SMILES: N1C2C(=NC=CC=2)N(O[C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])N=1.[N:43]1([CH2:48][CH2:49][CH2:50][NH2:51])[CH:47]=[CH:46][N:45]=[CH:44]1>CC(N(C)C)=O>[N:43]1([CH2:48][CH2:49][CH2:50][NH:51][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=3[Cl:39])(=[O:30])=[O:31])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Reactant: NCCCn1ccnc1
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added 3-imidazol-1-yl-propylamine (40 mg, 2 eq.). The mixture was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as a yellow solid.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][C:29]#[CH:30])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][C:29]#[CH:30])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Yield: 53.2 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.4 g.), conc. hydrochloric acid (1.4 ml.) and methanol (20 ml.) was treated in a similar manner to that of Example 51-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 0.7 g.), yellowish white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:32][CH2:11][CH2:10][CH2:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: OCCCc1cc(Cl)ccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCCCc1cc(Cl)ccc1Cl
Reaction time: 2.5 h
Yield: 93.3 %

Procedure:
Compound 66-2 (1.73 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (2.43 g) and N-chlorosuccinimide (1.24 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 2.5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.76 g) as a colorless oil.
Reaction SMILES: C(C1C=CC(C(C)(CCCCC(=O)CCCCC(C2C=CC(CC(C)C)=CC=2)(C)C(O)=O)C(O)=O)=CC=1)C(C)C.C([O:43][C:44](=[O:74])[C:45]([CH3:73])([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH2:46][CH2:47][CH2:48][C:49](=[O:66])[CH2:50][CH2:51][CH2:52][C:53]([CH3:65])([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:54]([O:56]CC)=[O:55])C.[OH-].[K+]>O.C(O)C>[CH3:65][C:53]([C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)([CH2:52][CH2:51][CH2:50][C:49](=[O:66])[CH2:48][CH2:47][CH2:46][C:45]([CH3:73])([C:67]1[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=1)[C:44]([OH:74])=[O:43])[C:54]([OH:56])=[O:55]
Reactant: CCOC(=O)C(C)(CCCC(=O)CCCC(C)(C(=O)OCC)c1ccccc1)c1ccccc1
Agent: CC(C)Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(CC(C)C)cc2)C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CCCC(=O)CCCC(C)(C(=O)O)c1ccccc1)(C(=O)O)c1ccccc1
Yield: 31.3 %

Procedure:
According to the procedure given for 210f, 209b (14.5 g, 31.1 mmol) was saponified with KOH (85%, 7.2 g, 108.6 mmol) in water (15 mL) and ethanol (45 mL) at reflux for 6 h. After the usual extractive workup, the crude material was purified by flash chromatography (silica gel; ethyl acetate/hexanes=1/20, 1/10, 1/2) to give 210b (4.0 g, 31%) as a white solid. Mp 44-46° C. 1H NMR (CDCl3): 10.25 (br., 2 H), 7.35-7.22 (m, 10 H), 2.32 (m, 4 H), 1.94-1.86 (m, 4 H), 1.57 (s, 6 H), 1.51-1.22 (m, 4 H). 13C NMR (CDCl3): δ 210.64, 182.66, 142.69, 128.66, 127.18, 126.29, 50.07, 42.97, 38.62, 22.20, 19.11. HRMS (LSIMS, gly): Calcd for C25H31O5 (MH+): 411.2171, found: 411.2144. HPLC: 95.2% pure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Product: O=[N+]([O-])c1ccc(-c2ccccc2)cc1
Yield: 97 %

Procedure:
From 4-nitro-bromobenzene and phenyl boronic acid, yield 97%; mp 110-113° C. (lit.,8 114-115° C.); IR: 1596, 1513, 1481, 1350 and 1236; 1H NMR (400 MHz; CDCl3): 8.32-8.28 (2H, m), 7.76-7.72 (2H, m), 7.65-7.61 (2H, m) and 7.52-7.42 (3H, m); 13C NMR (CDCl3): 147.6, 147.1, 138.7, 129.1, 128.8, 127.7, 127.3 and 124; m/z (EI) 199 (20%, M+), 169(70), 131 (85) and 119 (100)(Found: M+, 199.063. C12H9NO2 requires M, 199.063).
Reaction SMILES: [ClH:1].Cl.C([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)(=O)C>Cl>[ClH:1].[ClH:1].[ClH:1].[N:19]1([C:16]2[CH:15]=[CH:14][C:13]([NH:12][CH:9]3[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]3)=[CH:18][CH:17]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(=O)N1CCC(Nc2ccc(N3CCCCC3)cc2)CC1
Agent: Cl
Product: c1cc(N2CCCCC2)ccc1NC1CCNCC1
Temperature: 100 °C
Reaction time: 15 h
Yield: 217.5 %

