Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.[NH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][O:13][C:14]2=[O:19].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1/[CH:7]=[N:9]/[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][O:13][C:14]2=[O:19]
Reactant: Cn1ccnc1C=O
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: Cn1ccnc1/C=N/c1cccc2c1COC2=O
Yield: 99.9 %

Procedure:
A solution of 1-methyl-1H-imidazole-2-carbaldehyde (680 mg, 6.18 mmol), 4-aminoisobenzofuran-1(3H)-one (920.8 mg, 6.18 mmol) and anhydrous magnesium sulfate (7.41 g, 61.8 mmol) in acetonitrile (100 ml) was heated to reflux for two days. The mixture was filtered and the solvents were removed in vacuum. The crude product was re-crystallized from isopropanol to get the title compound (1.49 g, yield 68%). LC-MS (ESI) m/z: 242 (M+1)+. 1H-NMR (400 MHz, DMSO-d); 4.06 (s, 3H), 5.52 (s, 2H), 7.22 (s, 1H), 7.52 (s, 1H), 7.65-7.67 (m, 1H), 7.72-7.74 (m, 2H), 8.66 (s, 1H).
Reaction SMILES: C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[C:41]1([N:47]=[C:48]=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[C:50]([O:54][CH2:55][CH2:56][OH:57])(=[O:53])[CH:51]=[CH2:52].[N-]=C=O>>[C:50]([O:54][CH2:55][CH2:56][O:57][C:48](=[O:49])[NH:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:53])[CH:51]=[CH2:52]
Reactant: C=CC(=O)OCCO
Reactant: O=C=Nc1ccccc1
Agent: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [N-]=C=O
Product: C=CC(=O)OCCOC(=O)Nc1ccccc1
Temperature: 60 °C

Procedure:
A 500 ml round-bottom flask was initially charged with 0.25 g of 2,6-di-tert-butyl-4-methylphenol, 0.12 g of Desmorapid Z, 126.4 g of phenyl isocyanate, and the mixture was heated to 60° C. Subsequently, 123.3 g of 2-hydroxyethyl acrylate were added dropwise and the mixture was kept at 60° C. until the isocyanate content had fallen below 0.1%. This was followed by cooling. The product was obtained as a crystalline solid (preparation described in DE 2329142).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:14](=[O:15])[CH2:13][N:12]([CH3:16])[C:11]2=[O:17])=[C:4]([F:18])[CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH:14]([OH:15])[CH2:13][N:12]([CH3:16])[C:11]2=[O:17])=[C:4]([F:18])[CH:3]=1
Reactant: COc1cc(N2C(=O)CN(C)C2=O)c(F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N2C(=O)N(C)CC2O)c(F)cc1Cl
Temperature: 30 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
27.3 g (0.10 mol) of 3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-imidazolidine-2,4-dione are dissolved in 200 ml of methanol, and 5.7 g (0.15 mol) of sodium borohydride are added in portions at a rate such that the temperature increases to 30°-35° C. When the addition is complete, the mixture is stirred for a further 1 hour at 30° C. The mixture is poured into 500 ml of ice-water, and the precipitate which deposits is filtered off under suction. After drying, 25.2 g (92% of theory) of 3-(4-chloro-2-fluoro-5-methoxyphenyl)-4-hydroxy-1-methylimidazolidin-2-one are obtained in the form of colorless crystals having the melting point 138°-140° C.
Reaction SMILES: C(C(CCCC)C(O)CC(O)=O)C=C.[OH:15][CH:16]([CH2:26][CH2:27][CH:28]=[CH2:29])[CH:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([O:20]C)=[O:19]>>[OH:15][CH:16]([CH2:26][CH2:27][CH:28]=[CH2:29])[CH:17]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:18]([OH:20])=[O:19]
Reactant: C=CCCC(O)C(CC(C)C)C(=O)OC
Agent: C=CCC(CCCC)C(O)CC(=O)O
Product: C=CCCC(O)C(CC(C)C)C(=O)O

