Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[CH:31]=[CH:30][C:21]3[O:22][C:23]([CH3:29])([CH3:28])[C@@:24]4([CH3:27])[O:26][C@H:25]4[C:20]=3[CH:19]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([OH:40])=[N:34]1.N1C=CC=CC=1>O1CCOCC1>[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([O:40][C@H:25]2[C@@:24]([OH:26])([CH3:27])[C:23]([CH3:28])([CH3:29])[O:22][C:21]3[CH:30]=[CH:31][C:18]([S:15]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)(=[O:16])=[O:17])=[CH:19][C:20]2=3)=[N:34]1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2[C@@H]2O[C@@]21C
Reactant: Cn1nc(O)ccc1=O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cn1nc(O[C@@H]2c3cc(S(=O)(=O)c4ccc(O)cc4)ccc3OC(C)(C)[C@@]2(C)O)ccc1=O
Yield: 21.2 %

Procedure:
(3S,4S)-6-(4-tert-Butyldimethylsilyloxyphenyl)sulphonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (1.618 g) (see Preparation 14) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazin (1.33 g) (see J.Org.Chem, 1971, 36, 3372) were suspended in dry 1,4-dioxane (15 ml), pyridine (0.275 ml) was added and the mixture was heated under reflux (a calcium chloride drying tube was attached to the flask) for 3 days. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was separated and dried (anhydrous sodium sulphate), the solvent was removed under reduced pressure and the crude product was chromatographed on silica using 1:99 methanol:ethyl acetate as the eluent to yield (3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridazin-6-yl)oxy-3-hydroxy-6-(4-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (0.352 g) as a white solid. Found: C,58.13; H,5.00; N,5.70. C23H24N2O7S requires C,58.46; H,5.12; N,5.93%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH2:16])[CH:15]=1.[C:19](Cl)(Cl)=[S:20]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([N:16]=[C:19]=[S:20])[CH:15]=1
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1N=C=S

Procedure:
The product from Example 1, 5-(1H-indol-2-yl)-2-methoxy-phenylamine, (4.76 g, 20 mmol) was reacted with thiophosgene (1.9 mL, 25 mmol) according to the procedure for Example 23, Step A, to give [5-(1H-indol-2-yl)-2-methoxy-phenyl]-isothiocyanate (4.55 g), as a black solid.
Reaction SMILES: [Si](OCCCCCCCC#CC1C2C(=CC(OCOC)=CC=2)OCC1C)(C(C)(C)C)(C)C.[Si:33]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]1[C:59]2[C:54](=[CH:55][C:56]([O:60][CH2:61][O:62][CH3:63])=[CH:57][CH:58]=2)[O:53][CH2:52][C:51]1([C:65]1[CH:70]=[CH:69][C:68]([O:71]COC)=[CH:67][CH:66]=1)[CH3:64])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>>[Si:33]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]1[C:59]2[C:54](=[CH:55][C:56]([O:60][CH2:61][O:62][CH3:63])=[CH:57][CH:58]=2)[O:53][CH2:52][C:51]1([C:65]1[CH:66]=[CH:67][C:68]([OH:71])=[CH:69][CH:70]=1)[CH3:64])([C:36]([CH3:39])([CH3:37])[CH3:38])([CH3:35])[CH3:34]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: COCOc1ccc2c(c1)OCC(C)C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C
Product: COCOc1ccc2c(c1)OCC(C)(c1ccc(O)cc1)C2CCCCCCCCCO[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared from 3-(4-benzyloxy]phenyl)-4-[9-(t-butyldimethylsilyloxy)-1-nonynyl]-7-methoxymethyloxy-3-methylchroman according to the same method for the synthesis of 4-[9-(t-butyldimethylsilyloxy)-1-nonyl]-7-methoxymethyloxy-3-(4-methoxymethyloxyphenyl)-3-methylchroman described in International Patent Appln. No. PCT/KR97/00265.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:4]=2[CH:3]=1.[BH3-]C#N.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:4]=2[CH:3]=1
Reactant: CCCC1=Nc2cc(Cl)ccc2Oc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC1Nc2cc(Cl)ccc2Oc2ccccc21
Reaction time: 24 h
Yield: 95.4 %