Procedure:
A solution of 1-acetyl-4-[4-(piperidin-1-yl)phenylamino]piperidine dihydrochloride (0.70 g) in conc. hydrochloric acid (5 ml) was heated with stirring at 100° C. for 15 hours. After the solvent was distilled off, the residue was recrystallized from ethanol to obtain colorless crystals (0.5 g), m.p. 185°-189° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH:9]([N:11]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[CH:1]1([CH2:7][CH2:8][CH:9]([NH2:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CCC1CCCCC1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(N)CCC1CCCCC1
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A solution of 4.60 g 2-(3-cyclohexyl-1-methylpropyl)-1H-iso indole-1,3(2H)-dione and 7.26 g of hydrazine hydrate in 60 mL ethanol was heated to 70° C. The white precipitation was filtered off after cooling to room temperature. The mixture was washed with water and evaporated. 920 mg (37%) of a colourless oil were obtained.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:8][CH2:9][CH:10]=[CH2:11])[CH:5]1[O:7][CH2:6]1>>[CH2:9]([O:8][CH2:4][CH:5]([OH:7])[CH2:6][N:2]([CH3:3])[CH3:1])[CH:10]=[CH2:11]
Reactant: C=CCOCC1CO1
Reactant: CNC
Agent: *O[SiH2]*
Product: C=CCOCC(O)CN(C)C
Reaction time: 3.5 h
Yield: 98 %

Procedure:
A charge of 112.7 g (1.00 mol, 40%) dimethylamine is made to a 500 ml three-necked, round-bottomed flask. The amine is heated to 40° C. with stirring while 114.1 g (1.00 mol) allyl glycidyl ether is added over 2.5 hours while keeping the temperature below 50° C. After 3.5 hours at 50° C., GC analysis on a 30 M×0.53 mm SPB-5 polysiloxane column shows a single peak as 98% of the desired product. A viscous oil is obtained in quantitative yield. Analysis by 1H NMR (500 MHz, CDCl3) gives the following results: δ=2.61 (6H, s, —N(CH3)2), 2.62 and 2.71 (2H, m, —CH(OH)CH2N(CH3)2), 3.40 and 3.51 (2H, dd, —OCH2CH(OH)—), 4.04 (1H, bm, —CH2CH(OH)CH2—), 4.36 (2H, m, CH2═CHCH2—), 5.13 (1H, dd, CH2═CH—, cis isomer), 5.22 (1H, dd, CH2═CH—, trans isomer), 5.80 (1H, m, CH2═CH—). This data supports the following structure:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:14])=[C:10]([OH:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:15][N:16]1[CH2:21][CH2:20][C:19]([CH2:22]O)=[CH:18][CH2:17]1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:14])=[C:10]([O:13][CH2:22][C:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(Br)c(O)cc21
Reactant: CN1CC=C(CO)CC1
Product: CC(=O)N1CCc2cc(Br)c(OCC3=CCN(C)CC3)cc21

Procedure:
The title compound was prepared from 1-acetyl-5-bromo-6-hydroxyindoline (D64) and 1-methyl-1,2,5,6-tetrahydropyridine-4-methanol (J. Med. Chem., 1988, 31, 545) using the procedure of Description 8a in WO96/19477. The product was purified by acid/base extraction, then used in the next step.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:12][CH:13](O)[C:14]#[CH:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl.O>[CH3:15][CH:14]([O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:13]#[CH:12]
Reactant: Oc1cccc2ccccc12
Reactant: C#CC(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: C#CC(C)Oc1cccc2ccccc12
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a solution of 1-naphthol (200 mg, 1.38 mmol) and but-3-yn-2-ol (146 mg, 2.07 mmol) in anhydrous DCM (10 mL) under a N2 atmosphere and at 0° C. was added Ph3P (435 mg, 1.66 mmol) portion wise. The reaction mixture was stirred for 10 min and then DEAD (360 mg, 2.07 mmol) (70% solution in toluene) was slowly added. The resulting reaction solution was stirred at the room temperature for 24 h and then diluted with water (50 mL) and extracted with chloroform (3×50 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered concentrated in vacuo and the residue was purified by flash column chromatography using ethyl acetate/n-hexane (a gradient of 5-10%) to furnish 1-[(1-methyl-2-propyn-1-yl)oxy]naphthalene (176 mg, 65%) as a viscous oil.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].[N:18]1[NH:19][N:20]=[CH:21][CH:22]=1.CN(C)[C@@H]1CCCC[C@H]1N>O1CCOCC1.O.[Cu]I>[F:1][C:2]1[C:3]([N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(F)c1I
Reactant: c1cn[nH]n1
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(F)c1-n1ccnn1
Temperature: 100 °C

