Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH:9]=O)=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[NH2:18].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:23][O:22][C:20]1[CH:19]=[C:17]([NH:18][CH2:9][C:8]2[C:3]([NH:2][CH3:1])=[N:4][C:5]([S:11][CH3:12])=[N:6][CH:7]=2)[CH:16]=[C:15]([O:14][CH3:13])[CH:21]=1
Reactant: CNc1nc(SC)ncc1C=O
Reactant: COc1cc(N)cc(OC)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNc1nc(SC)ncc1CNc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (1.0 g, 5.46 mmol) and 3,5-dimethoxyaniline (840 mg, 5.46 mmol) in methanol (60 mL) was stirred at RT for 3 h, followed by the addition of sodium cyanoborohydride (520 mg, 8.20 mmol) and 1 mL of acetic acid. The reaction mixture was then stirred at RT for another 4 h. LCMS showed the reaction was completed. The reaction was quenched by 30 mL of 1N HCl, then stirred for 0.5 h and extracted with ethyl acetate (3×50 mL). The organic layers were separated, combined, washed with saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to afford the title compound (crude 1.2 g, 69%) as a white solid, which was directly used in the next step without further purification. MS (ES+) C15H20N4O2S requires: 320. found: 321 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.CN(C)[CH:10]=[C:11]([N:17]1[CH:21]=[CH:20][N:19]=[N:18]1)[C:12](OCC)=[O:13].[CH:23]1([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:38]=[C:37]([NH:39][NH2:40])[N:36]=[CH:35][N:34]=3)[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24]1>C(OCC)(=O)C>[CH:23]1([N:27]2[CH2:28][CH2:29][N:30]([C:33]3[N:34]=[CH:35][N:36]=[C:37]([N:39]4[C:12](=[O:13])[C:11]([N:17]5[CH:21]=[CH:20][N:19]=[N:18]5)=[CH:10][NH:40]4)[CH:38]=3)[CH2:31][CH2:32]2)[CH2:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Reactant: NNc1cc(N2CCN(C3CCC3)CC2)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CCN(C3CCC3)CC2)ncn1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
16 μl (23 mg, 0.2 mmol) of trifluoroacetic acid are added to a mixture of 211 mg (1.0 mmol) of the compound from Example 8A and 250 mg (1.0 mmol) of the compound from Example 9A in 4 ml of ethyl acetate, and the mixture is stirred at 100° C. for 20 h. The reaction mixture is concentrated under reduced pressure, more ethyl acetate and trifluoroacetic acid (the same amounts as above) are added and the mixture is stirred at 100° C. for 3 d. The reaction mixture is cooled to RT, and the precipitated solid is filtered off and washed with diethyl ether. The residue is suspended in 2 ml of water, dissolved by adding aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 195 mg (51% of theory)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)C1C=CC=CC=1>[Co]>[C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH3:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=Cc1ccccc1
Agent: [Co]
Solvent: OCCc1ccccc1
Solvent: OCc1ccccc1
Product: Cc1ccccc1
Yield: 50 %

Procedure:
It has long been desirable to prepare β-phenylethyl alcohol in a low cost process. This material is a valuable intermediate in the preparation of fragrances and of styrene, a commercial chemical with widely varying uses. In the past, it has been proposed that β-phenylethyl alcohol be prepared from benzyl alcohol. For example, the reaction has been described by Wender, I. et al., J. Am. Chem. Soc. 71 (1949), pages 4160-4161 in the presence of a cobalt catalyst. This early work is summarized by Orchin in Advances in Catalysis, Vol. V (1953), pages 393-414. This author reports that, at 185° C., a 50-60% yield of toluene and a 25-35% yield of β-phenylethanol is obtained. Other workers have experimented with this reaction, particularly Y. B. Kryukov et al., Neftekhimiya, 1970, 10 (1), at page 83. Here, a vapor phase reaction is described over an iron, alumina, vanadium and potassium catalyst at 450° C. and 50 atmospheres pressure. Unfortunately, in this latter reaction extremely low selectivities to the β-phenylethanol were obtained.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:28])[C:11]([CH3:27])([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH3:8].[CH3:29][O:30][C:31]1[CH:67]=[CH:66][C:34]([CH2:35][N:36]2[CH:40]([CH2:41][CH2:42]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:39][N:38]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=3)[C:37]2=[O:65])=[CH:33][CH:32]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:7]([O:9][C:10](=[O:28])[C:11]([CH3:27])([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:42][CH2:41][CH:40]2[CH2:39][N:38]([CH2:54][C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:59][CH:60]=3)[C:37](=[O:65])[N:36]2[CH2:35][C:34]2[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:67][CH:66]=2)=[CH:15][CH:14]=1)[CH3:8]
Reactant: COc1ccc(CN2C(=O)N(Cc3ccc(C(F)(F)F)cc3)CC2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2Cc2ccc(OC)cc2)cc1)Oc1ccccc1
Yield: 93.6 %