Procedure:
To a stirring solution of the title compound of Example 19 (2.6 g) in THF (100 mL) was added NaCNBH3 (1.0 g). The reaction was stirred for 24 hours. The solvent was removed under reduced pressure, and the residue was taken up in CHCl3 with HCl (1M, 25 mL). The resulting mixture was stirred for 1 hour at room temperature. The CHCl3 was separated, extracted with NaHCO3 (saturated) and brine. The solvent was then removed to yield a yellow oil (2.5 g). This material was purified by column chromatography to yield 1.7 g of the title compound. This material was employed in Example 21 without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][CH3:28])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[C@H:20]2[O:24][C:23](=[O:25])[NH:22][C@H:21]2[CH3:26])[CH:9]=1)([CH3:3])[CH3:2].[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:34]Br>>[F:29][C:30]([F:43])([F:44])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:40])[F:41])[CH:38]=1)[CH2:34][N:22]1[C@@H:21]([CH3:26])[C@@H:20]([C:11]2[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=2[C:8]2[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=2[O:27][CH3:28])[O:24][C:23]1=[O:25]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@H]1OC(=O)N[C@H]1C
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@H]1OC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1C

Procedure:
Following the procedure described in EXAMPLE 93, 40 mg of cis-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]4-methyl-1,3-oxazolidin-2-one and 42 mg of 3,5-bis(trifluoromethyl)benzyl bromide gave the title compound. Mass spectrum (ESI) 620.2 (M+1). 1H NMR signals are doubled because of atropoisomerism. 1H NMR (500 MHz, CDCl3): δ 7.82-7.94 (m, 2H), 7.62-7.74 (m, 3H), 7.39, 7.37 (d, J˜8 Hz, 1H), 7.25, 7.17 (br d, J=8.5 Hz, 1H), 7.00, 6.78 (s, 1H), 6.87, 6.84 (d, J=8.5 Hz, 1H), 5.59, 5.56 (d, J=4.5 Hz, 1H), 4.96 (d, J=16 Hz, 1H), 4.22, 4.11 (d, J=16 Hz, 1H), 3.76 (s, 2H), 3.58 (s, 1H), 3.40 (m, 0.4H), 2.85-3.00 (m, 1H), 2.78 (m, 0.5H), 1.23 (d, J=7 Hz, 3H), 1.06 (m, 3H), 0.88, 0.69 (d, J=6.5 Hz, 3H).
Reaction SMILES: ClC1C=CC(N[C@@H](C)C(O)=O)=CC=1OC(F)(F)F.C([Si](C)(C)O[C@@H]1CN(CCCNCC(OC)OC)CCC21CC2)(C)(C)C.C([Si](C)(C)[O:50][C@@H:51]1[CH2:58][N:57]([CH2:59][CH2:60][CH2:61][N:62]([CH2:80][CH:81](OC)OC)[C:63](=[O:79])[C@@H:64]([NH:66][C:67]2[CH:72]=[CH:71][C:70]([Cl:73])=[C:69]([O:74][C:75]([F:78])([F:77])[F:76])[CH:68]=2)[CH3:65])[CH2:56][CH2:55][C:52]21[CH2:54][CH2:53]2)(C)(C)C.C([Si](C)(C)O[C@@H]1CN(CCCN2CCN(C3C=CC(Cl)=C(OC(F)(F)F)C=3)[C@@H](C)C2=O)CCC21CC2)(C)(C)C>>[Cl:73][C:70]1[CH:71]=[CH:72][C:67]([N:66]2[CH2:81][CH2:80][N:62]([CH2:61][CH2:60][CH2:59][N:57]3[CH2:56][CH2:55][C:52]4([CH2:53][CH2:54]4)[C@H:51]([OH:50])[CH2:58]3)[C:63](=[O:79])[C@@H:64]2[CH3:65])=[CH:68][C:69]=1[O:74][C:75]([F:77])([F:76])[F:78]
Reactant: COC(CN(CCCN1CCC2(CC2)[C@H](O[Si](C)(C)C(C)(C)C)C1)C(=O)[C@H](C)Nc1ccc(Cl)c(OC(F)(F)F)c1)OC
Agent: COC(CNCCCN1CCC2(CC2)[C@H](O[Si](C)(C)C(C)(C)C)C1)OC
Agent: C[C@H](Nc1ccc(Cl)c(OC(F)(F)F)c1)C(=O)O
Agent: C[C@H]1C(=O)N(CCCN2CCC3(CC3)[C@H](O[Si](C)(C)C(C)(C)C)C2)CCN1c1ccc(Cl)c(OC(F)(F)F)c1
Product: C[C@H]1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1c1ccc(Cl)c(OC(F)(F)F)c1

