Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:9]([F:10])=[C:8]([C:11](N2C=CN=C2)=[O:12])[CH:7]=[CH:6][C:5]=1[CH2:18][CH2:19][C:20]1[N:21]=[C:22]([NH:25][C:26](=[O:28])[CH3:27])[S:23][CH:24]=1.[Cl-].[NH4+]>O1CCCC1.O>[F:3][C:4]1[C:9]([F:10])=[C:8]([CH2:11][OH:12])[CH:7]=[CH:6][C:5]=1[CH2:18][CH2:19][C:20]1[N:21]=[C:22]([NH:25][C:26](=[O:28])[CH3:27])[S:23][CH:24]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(C(=O)n3ccnc3)c(F)c2F)cs1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(CO)c(F)c2F)cs1
Temperature: -20 °C
Reaction time: 2.5 h
Yield: 75.8 %

Procedure:
Sodium borohydride (1.009 g, 26.66 mmol) was suspended in a mixture of tetrahydrofuran (36 ml) and water (9 ml), and the suspension was cooled to −20° C. A suspension of N-(4-{2-[2,3-difluoro-4-(1H-imidazol-1-ylcarbonyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (503.5 mg, 1.338 mmol) in anhydrous tetrahydrofuran (4 ml) was added dropwise. After stirring at not more than 0° C. for 2.5 hr, saturated aqueous ammonium chloride (50 ml) was added. The mixture was extracted 3 times with ethyl acetate, and the combined organic layer was washed with saturated aqueous ammonium chloride and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue were added methanol (0.5 ml) and diisopropyl ether (25 ml), and the mixture was stirred and filtered. The filtered product was dried under reduced pressure to give N-(4-{2-[2,3-difluoro-4-(hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (316.8 mg, 1.014 mmol, 75.8%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(OC(=O)C)(=O)C.[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O>[Cl-].[Zn+2].[Cl-]>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:3]1[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]1[CH:1]=[CH:29][C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[F:26]
Reactant: Cc1ccccc1-n1c(C)nc2ccsc2c1=O
Reactant: O=Cc1ccccc1F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1-n1c(C=Cc2ccccc2F)nc2ccsc2c1=O
Temperature: 25 °C
Yield: 136.9 %

Procedure:
Anhydrous zinc chloride (7.0 g, 51.4 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, then dioxane (100 mL) was added. To this mixture was added 2-methyl-3-(2-methylphenyl)-3H-thieno[3,2-d]pyrimidin-4-one (7.0 g, 27.34 mmol, preparation 2), acetic anhydride (7.7 mL, 82.0 mmol), and 2-fluorobenzaldehyde (8.6 mL, 10.2 mmol). The reaction was refluxed 14 hours, cooled to ambient temperature, and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layer was filtered to obtain a small amount of product which had precipitated. The filtrate was washed with water and brine, dried over magnesium sulfate and concentrated to leave a mustard colored solid. This material was added to the product which had previously been collected and the combined material was flash chromatographed on silica gel (60×185 mm) eluting with 25-40% ethyl acetate/hexane to afford 5.06 g (51%) of 3-(2-methyl-phenyl)-2-[2-(2-fluoro-phenyl)-vinyl]-3H-thieno[3,2-d]pyrimidin-4-one as a light yellow solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=O)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C(COC)OC>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[S:31])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCN1S(=O)(=O)c1ccc(N2CCCCC2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: O=S(=O)(c1ccc(N2CCCCC2)cc1)N1CCCC1=S
Yield: 57 %

Procedure:
A mixture comprising 5 g of 1-[4-(1-piperidyl)benzenesulphonyl]-2-pyrrolidinone, prepared as in Example 10 of the European Patent published under No. 0,033,578, and 3.28 g of Lawesson reagent (or 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide) in 100 cm3 of dimethoxyethane is heated to reflux for 1 hour. The mixture is allowed to return to room temperature and is evaporated to dryness, and the residue is chromatographed on silica (eluant: ethyl acetate/n-hexane, 1:1). 3.5 g of product are recovered. M.p. 195°-200° C. After crystallization in ethanol, 1.5 g of expected product are obtained. M.p. 211°-212° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:10]C)=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([OH:9])[C:3]=1[OH:10]
Reactant: COc1c(O)cc(F)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(F)cc(F)c1O
Temperature: -25 °C
Reaction time: 20 h