Procedure:
Cesium carbonate (2.49 g, 7.647 mmol) is added to a solution of 3-(4-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (1.77 g, 5.88 mmol) and toluene-4-sulfonic acid 2-[3-(4-methoxy-benzyl)-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (3.64 g, 6.47 mmol) in DMF (40 mL). The resultant mixture is stirred at 55° C. under an atmosphere of nitrogen for 18 h, then diluted with ethyl acetate. The organic layer is washed, then dried, concentrated, and purified by flash chromatography (acetone/hexanes gradient) to provide the title compound (3.80 g, 94%). 1H NMR (400 MHz, CDCl3): δ 7.57 (d, 2H, J=8.4 Hz), 7.37 (d, 2H, J=7.8 Hz), 7.23-7.19 (m, 4H), 7.13 (d, 2H, J=8.4 Hz), 6.97 (t, 1H, J=7.8 Hz), 6.86 (d, 2H, J=8.4 Hz), 6.81 (d, 2H, J=8.4 Hz), 6.67 (d, 2H, J=7.8 Hz), 4.66, 4.20 (ABq, 2H, J=14.9 Hz), 4.47, 4.43 (ABq, 2H, J=15.5 Hz), 4.20 (q, 2H, J=7.1 Hz), 3.89-3.85 (m, 2H), 3.80 (s, 3H), 3.61-3.55 (m, 1H), 3.31 (t, 1H, J=9.1 Hz), 3.26, 3.08 (ABq, 2H, J=13.6 Hz), 3.00 (t, 1H, J=9.1 Hz), 2.20-2.14 (m, 1H), 1.87-1.78 (m, 1H), 1.38 (s, 3H), 1.21 (t, 3H, J=7.1 Hz). MS [EI+] 691 (M+H)+. Rf=0.46 in 50% acetone in hexanes.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:10]=1)=[O:4].Br.[C:26]1([CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:10]=1)[CH2:2][N:42]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(CCCOCCCCCCNCc2ccccc2)cc1
Reactant: CCOC(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Agent: Br
Solvent: ClCCl
Product: CCOC(=O)Nc1cc(C(O)CN(CCCCCCOCCCc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
A solution of ethyl N-[5-bromoacetyl-2-(phenylmethoxy)phenyl]carbamate (0.58 g), N-[6-(3-phenylpropoxy)hexyl]benzenemethanamine hydrobromide (0.66 g) and DEA (0.48 g) in dichloromethane (15 ml) was stirred at room temperature under nitrogen for 26 h. Dichloromethane (50 ml) was added, the solution washed successively with 2N hydrochloric acid (50 ml), water (50 ml), 8% sodium bicarbonate solution (50 ml), dried and evaporated in vacuo. The residual brown oil (1.02 g) in absolute ethanol (20 ml) at 0° was treated with sodium borohydride (0.15 g), and the mixture was allowed to warm up to room temperature and stirred under nitrogen for 18 h. 2N Hydrochloric acid (5 ml) was cautiously added, the mixture stirred at room temperature for 5 min and evaporated in vacuo. The residue was partitioned between 8% sodium bicarbonate solution (10 ml) and EA (20 ml) and the organic phase dried and evaporated in vacuo to give a yellow oil. Purification by FCC on triethylamine deactivated silica (40 g) eluting with ER-CX (7:3) gave the title compound as a colourless oil (0.84 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][CH2:40][NH2:41]>COCCOC.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:41][CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][CH2:29][NH2:28])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: NCCCNCCCCNCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Solvent: CN(C)C=O
Product: NCCCNCCCCNCCCNC(=O)Cc1ccc(O)c(F)c1
Reaction time: 48 h