Procedure:
The title compound was produced in analogy with example 83, steps D-F. Thus, (S)-2-(4-chloro-3-trifluoromethoxy-phenylamino)-propionic acid (intermediate 19) was coupled with {3-[(S)-4-(tert-butyl-dimethyl-silanyloxy)-6-aza-spiro[2.5]oct-6-yl]-propyl}-(2,2-dimethoxy-ethyl)-amine (example 83C) in step D, leading to (S)—N-{3-[(S)-4-(tert-butyl-dimethyl-silanyloxy)-6-aza-spiro[2.5]oct-6-yl]-propyl}-2-(4-chloro-3-trifluoromethoxy-phenylamino)-N-(2,2-dimethoxy-ethyl)-propionamide. This was cyclized to (S)-1-{3-[(S)-4-(tert-butyl-dimethyl-silanyloxy)-6-aza-spiro[2.5]oct-6-yl]-propyl}-4-(4-chloro-3-trifluoromethoxy-phenyl)-3-methyl-piperazin-2-one in step E. Finally, deprotection in step F afforded the title compound. Light yellow gum, MS: 476.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:18](Br)[CH3:19].[OH-].[Na+]>ClCC(Cl)(Cl)Cl>[CH2:18]([C:11]1[CH:12]=[CH:13][C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:9][CH:10]=1)[CH3:19]
Reactant: CN1CCC(c2ccccc2)CC1
Reactant: CCBr
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1ccc(C2CCN(C)CC2)cc1
Temperature: 0 °C

Procedure:
To a solution of 3.5 g of 1-methyl-4-phenyl-piperidine in 50 ml of tetrachloroethane are added, with stirring, 2.7 g of finely powdered aluminium chloride and subsequently 2.5 g of ethyl bromide, and the reaction mixture is stirred at 50° for 4 hours. An addition of 50 g of ice is made, the mixture is rendered alkaline (pH=14) with concentrated sodium hydroxide solution, and extracted three times with 100 ml of ethyl acetate each time. The organic phases are dried over sodium sulphate and concentrated in vacuo. After distillation of the residue under high vacuum, chromatographic purification of the fraction boiling at 85°-100° (0.04 mm), on silica gel with chloroform and a small amount of methanol as the eluant, yields crude 4-(4-ethylphenyl)-1-methyl-piperidine, which can be further purified by fractional crystallisation of the hydrochloride (m.p. 209°-210°).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][S:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=2)([C:14]([NH:16][OH:17])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CO.O1CCOCC1>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][CH2:18][C:11]2([C:14]([NH:16][OH:17])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:21][CH:22]=1)[C:28]#[C:29][CH3:30]
Reactant: CC#CCOc1ccc(SCC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CC#CCOc1ccc(SCC2(C(=O)NO)CCNCC2)cc1
Reaction time: 1 h
Yield: 842.7 %

Procedure:
To a solution of 0.143 g (0.033 mmol) of tert-butyl-4-({[4-(2-butynyloxy) phenyl]sulfanyl}methyl)-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxylate in 5 mL of CH2Cl2 and 1 ml of MeOH was added 5 mL of 4M HCl in dioxane and stirred for 1 h. The reaction was concentrated in vacuo and the residue was triturated with ether and filtered to provide 0.093 g (76%) of the desired product as a pale orange solid. Electrospray Mass Spec: 335.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.O>C(O)C>[O:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccco2)cc1
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2ccco2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-(4-nitrophenyl)furan (0.378 g, 2 mmol, prepared according to the method of Heterocycles, 1990, 31, 1951) in ethanol (20 mL) was heated to 70° C. and added stannous chloride dihydrate (2.26 g, 10 mmol) and the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature and poured into water (50 mL), the whole was extracted with ethyl acetate (30 mL×2). The organic layer was dried over Na2SO4, filtered through celite and concentrated to give the crude subtitle compound (0.35 g).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[NH:10]2)[N:4]=1)=O.[CH3:25][NH2:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:25][NH:26][CH2:1][C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[NH:10]2)[N:4]=1
Reactant: O=Cc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CNCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-formyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate (340 mg, 1.03 mmol) in DCE (10 mL) was added MeNH2 (1032 μl, 2.065 mmol). After stirring for 1 h at rt, sodium triacetoxyborohydride (438 mg, 2.07 mmol) was added and the mixture was stirred overnight, whereupon it was quenched with saturtaed NaHCO3 (aq) at 0° C. and extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude material (assumed quantitative) was used as such in step 4.
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.[NH2:6][C:7]1[C:17](Br)=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=1>CCOC(C)=O>[NH2:6][C:7]1[C:17]([C:5]#[C:4][CH:1]2[CH2:3][CH2:2]2)=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=1
Reactant: C#CC1CC1
Reactant: CCOC(=O)c1cnc(N)c(Br)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(N)c(C#CC2CC2)c1
Yield: 78.2 %