Procedure:
3,5-Difluoro-2-methoxyphenol (1.0 g, 6.3 mmol, prepared as described in Jones, Lyn H.; Randall, Amy; Barba, Oscar; Selby, Matthew D., Organic & Biomolecular Chemistry 2007, 5, 3431-3433) was dissolved in dry dichloromethane (11 mL), cooled to −20 to −30° C. and treated in portions with boron tribromide (BBr3) solution in dichloromethane (1.0 M; 13 mL, 13 mmol). The cooling bath was removed and the mixture was stirred for 20 h at 20° C. The mixture was cooled to −30° C., treated in portions with water (3 mL) and then warmed to 20° C. 6 M HCl (10 mL) and ethyl acetate (30 mL) were added, and the mixture was stirred for 20 min to produce two clear phases. The aqueous phase was extracted with ethyl acetate (20 mL), and the combined organic phases were washed with saturated NaCl (10 mL), dried (Na2SO4) and rotary evaporated to give the title compound as an oil which solidified upon standing (720 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 6.51 (ddd, J=9.5, 2.8, 2.1 Hz, 1H), 6.45 (ddd, J=10.3, 8.7, 2.9 Hz, 1H), 5.71 (s, 1H), 5.06 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −119.56, −136.16; EIMS m/z 146.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1.[Mg+2].[Cl-].[Cl-].C(N(CC)CC)C.[CH2:31]=[O:32]>CC#N.CCOC(C)=O>[CH:31]([C:7]1[C:2]([OH:1])=[CH:3][C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:5][CH:6]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(O)ccn2)CC1
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cc(O)c(C=O)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.1 %

Procedure:
To a mixture of t-butyl 4-(4-hydroxypyridin-2-yl)piperazine-1-carboxylate (5.03 g, 18.0 mmol) and MgCl2 (3.42 g, 36 mmol) in CH3CN (100 mL) was added triethylamine (15.1 mL, 90 mmol). After the mixture was stirred for 10 minutes at ambient temperature, paraformaldehyde (5.4 g, 180 mmol) was added to the mixture. The mixture was stirred for 18 hours at 60° C., and then cooled to room temperature. The mixture was then diluted with EtOAc (400 mL) and washed with 1 M Rochelle salt solution (200 mL) and saturated NH4Cl solution (200 mL). The organic layer was concentrated under the reduced pressure and purified by column chromatography (30%-80% EtOAc/hexanes) to yield 1.5 g (27%) of t-butyl 4-(5-formyl-4-hydroxypyridin-2-yl)piperazine-1-carboxylate as white solid. MS m/z 308.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ (ppm) 11.37 (1H, s), 9.64 (1H, s), 8.27 (1H, s), 5.98 (1H, s), 3.71 (4H, m), 3.56 (4H, m), 1.48 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(O)(=O)C.CCOC(C)=O>[C:34]([NH:23][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Temperature: 130 °C
Reaction time: 72 h
Yield: 88.7 %

Procedure:
A mixture of 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonamide (example 266) (300 mg, 0.639 mmol) and acetic anhydride (2.42 mL, 25.6 mmol) in acetic acid (5 mL) was stirred at 130° C. for 3 days. Cooled to rt, diluted with EtOAc, extracted with sat. NaHCO3-sol., dried over Na2SO4, filtered off and evaporated totally to give a crude product, which was purified by silica gel column chromatography with n-heptane/ethyl acetate followed by trituration with diethyl ether/n-heptane to give the title compound (290 mg, 88%) as a white solid. MS (ISP) 512.0 [(M+H)+]; mp 244° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8](C)[CH:9]=[O:10].[Br:12][C:13]1[CH:14]=[C:15](C(O)=O)[CH:16]=[N:17][CH:18]=1>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([C:9]([NH2:8])=[O:10])[CH:16]=[N:17][CH:18]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cncc(Br)c1