Procedure:
To 3-fluoro-2-iodobenzoic acid (4.5 g, 16.9 mmol) dissolved in dioxane (33.8 mL) and H2O (0.09 mL) was added Cs2CO3 (11.02 g, 33.8 mmol), CuI (161 mg, 0.85 mmol), 2H-1,2,3-triazole (1.96 mL, 33.8 mmol), and trans-N,N-dimethyl-1,2-cyclohexanediamine (0.53 mL, 3.38 mmol). The mixture was then heated to 100° C. overnight, cooled to room temperature, diluted with H2O, and extracted with EtOAc. The aqueous layer was then acidified and extracted with EtOAc. The combined organics were dried and concentrated. From this concentrate a solid precipitated to provide intermediate A-33 (285 mg, 8%). MS (ESI) mass calcd for C9H6FN3O2, 207.0. m/z found 208.1 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 6.81-6.77 (m, 1H), 6.46-6.40 (m, 2H), 6.30-6.23 (m, 1H), 6.18-6.12 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C@@:8]2([OH:28])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]2[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:5]=[CH:4][CH:3]=1.[CH3:29]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>C(Cl)(Cl)Cl.O.O1CCOCC1>[OH:28][C@:8]1([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:29])[N:7]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CB1OB(C)OB(C)O1
Reactant: CC(C)(C)OC(=O)N1CC[C@](O)(c2cccc(Cl)n2)[C@@H](OC(=O)C(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cccc([C@@]2(O)CCN(C(=O)OC(C)(C)C)C[C@@H]2OC(=O)C(C)(C)C)n1
Temperature: 88 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
A 1,4-dioxane (46 mL)-water (12 mL) solution of tert-butyl (3S,4S)-4-(6-chloropyridin-2-yl)-4-hydroxy-3-(pivaloyloxy)piperidine-1-carboxylate (2.30 g, 5.57 mmol) synthesized in Reference Synthesis Example 152, 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.2 mL, 13.4 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride-dichloromethane complex (915 mg, 1.12 mmol), and sodium carbonate (1.20 g, 11.3 mmol) was stirred under argon atmosphere at 88° C. for 3 hours. After completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and extraction from the resultant mixture with chloroform was performed. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain the title compound (1.50 g, yield 69%).
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:18][C:19]([F:44])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:31][C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:44][C:19]([F:18])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:38][CH2:39][CH2:40][CH2:41][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[O:31][C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:23]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Product: CCOC(=O)c1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4Oc4ccccc43)CC2)cc1

Procedure:
Step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 80 and the compound prepared in step (a) of Example 96 were used as the starting compounds. Thus, ethyl 4-[4-[4-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-xanthen-9-yl]butyl]piperazin-1-yl]benzoate was obtained.
Reaction SMILES: [C:1]1(C(O)=O)[C:2]([C:7]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O.CC(C)=O>[C:7]([OH:9])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:1]=1
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1
Temperature: 80 °C

Procedure:
To a solution of 1,2-benzenedicarboxylic acid, 4-bromo, 2-methyl ester and 1,2-benzenedicarbocylic acid, 4-bromo, 1-methyl ester (2.07 g; 8 mmol), triethylamine (6.0 ml; 0.043 mol), and toluene (80 ml) was added diphenylphosphoryl azide (5.0 g; 0.018 mol). The reaction mixture was heated at 80° C. for 2 hours at which time acetone (200 ml) and water (40 ml) was added. The reaction mixture was heated further at 80° C. for 8 hours, cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with 15% ethyl acetate/hexane) to provide benzoic acid, 2-amino-4-bromo, methyl ester (0.514 g, as a white solid) and benzoic acid, 2-amino-5-bromo, methyl ester (0.930 g, as a white solid).