Procedure:
Cyclopropyl acetylene (3 mmol) was reacted with ethyl 6-amino-5-bromonicotinate (245 mg, 1 mmol) as described in procedure A of Example 1. Ethyl 6-amino-5-(2-cyclopropylethynyl)nicotinate (180 mg) was obtained as a solid after silica gel column chromatography (EtOAc:hexanes, 1:1). LC/MS; (M+H)+=231.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:23](O)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:10]([O:9][C:7](=[O:8])[NH:14][C@@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23](=[O:24])[N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: C1CSCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCSCC1

Procedure:
Thiomorpholine (38 mmol) and Boc-L-phenylalanine (19 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) with the following workup: the reaction mixture was concentrated, diluted with ethyl acetate, then washed first with 1 N HCl three times, then with 2 N NaOH, the organic layer dried over MgSO4 and concentrated. The resulting foam was used without further purification. Yield 6.3 g, 95%.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC1C=C(OC)C=CC=1>O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[C:1]([O:9][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: ClCc1ccccc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COc1cccc(C)c1
Product: O=C(OCc1ccccc1)c1ccccc1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
A mixture comprising benzoic acid (2.45 g, 20 millimoles, Aldrich, 99%), sodium hydroxide (1.90 g, 22.5 millimoles, 50% w/w solution in water, Aldrich) and water (247.2 g) was stirred magnetically at room temperature for about two hours until the solids dissolved in water. The excess molar concentration of sodium hydroxide was 0.125. Next, the aqueous phase was transferred to a three-necked 500 mL flask and warmed up to 45° C. The organic phase consisting of benzyl chloride (7.60 g, 60 millimoles, Aldrich, 97%), 3-methylanisole (GC standard, 0.616 g, 5 millimoles, Aldrich, 99%), and Adogen 464 (0.905 g, 2 millimoles, Aldrich) was added to the aqueous phase and the two phase system was stirred mechanically (600 rpm, a calibrated photo-tachometer) for three hours at 45° C. The organic phase:aqueous phase weight ratio was 1:27. The aliquot, taken after 180 minutes after the addition of the organic phase, was briefly centrifuged, the phases were separated and the organic phase was injected into the GC instrument. The yield of benzyl benzoate based on the limiting reactant (benzoic acid) was 87%. Benzyl Benzoate was accompanied by a small quantity of benzyl alcohol (less than 5%).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[OH:20][CH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[OH:20][CH2:21][C:22]1[CH:27]=[C:26]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OCc1cccc(B(O)O)c1
Product: O=C(O)c1cccc(COc2ccc(-c3cccc(CO)c3)cc2)c1

Procedure:
3-(3′-Hydroxymethyl-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure 1 from 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 3-(hydroxymethyl)phenylboronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). Mass spectrum MH+=335.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:16]=[C:15]([CH:17]=[N:18]C(OC)=O)[S:14][C:9]=2[N:10]([CH2:12][CH3:13])[CH:11]=1)=[O:5])C.[OH-:24].[Na+].Cl>O>[CH2:12]([N:10]1[CH:11]=[C:6]([C:4]([OH:3])=[O:5])[C:7](=[O:23])[C:8]2[CH:16]=[C:15]([CH:17]=[N:18][O:24][CH2:6][C:4]([OH:5])=[O:3])[S:14][C:9]1=2)[CH3:13]
Reactant: CCOC(=O)c1cn(CC)c2sc(C=NC(=O)OC)cc2c1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(C=NOCC(=O)O)sc21
Reaction time: 3 h
Yield: 40 %