Procedure:
According to the General Procedure using 3-fluoro-4-hydroxyphenylacetic acid (85 mg, 0.50 mMol), dicyclohexylcarbodiimide (106 mg, 0.31 mMol), and spermine (512 mg, 2.53 mMol) in DME/DMF (4 ml, 3:1), activation during 2 h and coupling over 48 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was in fractions 12-19 and was homogeneous when monitored by tlc on silica (CH2Cl2 /MeOH/NH4OH, 4:2:1), Rf =0.19, (39 mg, 22%), lyophilisation gave 30 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, 2H2O) 1.6-2.2 (m, 8H, 4×CH2 --CH2), 2.85-3.2 (m, 10H, 5×CH2 --N), 3.4 (t, J=7, 2H, CON2H--CH2 --CH2), 3.6 (s, 2H, Ar--CH2 --CO), 6.8-7.1 (m, 2H, 2×ArH 5,6), and 7.1 (d, 3 J H--F=11, H, ArH 2)ppm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][OH:8].I[CH2:10][CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[CH2:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][OH:8])[CH3:11]
Reactant: OCC1COCCN1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCOCC1CO

Procedure:
Morpholin-3-ylmethanol (500 mg) and iodoethane (666 mg) in N,N-dimethylformamide was treated with K2CO3 (1.1 g) overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to provide the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]#[CH:24])[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH:42]3[CH2:47][CH2:46][CH2:45][N:44]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:43]3)(=[O:41])=[O:40])=[CH:35][CH:34]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.O>[C:11]([O:10][C:9]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]1[N:6]=[CH:7][C:2]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH:42]3[CH2:47][CH2:46][CH2:45][N:44]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:43]3)(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[N:3][C:4]=1[C:23]#[CH:24])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#Cc1nc(-c2ccc(S(=O)(=O)C3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (2 g, 5.022 mmol) and tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylpiperidine-1-carboxylate (2.324 g, 5.148 mmol) were dissolved in MeCN (40.00 mL)/water (8.000 mL). K3PO4 (2.131 g, 10.04 mmol) was added and the mixture was degassed/flushed via nitrogen cycles (×5). Pd[P(tBu)3]2. (128.3 mg, 0.2511 mmol) was added and the reaction mixture placed under an atmosphere of nitrogen using vacuum/nitrogen cycles (×5). The reaction mixture was stirred at ambient temperature for 1 hour and then poured onto a stirred mixture of ethylacetate and saturated aqueous sodium metabisulphite at 10° C. The mixture was stirred for 5 minutes, shaken well and separated. The organic layer was washed with brine (×1), dried over MgSO4, filtered and the solution passed through a Florisil eluting with Ethylacetate. The filtrate was concentrated in vacuo and the residue purified by column chromatography (ISCO Companion, 330 g column, eluting with 0 to 40% Petroleum/Petroleum Ether, loaded in DCM) to give tert-butyl 3-[4-[5-[bis(tert-butoxycarbonyl)amino]-6-ethynyl-pyrazin-2-yl]phenyl]sulfonylpiperidine-1-carboxylate as a beige solid (2.45 g, 76% Yield). H NMR (400.0 MHz, DMSO) δ 9.38 (s, 1H), 8.48 (d, 2H), 8.08 (d, 2H), 5.02 (s, 1H), 4.12-3.88 (m, 1H), 3.76 (br d, 1H), 3.43 (br s, 1H), 2.90-2.78 (m, 2H), 2.09 (br s, 1H), 1.75-1.61 (m, 2H) and 1.38-1.18 (m, 28H) ppm;
Reaction SMILES: COCCN(S(F)(F)F)CCOC.[C:14]([O:18][C:19]([NH:21][C@H:22]([CH3:33])[C:23]([NH:25][CH:26]([CH2:31][OH:32])[C:27]([O:29][CH3:30])=[O:28])=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].BrC(Cl)(Cl)Cl>C(Cl)Cl>[C:14]([O:18][C:19]([NH:21][C@@H:22]([C:23]1[O:32][CH:31]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[N:25]=1)[CH3:33])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)C(CO)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: COCCN(CCOC)S(F)(F)F
Solvent: ClC(Cl)(Cl)Br
Solvent: ClCCl
Product: COC(=O)c1coc([C@@H](C)NC(=O)OC(C)(C)C)n1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Deoxo-fluor™ (Bis-(2-methoxy)amino sulfur trifluoride, 1.4 mL, 7.6 mmol) was added drop-wise to a solution of methyl 2-((R)-2-(tert-butoxycarbonylamino)propanamido)-3-hydroxypropanoate (2.0 g, 6.9 mmol) in CH2Cl2 (50 mL) at −20° C. The solution was stirred for 30 min and BrCCl3 (2.45 mL, 24.8 mmol) was added drop-wise. The reaction was stirred at 2-3° C., for 8 h., quenched with sat. aq. NaHCO3 solution and extracted with ethyl acetate. The organic layer was concentrated and chromatographed on silica gel (30% ethyl acetate/70% hexanes) to yield 65% of (R)-methyl 2-(1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][Cl:5].[Cl:8][CH2:9]C(O)CO>CC1C=CC(S(O)(=O)=O)=CC=1>[Cl:5][CH2:4][CH:3]1[O:6][CH:7]([CH2:9][Cl:8])[CH2:1][O:2]1
Reactant: OCC(O)CCl
Reactant: COC(CCl)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: ClCC1COC(CCl)O1
Yield: 93.6 %