Procedure:
The compound of interest (4.3 g) was obtained as an oil substance in the same way as in paragraph (10-b) using methyl 3-hydroxy-2-isobutyl-6-heptenoate (4.5 g, 21 mmol). This compound was used in the next reaction without being purified.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1.[Cl-].[Na+]>C1COCC1>[Cl:18][C:19]1[N:20]=[N:21][C:22]([O:16][CH2:15][C:14]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=3)=[N:11][O:12][C:13]=2[CH3:17])=[CH:23][CH:24]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1CO
Reactant: Clc1ccc(Cl)nn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 632 mg, 14 mmol) in THF (21 mL) was added a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (3.0 g, 14 mmol) in THF (42 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of 3,6-dichloropyridazine (2.2 g, 14 mmol) in THF (42 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (4.3 g, 92%) which was obtained as an off white solid. MS: m/e=320.0 [M+H]+.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:15][CH2:14][C:13]2=[O:29])[CH2:8][CH2:7]1)=O)C.CSC.CS(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:23]1([C:16]2[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:12]([CH:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)[C:13](=[O:29])[CH2:14][N:15]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)N1CCC(N2C(=O)CN=C(c3ccccc3)c3ccccc32)CC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CSC
Product: O=C1CN=C(c2ccccc2)c2ccccc2N1C1CCNCC1
Temperature: 70 °C
Yield: 87.9 %

Procedure:
A mixture of 100 mg (0.26 mmol) of the above product 12, 0.5 ml of methyl sulfide and 0.5 ml of methanesulfonic acid is heated at 70° C. for 5 hours. The reaction mixture is mixed with ice, basified with potassium carbonate and extracted with methylene chloride. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated to give 73 mg of 1,3-dihydro-5-phenyl-1-(4-piperidinyl)-2H-1,4-benzodiazepin-2-one 13 as powders. The yield is 90%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]=[C:16](Br)Br)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN1C(=O)N(C)CCC1.Br[CH2:35][CH2:36][O:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1.[NH4+].[Cl-]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[N:7]([CH3:8])[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:35][CH2:36][O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Reactant: BrCCOC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCCOC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 10.0 g (25.2 mmol) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 400 ml THF was treated at −78° C. with 33.0 ml (68.3 mmol) of BuLi (ca 1.6 M in hexane) and stirred for 2 h, then 27.8 ml (230.4 mmol) of DMPU were added and 10 min later 19.0 ml (125.9 mmol) of 2-(2-bromoethoxy)tetrahydro-2H-pyran dissolved in 20 ml were dropped in during 20 min. The reaction was warmed up to RT and stirred over night (approx. 16 h). An aqueous solution of saturated NH4Cl was added and the mixture was extracted with Et2O (3×). The organic phase was washed with H2O (2×), aqueous 10% NaCl and dried with Na2SO4, filtered and evaporated to give after flash column chromatography on silica gel (hexane/EtOAc 19:1 to 3:1) 3.5 g (38%) of trans-Methyl-{4-[4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-cyclohexyl}-carbamic acid tert-butyl ester, MS: 366 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:14]([OH:20])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH:11]=[N:12][CH:13]=2)=[CH:6][N:5]=[C:4]2[N:21](COCC[Si](C)(C)C)[CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[C:3]=12.[CH3:40][NH:41][CH3:42].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.CNC.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C=O)C>[CH3:40][N:41]([CH3:42])[C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:14]([OH:20])[C:15]([N:17]([CH3:18])[CH3:19])=[O:16])[CH:11]=[N:12][CH:13]=2)=[CH:6][N:5]=[C:4]2[NH:21][CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[C:3]=12
Reactant: CNC
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(-c3cncc(C(O)C(=O)N(C)C)c3)c(Cl)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cncc(C(O)C(=O)N(C)C)c3)c(N(C)C)c12
Temperature: 150 °C
Reaction time: 1 h
Yield: 1.1 %