Procedure:
To the solution obtained in Example V containing 4,7-dihydro-7-ethyl-2-carbomethoxyiminomethyl-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester was added 0.15 g (3.7 mmols) of sodium hydroxide in 5 ml of water. The medium was maintained under stirring for 3 hours at room-temperature. The precipitate formed was filtered out, washed with ethanol and then with ethyl ether. The product so obtained was then taken up in 200 ml of water and the solution was acidified with concentrated hydrochloric acid. The precipitate so formed was filtered out, washed with water and then with ethanol. After drying, 4,7-dihydro-7-ethyl-2-carboxymethoxyiminomethyl-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid was obtained in a yield of 40%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]>C(OCC)(=O)C.[Pd]>[NH2:15][C:13]1[CH:12]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(OCC)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(N)cc(OCC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
The compound (8.49 g, 35.49 mmol) prepared in step 1 was dissolved in ethyl acetate, added with 10%-palladium (Pd) (900 mg). The reaction mixture was stirred at room temperature for one day under hydrogen gas. Once the reaction was completed, the solution was celite-filtered and the filtrate was concentrated under reduced pressure. The residue purified by flash column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (6.98 g, yield: 94%, yellow liquid).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[C:22]([C:23]#[N:24])=[CH:21][NH:20][N:19]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)CC(=O)C(F)(F)F)c1
Reactant: N#Cc1c[nH]nc1N
Product: Cc1cccc(-c2cc(C(F)(F)F)n3ncc(C#N)c3n2)c1
Yield: 54.3 %

Procedure:
Reaction of 1-(3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (230 mg, 1.0 mmol), prepared from commercially available 3-methyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (164 mg, 54%). MS (ISP) 303.2 [(M+H)+]; mp 202° C.
Reaction SMILES: CO[CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[F:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH2:12]>C(Cl)Cl>[F:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:12][CH:3]=[CH:4][C:5](=[O:7])[CH3:6]
Reactant: COC=CC(C)=O
Reactant: NCc1ccccc1F
Solvent: ClCCl
Product: CC(=O)C=CNCc1ccccc1F
Yield: 98.3 %

Procedure:
A solution of 4-methoxy-3-buten-2-one (0.1 g, 1 mmol) and 2-fluorobenzylamine (0.125 g, 1 mmol) in dry CH2Cl2 (5 mL) is stirred under reflux for 2 h. The solvent is evaporated under pressure to afford the title compound 56 as a yellow oil (Yield 0.19 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[N:5]([C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([NH2:20])[C:14]=1[N+:21]([O-:23])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[F:25][C:26]1[CH:27]=[N:28][NH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:24])[N:5]([C:13]1[CH:18]=[C:17]([N:28]2[CH:27]=[C:26]([F:25])[CH:30]=[N:29]2)[N:16]=[C:15]([NH2:20])[C:14]=1[N+:21]([O-:23])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Cl)nc(N)c1[N+](=O)[O-]
Reactant: Fc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N(Cc1ccccc1)c1cc(-n2cc(F)cn2)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
(2-Amino-6-chloro-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (100mg, 0.285 mmol), 4-fluoropyrazole (24.5 mg, 0.285 mmol) and potassium carbonate (118 mg 0.855 mmol) were stirred together in 5 mL of acetonitrile, under nitrogen. Heated the reaction to reflux for 3 hours and then allowed to cool to ambient temperature over night.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29](O)=[O:30])[CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:34](CC)CC)C.C(Cl)(=O)OCC.N>O1CCCC1>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([NH2:34])=[O:30])[CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N(CCCCOCC(=O)O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)N(CCCCOCC(N)=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
1.50 g of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid was dissolved in 20 ml of anhydrous tetrahydrofuran and 0.500 ml of triethylamine was added and then 0.376 ml of ethyl chlorocarbonate was added while stirring under ice cooling. After stirring under ice cooling for 45 minutes, a solution of saturated ammonia in 20 ml of tetrahydrofuran was added, followed by stirring for one hour. After removing an ice bath and stirring at room temperature for 18 hours, almost all of the solvent was evaporated. The residue was combined with water and then extracted with ethyl acetate. The extract was washed in turn with an aqueous saturated sodium hydrogen carbonate solution, 1N sodium hydroxide solution and water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether and then dried under reduced pressure to obtain 1.19 g of the desired product.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.O[C:14]1C=CC(C)=CC=1S>>[NH2:1][C@H:2]1[CH2:8][S:7][C:6]2[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1
Reactant: N[C@@H]1COc2ccccc2SC1
Reactant: Cc1ccc(O)c(S)c1
Product: Cc1ccc2c(c1)SC[C@H](N)CO2

Procedure:
The title compound (Ib) is prepared according to a reaction sequence identical to that employed for the synthesis of 3-(R)-amino-3,4-dihydro-2H-1,5-benzoxathiepine (Ia-1) but using, as starting material, 2-hydroxy-5-methylthiophenol (IVb) instead of 2-hydroxythiophenol. The title compound (Ib) is obtained in the form of a yellow oil.