Procedure:
124 g (1 mol) of chloroacetaldehyde dimethyl acetal and 110 g (1 mol) of 3-chloro-1,2-propanediol are heated together with 0.3 g p-TSA and the resultant methanol removed by distillation. Once 32 g of methanol have passed over, the reaction mixture is washed with weakly alkaline water, the organic phase separated and dried over Na2SO4. After fractionation, 160 g (93%) of 2,4-bis(chloromethyl)-1,3-dioxolane are obtained. Bp.: 98° C. (1500 Pa); IR: 1191, 1049, 1007 cm−1 (acetal); MS: m/e=169 (M−1), 140, 123, 121, 105, 93, 77, 75, 63, 57.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:23]([C:26]1[CH:27]=[C:28]([O:36][CH3:37])[C:29]([OH:35])=[C:30](B(O)O)[CH:31]=1)[CH:24]=[CH2:25]>>[OH:22][C:15]1[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:30]3[CH:31]=[C:26]([CH2:23][CH:24]=[CH2:25])[CH:27]=[C:28]([O:36][CH3:37])[C:29]=3[OH:35])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Reactant: C=CCc1cc(OC)c(O)c(B(O)O)c1
Product: C=CCc1cc(OC)c(O)c(-c2cccc(-c3cccc(-c4cccc(OC)c4O)n3)n2)c1
Yield: 37 %

Procedure:
6-(2-Hydroxy-3-methoxyphenyl)-6′-(5-allyl-2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 5-allyl-2-hydroxy-3-methoxyphenylboronic acid in 37% yield using method F; δH [2H6]-DMSO 13.53,(1H, s), 13.31,(1H, s), 8.35-8.20,(4H, m), 8.16,(2H, d), 7.70,(1H, s), 7.53,(1H, s), 7.09,(1H, d), 6.93,(2H, m), 6.05,(1H, m), 5.14,(1h, d), 5.06,(1H, d), 3.85,(6H, s), 3.40,(2H, d).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25](Br)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:29]1[O:33][N:32]=[C:31]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:30]=12>>[N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([C:35]3[CH:36]=[CH:37][C:30]5[C:31]([CH:34]=3)=[N:32][O:33][N:29]=5)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccc2nonc2c1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Br)cccc2[nH]1
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(-c3ccc4nonc4c3)cccc2[nH]1

Procedure:
This compound is synthesized from compound 194 (see example 156) and benzo[1,2,5]oxadiazol-5-yl-boronic acid analogously to the method described in Example 156.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([O:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[CH:37]=[O:38])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([O:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[C:37]([OH:6])=[O:38])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)ccc2C=O)C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)ccc2C(=O)O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution of sodium chlorite (320 mg; 3.54 mmol; 5.5 eq.) and sodium dihydrogenphosphate (278 mg; 2.32 mmol; 3.6 eq.) in water (2 mL) was added dropwise to a mixture of 2-methyl-2-butene (0.64 mL) and (S)-3-(5-fluoro-2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (208 mg; 0.64 mmol; 1 eq.) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 16 hours and the 1,4-dioxane concentrated in vacuo. The aqueous solution was diluted with water and the pH made acidic with 0.1M HCl. The mixture was extracted with DCM (2×) and the combined organic phase was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (202 mg, 93%) as a white solid. HPLC (max plot) 94.3%; Rt 3.89 min. UPLC/MS: (MS−) 338.4 ([M−H]−).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])[CH:6](O)[C:7]([CH3:9])=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])/[CH:6]=[C:7](\[CH3:9])/[CH2:8][P:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:26])[CH3:2]
Reactant: C=C(C)C(O)C(NC=O)C(=O)OCC
Reactant: CCOP(OCC)OCC
Agent: O=S(Br)Br
Product: CCOC(=O)C(/C=C(\C)CP(=O)(OCC)OCC)NC=O