Procedure:
Oxalyl chloride (1.33 ml) and N,N-dimethylformamide (catalytic amounts) were added dropwise under ice-cooling to a solution of 5-bromopyridine-3-carboxylic acid (2.02 g) in dichloromethane, and stirred for an hour. The solvent was evaporated in a evaporator, the residue was dissolved in tetrahydrofuran (10 ml), to which ammonia water (28%; 1 ml) was added dropwise under ice-cooling, and stirred at room temperature for 0.5 hours. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was purified with column chromatography to give 5-bromopyridine-3-carboxamide (734 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].N12CCCN=C1CCCCC2.Cl.Cl.[CH:34]12[NH:42][CH2:41][CH:38]([NH:39][CH2:40]1)[CH2:37][CH2:36][CH2:35]2>C(#N)C>[Cl:1][C:2]1[C:3]([N:39]2[CH2:40][CH:34]3[NH:42][CH2:41][CH:38]2[CH2:37][CH2:36][CH2:35]3)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: C1CC2CNC(C1)CN2
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3CC4CCCC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A suspension of 1.0 g (3.34 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 30 ml of acetonitrile, 1.52 g (10.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 0.72 g (3.62 mmol) of 6,8diazabicyclo[3.2.2]nonane, dihydrochloride was heated under reflux for 3 hr, then stirred at room temperature overnight. The precipitate was removed by filtration and washed with acetonitrile and ether to give 0.82 g of the title compound, mp 217°-220° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[CH3:23][C:24]([OH:28])([C:26]#[CH:27])[CH3:25]>CN(C)C=O.C(NCC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=[C:2]([C:27]#[C:26][C:24]([CH3:25])([OH:28])[CH3:23])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(C)(O)C#Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Yield: 51.9 %

Procedure:
A mixture of 382 mg (1 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 93 mg (1.1 mmole) 2-methyl-3-butyn-2-ol, 38 mg copper(I)-iodide and 35 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 1 hour in 5 ml dimethylformamide and 5 ml diethylamine. The solvents are removed and the residue is diluted with dichloromethane. The dichloromethane solution is washed twice with water, dried over magnesiumsulfate and concentrated in vacuo. Flash chromatography (silicagel, hexane/ethyl acetate 7/3 ) and recrystallisation of the residue from ethanol yields 200 mg (52%) pure 4-[4-(4-amino-benzenesulfonyl)-6-pyrrolidine-1-yl-pyridine-2-yl]-2-methyl-but-3-yn-2-ol als a white solid mp.: 168-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([NH2:8])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[O:38][C:39](=O)[C:40]1[CH:45]=[CH:44][C:43]([C:46]2[NH:50][N:49]=[N:48][N:47]=2)=[CH:42][C:41]=1[F:51]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([NH:8][C:39](=[O:38])[C:40]2[CH:45]=[CH:44][C:43]([C:46]3[NH:50][N:49]=[N:48][N:47]=3)=[CH:42][C:41]=2[F:51])[CH:7]=1
Reactant: COC(=O)c1ccc(-c2nnn[nH]2)cc1F
Reactant: Nc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1)c1ccc(-c2nnn[nH]2)cc1F
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a stirred solution of 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenylamine (60 mg, 0.16 mmol) in dry tetrahydrofuran (15 ml) was added lithium bis(trimethylsilyl)amide at −30° C. and stirring continued for 30 minutes at that temperature. To this was added a solution of 2-fluoro-4-(1H-tetrazol-5-yl)-benzoic acid methyl ester (42 mg, 0.19 mmol) in tetrahydrofuran (5 ml) at −30° C. The temperature was then allowed to slowly rise to 25° C., and the reaction mixture was allowed to stir for 13 h. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride, extracted with ethyl acetate (3×5 ml). Combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel (ethyl acetate to 4% methanol/ethyl acetate) gave the desired final compound as light yellow powder (30%). MS (Turbo Spray): m/z=566.4 (M+H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@H:2]1[CH2:11][C:12]([OH:14])=O.Cl.[NH:16]1[CH2:27][S:26][CH2:25][C@@H:17]1[C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19].C1C2C(=CC=CC=2)CC1CCC(O)=O.Cl.N1CSC[C@H]1C(N1CCCC1)=O>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@H:2]1[CH2:11][C:12]([CH:25]1[S:26][CH2:27][NH:16][C@H:17]1[C:18]([N:20]1[CH2:21][CH2:22][CH2:23][CH2:24]1)=[O:19])=[O:14]
Reactant: O=C(O)C[C@@H]1CCc2ccccc2C1
Reactant: O=C([C@H]1CSCN1)N1CCCC1
Agent: Cl
Agent: O=C(O)CCC1Cc2ccccc2C1
Agent: O=C([C@@H]1CSCN1)N1CCCC1
Product: O=C(C[C@@H]1CCc2ccccc2C1)C1SCN[C@H]1C(=O)N1CCCC1
Yield: 59 %

Procedure:
Colorless crystals of 1-{3-[(R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-D-thioprolyl}pyrrolidine were prepared in the same manner as in Example 25, except that (R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and 1-D-thioprolylpyrrolidine hydrochloride were used instead of 3-(indan-2-yl)propionic acid and 1-L-thioprolylpyrrolidine hydrochloride, respectively (yield: 59%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[S:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[S:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccsc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2ccsc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 66.3 %

Procedure:
Using the procedure of Example 31, 250 mg of the product of Example 30 (isomer B) in 4 ml of methanol and then the addition of 0.3 ml of sodium hydroxide (10N) were reacted to obtain 160 mg of the expected product melting at 203° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[C:5]([C:14](O)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[C:5]([C:14]([N:39]=[N+:40]=[N-:41])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: N#Cc1c(N2CCOCC2)sc(C(=O)N=[N+]=[N-])c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of 4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (0.38 g, 0.99 mmol) and TEA (0.414 mL, 2.97 mmol) in anhydrous THF (15 mL) was added diphenylphosphoryl azide (0.341 mL, 1.58 mmol) in one portion, under nitrogen. The reaction mixture was allowed to stir at rt overnight, and was concentrated. The residue was purified by column chromatography to give 4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carbonyl azide (0.318 g, 79%).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH:9]=[C:10]([F:15])[CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>O1CCCC1.O.C(Cl)Cl.[NH4+].[OH-]>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:8]1[CH:9]=[C:10]([F:15])[CH:11]=[C:12]2[C:7]=1[O:6][C@@H:5]([CH2:4][NH2:1])[CH:14]=[CH:13]2
Reactant: COc1ccccc1-c1cc(F)cc2c1O[C@@H](CN=[N+]=[N-])CC2
Agent: [NH4+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1ccccc1-c1cc(F)cc2c1O[C@@H](CN)C=C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-2-azidomethyl-8-(2-methoxyphenyl)-6-fluoro-chroman (190 mg, 0.32 mmol) in tetrahydrofuran (10 mL) and water (0.5 mL) was added triphenylphosphine (0.26 g, 10 mmol) and the reaction mixture stirred at room temperature for 24 hours. The solvent was removed under vacuum to form a colorless oil. Chromatography with 0–5% methanol in methylene chloride plus 1% NH4OH afforded {[(R)-8-(2-methoxyphenyl)-6-fluoro-2H-chromen-2-yl]methyl}amine as a colorless oil. The colorless oil was dissolved in ethyl acetate and made into its hydrochloride salt (119 mg, 61%) as an off-white crystalline solid, mp 198–200° C.; [α]D25=+173.89° (c=5.2 mg/0.7mL MeOH).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][CH2:19][CH:20]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH:20]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH2:19][CH2:18][CH2:17][N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:15])[O:7]3)[CH2:3][CH2:2]2)=[CH:26][CH:25]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: O=C1OC2(CCN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c2ccccc21

Procedure:
A mixture of 4.0 g. of 1,3-dihydrospiro[isobenzofuran-1,4'-piperidine]-3-one, 6.4 g. of 4-chloro1,1-di(4-fluorophenyl)butane, 10 g. of potassium carbonate, and 25 ml. of 1-butanol is heated under reflux for 48 hours and filtered. The filtrate is diluted with water and extracted with benzene. The benzene solution is dried over potassium carbonate and concentrated to an oil, 1,3-dihydro-1'-[4,4-di(4-fluorophenyl)butyl]spiro[isobenzofuran-1,4'-piperidine]-3-one. The oil is converted to a crystalline hydrochloride salt, m.p. 182°-183° (from benzene).
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3]1.[NH2:27][CH2:28][C@H:29]([OH:44])[CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1>>[OH:43][C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:30][C@@H:29]([OH:44])[CH2:28][NH:27][CH:17]2[CH2:16][CH2:15][N:14]([C:11]3[CH:12]=[CH:13][C:8]([CH:7]=[C:6]4[S:5][C:4]([N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)=[N:3][C:2]4=[O:1])=[CH:9][CH:10]=3)[CH2:19][CH2:18]2)=[CH:37][C:36]=1[NH:38][S:39]([CH3:42])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCCCC4)=NC3=O)cc2)CC1
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CNC2CCN(c3ccc(C=C4SC(N5CCCCC5)=NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 25) and N-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Intermediate 14) according to the procedure of Example 1 as a yellowish solid; mp >95° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.55-1.70 (m, 6 H), 1.85-2.00 (m, 2 H), 2.55-2.90 (m, 6 H), 2.92 (s, 3 H), 3.60 (br s, 2 H), 3.70-3.95 (m, 6 H), 6.61 (dd, J=8.8, 2.9 Hz, 1 H), 6.75-6.80 (m, 2 H), 7.02 (d, J=9.0 Hz, 2 H), 7.45 (d, J=9.0 Hz, 2 H), 7.50 (s, 1 H); MS (ES) m/z: 315.6 ((M+2H)2+, 100%); 630.1 (MH+, 100%); HRMS Calcd. for C30H40N5O6S2 (MH+): 630.2420. Found: 630.2397.
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[F:24][C:25]1[CH:26]=[C:27]([CH:32]([OH:36])[C:33](O)=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1>>[CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH:22][C:33](=[O:34])[CH:32]([C:27]2[CH:28]=[C:29]([F:31])[CH:30]=[C:25]([F:24])[CH:26]=2)[OH:36])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Product: CCCC(NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (3,5-Difluoro-phenyl)-hydroxy-acetic acid to afford the title compound: H1 NMR (400 MHz, CDCl3) 0.8 (m, 3H), 1.40 (m, 2H), 1.48 (s, 2H), 1.70, (m, 2H), 2.20 (m, 4H), 2.42, (m, 2H), 3.58 (m, 4H), 4.80 (m, 0.5H), 4.90 (m, 0.5H), 5.12 (m, 0.5H), 5.20 (m, 0.5H), 6.72 (m, 1H) 7.08 (m, 2H), 7.39 (s, 0.5H) 7.40 (s, 0.5H), 7.46 (s, 0.5H), 7.47 (s, 0.5H); MS m/z 494.4 (M+1).
Reaction SMILES: C1COC([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:19]=[N:20][N:21]3[C:26]([OH:27])=[N:25][CH:24]=[N:23][C:22]=23)(C2C=CC=CC=2)O1.Cl.[OH2:29].CO>CC(C)=O>[C:18]([C:16]1[CH:17]=[CH:12][C:13]([C:18]2[CH:19]=[N:20][N:21]3[C:26]([OH:27])=[N:25][CH:24]=[N:23][C:22]=23)=[CH:14][CH:15]=1)(=[O:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:12]=1
Reactant: O
Reactant: Oc1ncnc2c(-c3ccccc3C3(c4ccccc4)OCCO3)cnn12
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Product: O=C(c1ccccc1)c1ccc(-c2cnn3c(O)ncnc23)cc1
Reaction time: 2 h

Procedure:
A mixture of 8-(4-α,α-ethylenedioxybenzylphenyl)-4-hydroxypyrazolo[1,5-a]-1,3,5-triazine (0.20 g), conc. hydrochloric acid (0.5 ml), water (1 ml), methanol (4 ml) and acetone (1 ml) is stirred at 45°-60° C. for 2 hours. After cooling, the resulting precipitate is separated by filtration, washed with water and dried to give the title compound (0.15 g).