Procedure:
2-{5-[4-Chloro-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-2-hydroxy-N,N-dimethyl-acetamide (18 mg, 0.317 mmol) was dissolved in a solution of dimethyl amine (2 mL, 17.7 mmol) and 1,4 dioxane (1 mL). The mixture was heated for at 150° C. for 15 hours in a sealed vessel and concentrated under in vacuo. To the residue were added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (14.5 mg, 0.0381 mmol), dimethylamine hydrochloride salt (12 mg, 0.147 mmol), N,N-dimethylformaldehyde and N,N-Diisopropylethylamine (33 μL, 0.317 mmol). After stirring at 23° C. for 1 hour, the mixture was concentrated. The crude product was dissolved in 1 mL TFA and stirred at 23° C. for 1 hour. The solvent was evaporated and the resulting oil was dissolved in 1 mL DMSO and 50 μL ethylenediamine and purified by mass triggered reverse phase HPLC to afford 2-{5-[4-Dimethylamino-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-2-hydroxy-N,N-dimethyl-acetamide (1.60 mg, 0.00359 mmol, 1.1% yield). 1H-NMR [500 MHz, d6-DMSO] δ: 8.56 (d, 2H), 7.99 (s, 1H), 7.63 (s, 1H), 7.32 (m, 1H), 7.24 (dd, 1H), 7.04 (d, 1H), 6.97 (t, 1H), 5.57 (s, 1H) 3.68 (s, 4H), 2.95 (s, 4H), 2.82 (s, 3H), 2.18 (s, 6H); MS [MH+] m/z: 446.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:28]=[C:11]3[N:12]=[C:13]([CH3:27])[C:14]([C@H:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[C:15](I)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:40]=2)[O:35][CH2:34][CH2:33]1)[CH:30]=[CH2:31].C([O-])([O-])=O.[Na+].[Na+].N#N>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:29]([CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:15]3[N:10]4[N:9]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=5)[CH:28]=[C:11]4[N:12]=[C:13]([CH3:27])[C:14]=3[C@H:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])[CH:40]=2)[O:35][CH2:34][CH2:33]1)[CH:30]=[CH2:31]
Reactant: C=CCC1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C=CCC1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)cc21
Temperature: 90 °C
Yield: 190.6 %

Procedure:
A solution of (S)-methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.375 g, 0.374 mmol), 2-(4-allylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.123 g, 0.411 mmol) and 2.0 M Na2CO3 (0.374 ml, 0.747 mmol) in DMF (3.74 ml) was sparged with N2 for 10 min, treated with Pd(Ph3P)4 (0.030 g, 0.026 mmol), sparged for 5 minutes, then heated (90° C.) for 16 h. The reaction was cooled, diluted with water (20 mL) and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and concentrated and the residue was purified by biotage (40 g SiO2, 0% (3 CV), 0-40% (15 CV), 60% (2 CV), EtOAc in hexanes). Fractions containing desired product combined, concentrated and re-purified (40 g SiO2, 0% (3 CV), 0-60% (15 CV), 60% (2 CV), EtOAc in hexanes) to afford the desired product (0.431 g, 0.713 mmol, 44.6% yield). LCMS (M+H)=606.4.
Reaction SMILES: P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.O=[C:19]1[CH:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[N:22]2[C:37](=[O:39])[CH2:38][C@H:21]2[CH2:20]1.C(N(C(C)C)CC)(C)C.[N-:49]=[N+:50]=[N-:51].[K+].O1CCOCCOCCOCCOCCOCC1>CN(C)C1C=CN=CC=1.C(#N)C>[N:49]([C:19]1[CH2:20][C@@H:21]2[CH2:38][C:37](=[O:39])[N:22]2[C:23]=1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:25])=[N+:50]=[N-:51]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1C[C@@H]2CC(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CN(C)c1ccncc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Reaction time: 0.08 h
Yield: 19.2 %

Procedure:
Diphenyl chlorophosphate (10.9 microliter, 52.6 micromol) was added to a stirred, 0° C. solution of a p-nitrobenzyl 2-oxo-carbapenam-3-carboxylate (15.4 mg, 50.6 micromol), 4-dimethylaminopyridine (1.3 mg, 11 micromol), and diisopropylethylamine (10.4 microliter, 59.7 micromol) in anhydrous acetonitrile (500 microliter). After 5 min., potassium azide (12.6 mg, 155 micromol), and 1,4,7,10,13,16-hexaoxacyclooctadecane (13.3 mg, 50.3 micromol) were added. After an additional 5 min. the mixture was washed three times with water, dried over anhydrous magnesium sulfate, filtered, and evaporated under vacuum. The residue was applied to one 20 cm×20 cm 250 micron silica gel preparative thin layer chromatography plate and developed with diethyl ether. Elution with ethyl acetate and evaporation of the eluate under vacuum provided 3.2 mg (19%) p-nitrobenzyl 2-azido-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:7][CH:8]=1)=O.[CH:18]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]2[CH2:25][CH2:26][NH2:27].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:18]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]2[CH2:25][CH2:26][NH:27][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:7][CH:8]=1
Reactant: NCCC1CC2CCC1C2
Reactant: NC(=O)c1cccc(-c2ccc(C=O)cn2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC(=O)c1cccc(-c2ccc(CNCCC3CC4CCC3C4)cn2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 3-(5-formylpyridin-2-yl)benzamide (Preparation 12, 108 mg, 0.48 mmol) in DCM (75 mL) was added 2-bicyclo[2.2.1]hept-2-ylethylamine (333 mg, 2.39 mmol), AcOH (80 μL, 1.4 mmol) and sodium triacetoxyborohydride (302 mg, 1.42 mmol). The mixture was stirred at rt for 16 h. EtOAc (100 mL) was added and the organic phase washed with aqueous NaHCO3 (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (10% MeOH: DCM to 20% MeOH: DCM) to give the title compound: RT=2.62 min; m/z (ES+)=350.0 [M+H]+.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][OH:8])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+].CCOCC>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:8][CH2:7][CH2:6][C:5]1[S:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[CH:4]=1
Reactant: OCCc1cc2ccccc2s1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: BrCCCCCCOCCc1cc2ccccc2s1

Procedure:
2-Benzo[b]thiopheneethanol (2.20 g), 1,6-dibromohexane (2.59 ml), TAB (0.25 g), aqueous 12.5M sodium hydroxide (9 ml), and ether (20 ml) were stirred overnight at room temperature. The mixture was diluted with water (50 ml), extracted with ether (3×50 ml), and the combined, dried extracts were evaporated. The residual oil was purified by FCC eluting with cyclohexane-diethyl ether (100:0→98:2) to give the title compound as a colourless oil (2.73 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[Cl-].[NH4+].C(O)C.O>O1CCCC1.[Fe]>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CSc2ccc([N+](=O)[O-])cc2)cs1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CSc2ccc(N)cc2)cs1
Yield: 93.6 %

Procedure:
To a mixture of 2-acetylamino-4-(4-nitrophenylthiomethyl)thiazole (11 g) and ammonium chloride (2 g) in a mixture of tetrahydrofuran (200 ml), ethanol (200 ml) and water (100 ml) was added portionwise the iron powder (17 g) at 80° C. with stirring. The mixture was refluxed for 3 hours with stirring. The reaction mixture was filtered by suction and the filtrate was concentrated under reduced pressure and then the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-4-(4-aminophenylthiomethyl)thiazole (9.3 g, yield: 93.6%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C@@H:9]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]3[C:30]4[CH2:38][CH2:37][NH:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)(=[O:27])=[O:26])=[CH:21][C:20]=2[S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40])[CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2]1.[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[CH2:59][N:60]2[CH2:65][CH2:64][C:63](=O)[CH:62]([F:67])[CH2:61]2)=[CH:49][CH:48]=1>>[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[CH2:59][N:60]2[CH2:65][CH2:64][CH:63]([N:36]3[CH2:37][CH2:38][C:30]4[C:29]([NH:28][S:25]([C:22]5[CH:23]=[CH:24][C:19]([NH:18][C@H:9]([CH2:8][CH2:7][N:4]6[CH2:5][CH2:6][O:1][CH2:2][CH2:3]6)[CH2:10][S:11][C:12]6[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=6)=[C:20]([S:39]([C:42]([F:43])([F:44])[F:45])(=[O:41])=[O:40])[CH:21]=5)(=[O:27])=[O:26])=[N:34][CH:33]=[N:32][C:31]=4[CH2:35]3)[CH:62]([F:67])[CH2:61]2)=[CH:49][CH:48]=1
Reactant: O=C1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1F
Reactant: O=S(=O)(Nc1ncnc2c1CCNC2)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Product: O=S(=O)(Nc1ncnc2c1CCN(C1CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC1F)C2)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Yield: 12.1 %

Procedure:
Following General Reductive Amination Procedure 2, (R)-4-(4-Morpholino-1-(phenylthio)butan-2-ylamino)-N-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(trifluoromethylsulfonyl)benzenesulfonamide (34 mg, 0.05 mmol) and 1-((4′-chlorobiphenyl-2-yl)methyl)-3-fluoropiperidin-4-one (19 mg, 0.059 mmol) afforded the title compound (6 mg, 12% yield).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:9][CH2:10][CH2:11][C:12](O)=[O:13].FC(F)(F)S(O)(=O)=O.C(Cl)(Cl)Cl>O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:12](=[O:13])[CH2:11][CH2:10][Cl:9]
Reactant: Oc1cccc(O)c1
Reactant: O=C(O)CCCl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(CCCl)c1ccc(O)cc1O
Temperature: 80 °C
Yield: 66.9 %

Procedure:
To a stirred mixture of resorcinol (200 9, 1.82 mol) and 3-chloropropionic acid (200 g, 1.84 mol) was added trifluoromethane sulfonic acid (1 kg) in one portion. The solution was heated slowly over about 45 minutes at about 80° C. then cooled to room temperature over about 15 minutes and poured into chloroform (4.0 L). The organic portion was slowly poured into water (4.0 L) and the layers separated. The aqueous layer was extracted with chloroform (2×2.0 L). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo gave an orange semi-solid (244.1 g) which was used crude in the next step. 1H-NMR (300 MHz, CDCl3): 12.56 (1H, s), 7.63 (1H, d, J=7.6 Hz), 6.37-6.46 (2H, m), 3.92 (2H, t, J=6.3 Hz), 3.41 (2H, t, J=6.3 Hz).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)=[O:7].[C:15](Cl)(=[O:25])[C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[CH2:4]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15](=[O:25])[C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:14][C:11]3[CH:10]=[CH:9][C:8]([C:6]([O:5][CH2:4][CH2:3][CH2:2][CH3:1])=[O:7])=[CH:13][CH:12]=3)=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)=[O:7])[CH2:3][CH2:2][CH3:1]
Reactant: CCCCOC(=O)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Product: CCCCOC(=O)c1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(C(=O)OCCCC)cc3)cc2)cc1

Procedure:
Butyl p-hydroxybenzoate and terephthalic dichloride are allowed to react in a similar procedure to Example 5. The product is recrystallized from hexane-chloroform (1:1) to give di(p-butoxycarbonylphenyl)terephthalate, m.p. 128°-131° C., as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10](Cl)=[O:11])=[C:4]([CH3:13])[CH:3]=1.C(=O)([O-])O.[Na+].[CH3:19][O:20][C:21]([C:23]1([NH:31][OH:32])[CH2:28][CH2:27][N:26]([O:29][CH3:30])[CH2:25][CH2:24]1)=[O:22]>C1COCC1>[CH3:19][O:20][C:21]([C:23]1([N:31]([C:10](=[O:11])[CH2:9][C:5]2[C:6]([CH3:8])=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:13])[OH:32])[CH2:28][CH2:27][N:26]([O:29][CH3:30])[CH2:25][CH2:24]1)=[O:22]
Reactant: COC(=O)C1(NO)CCN(OC)CC1
Reactant: Cc1cc(Cl)cc(C)c1CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(N(O)C(=O)Cc2c(C)cc(Cl)cc2C)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4-chloro-2,6-dimethyl-phenyl)-acetyl chloride (2.90 g, 13.4 mmol) in THF (25 ml) was added sodium hydrogen carbonate (1.90 g, 22.7 mmol) at 0° C., followed by 4-hydroxyamino-1-methoxy-piperidine-4-carboxylic acid methyl ester (preparation example 11, step 3; compound P4ii.2) (2.73 g, 13.4 mmol) dissolved in THF (25 ml) dropwise. The reaction mixture was stirred at 0° C. for 30 minutes, then further 30 minutes at room temperature. After completion of the reaction indicated by TLC and LC/MS, the reaction mixture was filtered and the residue (NaCl) washed with THF. The filtrate was concentrated to dryness and stirred several times with little amounts of an ether/hexane mixture (1:1) to remove side products. Finally, the compound was washed with ether to yield pure 4-{[2-(4-chloro-2,6-dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (compound P3ii.34) as white solid. Yield: 3.7 g, mp 228-231° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[C:25]([C:29]5[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=5[F:37])=[CH:26][CH:27]=[CH:28][N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[F:37][C:30]1[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:29]=1[C:25]1[C:24]2[N:23]([N:22]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][CH:16]=3)[N:38]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)c(F)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)c(F)c1

Procedure:
[8-(2-Fluoro-4-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine was prepared from 4-{4-[8-(2-fluoro-4-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (0.253 g, 0.488 mmol) and trifluoroacetic acid (1 mL) in a manner analogous to Example 312 to give product (0.179 g, 88%). MP=95-98° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.64 (s, 1H), 8.78 (d, 1H), 7.80 (m, 1H), 7.58 (m, 3H), 7.15 (m, 3H), 6.98 (m, 2H), 3.85 (s, 3H), 3.05 (m, 2H), 2.55 (br m, 3H), 2.25 (br m, 1H), 1.65 (m, 2H), 1.45 (m, 2H). MS=418 (MH)+.