Procedure:
By reaction of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in a manner analogous to that described in Example 1, E-2-formylamino-4-methyl-5-diethylphosphono-3-pentenoic acid ethyl ester is obtained in the form of a pale yellow oil.
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.N1C=CC=CC=1.Cl[C:16]([O:18][CH3:19])=[O:17]>C(Cl)Cl>[C:16](=[O:17])([O:18][CH3:19])[O:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: OC1C=CCCCC1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)OC1C=CCCCC1
Temperature: 10 °C
Yield: 94.9 %

Procedure:
To a solution of cyclohept-2-enol (8.3 g, 74.0 mmol) in DCM (227 ml) and pyridine (35.9 ml, 444 mmol), was added methyl chloroformate (14.24 ml, 185 mmol) with cooling in an ice bath at such a rate that T<10° C. Once addition was complete, the reaction was allowed to mix and warm to ambient temperature overnight. The reaction mixture was washed with 2×150 mL 1N aqueous hydrochloric acid. The combined washes were back-extracted with 100 mL DCM. The combined DCM layers were then washed with 150 mL of an aqueous saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (11.95 g, 70.2 mmol, 95% yield) as an oil that was used without further purification. 1H NMR (400 MHz, DMSO-d6) 5 ppm 5.83 (dddd, J=11.81, 7.03, 5.17, 2.15 Hz, 1H), 5.65 (d, J=11.71 Hz, 1H), 5.17 (d, J=6.64 Hz, 1H), 4.71 (d, J=4.30 Hz, 1H), 3.69 (s, 2H), 1.99-2.23 (m, 2H), 1.79-1.94 (m, 2H), 1.56-1.72 (m, 3H), 1.34 (d, J=3.51 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[C:5]2[O:10][C:11](=[O:14])[O:12][CH2:13][C:4]=12.CCOC(S)=[S:19]>>[SH:19][CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[C:5]2[O:10][C:11](=[O:14])[O:12][CH2:13][C:4]=12
Reactant: CCOC(=S)S
Reactant: Cc1ncc(CCl)c2c1OC(=O)OC2
Product: Cc1ncc(CS)c2c1OC(=O)OC2

Procedure:
5-Chloromethyl-8-methyl-2-oxo-4H-m-dioxino-[4,5-c]pyridine is converted to the corresponding ethyl xanthogenate and reduced in accordance with the procedure of Example 19, Step B, to give 5-mercaptomethyl-8-methyl-2-oxo-4H-m-dioxino[4,5-c]pyridine.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][CH:17]=2)[CH:8]=1)C.O.[OH-].[Li+]>O1CCCC1.O>[C:26]([O:25][C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][O:13][C:9]2[CH:8]=[C:7]([CH2:6][CH:5]([O:30][CH2:31][CH3:32])[C:4]([OH:33])=[O:3])[CH:12]=[CH:11][CH:10]=2)=[CH:21][CH:20]=1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C(Cc1cccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1cccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 70.9 %

Procedure:
3-{3-[2-(4-tert-Butoxycarbonylaminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester (described in Example 48) (0.8 g; 1.74 mmole) was dissolved in tetrahydrofuran (15 ml). Lithium hydroxide hydrate (0.073 g; 1.74 mmole) dissolved in water (5 ml) was added slowly. The reaction mixture was stirred at room temperature for 4.5 hours. More lithium hydroxide hydrate (0.036 g; 0.87 mmole) was added and the stirring continued for 2 more hours. Tetrahydrofuran was carefully evaporated and a large amount of water was added. pH was adjusted to about 12 with sodium hydroxide (2M) and the solution was extracted with ethyl acetate. The water phase was cooled to <10° C., acidified with potassium hydrogensulfate (1 M) and extracted with ethyl acetate. The organic phase was washed with water and dried with sodium sulfate. Evaporation gave 0.53 g (70.9% yield) of 3-{3-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid.