Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:9])=[O:5].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[C:29]([N+:35]([O-])=O)[CH:28]=1.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][C:29]=2[NH2:35])[CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCl
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)NCC1CCNCC1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Nc1cc(Cl)ccc1CN1CCC(CNC(=O)CNC(=O)c2cc(C(F)(F)F)ccc2N)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 4-chloro-2-nitrobenzyl chloride (0.050 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.7 mL) was stirred overnight at 50° C. The reaction mixture was cooled, loaded onto Variant™ SCX column and washed with 50% CHCl3/CH3OH (10 mL) and CH3OH (10 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material was added ethanol (3 mL) and 10% Pd—C (15 mg), and the mixture was stirred under H2 at room temperature for 1.5 h. Filtration, concentration, and preparative TLC afforded 4-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]-1-(2-amino-4-chlorobenzyl)piperidine (Compound No. 1919) (5.1 mg, 14%): The purity was determined by RPLC/MS (90%); 1H NMR (400 MHz, CDCl3) δ1.09-1.32 (m, 4H), 1.41-1.59 (m, 1H), 1.66 (d, J=12.5 Hz, 2H), 1.88 (t, J=11.5 Hz, 2H), 2.82 (d, J=11.5 Hz, 2H), 3.17 (t, J=6.5 Hz, 2H), 3.42 (s, 2H), 4.05 (d, J=5.5 Hz, 2H), 4.85 (br s, 1H), 5.92 (br s, 2H), 6.25-6.36 (m, 1H), 6.55-6.66 (m, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 7.26 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.68 (s, 1H); ESI/MS m/e 498.2 (M++H, C23H27ClF3N5O3).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[OH-].[Na+].[CH2:10]1[O:12][CH2:11]1>O>[OH:12][CH2:11][CH2:10][NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4]
Reactant: C1CO1
Reactant: N[C@@H](CS)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@H](CS)NCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
109.5 g (0.9 mol) L-cysteine was placed in a 2000 ml flask, and dissolved with 1000 ml water, to which was added 24 ml of 1 mol/l NaOH solution. In an ice bath, 96 ml (1.8 mol) ethylene oxide was slowly added dropwise into the cysteine solution. After stirring 1 h, the ice bath was removed and the mixture was warmed to room temperature and further reacted for 1 h. The reaction product was extracted with 1000 ml anhydrous ethyl ether for four times, while collecting the aqueous layers. The aqueous layers were evaporated to dryness obtaining a yellow crystal product. The yellow crystal product was recrystallized with water:ethanol=85 ml:350 ml, filtered, washed with 2000 ml of 95% ethanol, and dried obtaining 121.8 g of a white crystal product, yield 74.3%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[N:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:17]=[C:16]4[C:12]([CH:13]=[CH:14][NH:15]4)=[CH:11][CH:10]=3)[CH:5]=[N:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccncc1
Reactant: Clc1cncc(Nc2ccc3cc[nH]c3c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: c1cc(-c2cncc(Nc3ccc4cc[nH]c4c3)n2)ccn1
Yield: 36.4 %

Procedure:
A mixture of (6-chloro-pyrazin-2-yl)-(1H-indol-6-yl)-amine (0.070 g, 0.2868 mmol), pyridine-4-boronic acid (0.042 g, 0.344 mmol), sodium carbonate (0.150 g, 1.43 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0165 g, 0.0143 mmol) in DME:water (3:2, 5 mL) was heated at reflux for 20 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to yield N-(6-pyridin-4-ylpyrazin-2-yl)-1H-indol-6-amine (0.030 g, 36.5%) as a yellow solid. 1H NMR (CD3OD) δ 8.73-8.72 (d, J=5.68 Hz, 2H), 8.51 (s, 1H), 8.23-8.20 (m, 4H), 7.56-7.54 (d, J=8.46 Hz, 1H), 7.22 (d, J=2.99 Hz, 1H), 7.14 (dd, J=10.18, 1.74 Hz, 1H), 6.45 (d, J=2.75 Hz, 1H); MS (API-ES/Positive); m/z: 288 (M+H)+.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[NH4+]>C(OCC)C>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:15]
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(Cl)CCCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(CCCCBr)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a typical run, 2.6 equivalents of phenyl magnesium bromide are added to 1.0 equivalent of 5-bromopentanoyl chloride dissolved in dried diethyl ether under inert atmosphere at 0° C. and stirred during 15 minutes. After this time the mixture is warmed up to room temperature, and then ammonium chloride is added slowly to the mixture, and worked up in the usual manner to produce 5-bromo-1,1-diphenyl-1-pentanol as a white solid. The crude product is then refluxed during 6 hours with p-toluenesulfonic acid (ratio 60:1) under benzene, and worked up in the usual manner to yield 5-bromo-1,1-diphenyl-1-pentene as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27]>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: NCc1ccccn1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCc3ccccn3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and pyridin-2-ylmethyl amine to afford the title compound. MS: m/e=349 (M+H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[CH:23]([Si:25]([O:30][CH3:31])([O:28][CH3:29])[O:26][CH3:27])=[CH2:24]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH3:27][O:26][Si:25]([O:30][CH3:31])([O:28][CH3:29])[CH:23]=[CH:24][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])=[CH:17][CH:18]=1
Reactant: C=C[Si](OC)(OC)OC
Reactant: CC(C)(C)OC(=O)Oc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CO[Si](C=Cc1ccc(OC(=O)OC(C)(C)C)cc1)(OC)OC

Procedure:
Into a mixture of 20 ml of triethylamine and 40 ml of acetonitrile, were dissolved 15.0 g (54.9 mmol) of 1-(t-butoxycarbonyloxy)-4-bromobenzene synthesized in the step (i) and 9.76 g (65.9 mmol) of vinyltrimethoxysilane, and the reaction system was substituted by argon by bubbling argon in thus obtained solution. In the reaction system, was added 246.5 mg (1.1 mmol) of palladium acetate as a catalyst, the mixture was refluxed for one night. After completion of the reaction, solvent was removed, and the obtained residue was extracted by hexane. Hexane was removed from the extraction to prepare 9.5 g of 1-(2-trimethoxysilylvinyl)-4-(t-butoxycarbonyloxy)benzene being the objective compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[O-:5])[CH3:2].[C:13](#[N:16])[CH:14]=[CH2:15].[H-].[Na+].C(O)(=O)C>C(O)C>[C:13]([CH2:14][CH2:15][P:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])(=[O:5])[O:3][CH2:1][CH3:2])#[N:16]
Reactant: CCOC(OCC)P([O-])OCC
Reactant: C=CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(OCC)P(=O)(CCC#N)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The starting material can be prepared as follows: A solution of 20 g of ethyl(diethoxymethyl)phosphonite (Aust. J. Chem. 33, 292 (1980)) and 5 g of acrylonitrile in 25 ml of ethanol is added to a stirred mixture of 1 g of sodium hydride (50% dispersion in oil) in 25 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 26 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl 2-cyanoethyl(diethoxymethyl)phosphinate, b.p. 114° C./0.01 mbar, 31P=+40.8 ppm (CDCl3).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[S:10][C:9]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:8]=2[CH:7]=1)=[O:5].S(=O)(=O)(O)O.P([O-])([O-])(O)=O.[K+].[K+].C(OCC)(=O)C>O>[CH3:14][C:12]1([CH3:15])[CH2:13][C:8]2[C:7]3[CH2:2][CH2:3][C:4](=[O:5])[C:6]=3[S:10][C:9]=2[CH2:11]1
Reactant: CC1(C)Cc2cc(C(=O)CCCl)sc2C1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)Cc2sc3c(c2C1)CCC3=O
Temperature: 90 °C
Yield: 37 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with crude 105e (2.86 g, 10.0 mmol presuming quantitative yield) and 98% sulfuric acid. The reaction mixture was heated in a 90° C. oil bath overnight. The reaction mixture was placed into an ice/acetone bath, and a cold (5° C.) solution of dipotassium hydrogen phosphate (105 g, 0.603 mol) in water (300 mL) was added in one portion. The resulting mixture was shaken with ethyl acetate (300 mL) and filtered. The filter cake was washed with ethyl acetate (100 mL). The ethyl acetate layer of the filtrate was separated, dried over sodium sulfate and evaporated under reduced pressure on a rotary evaporator. the resulting residue was purified by flash column chromatography (silica, 80:20 hexanes/ethyl acetate) to afford 105f in 37% yield over two steps (683 mg) as an amorphous brown solid: mp 60-62° C.; 1H NMR (500 MHz, CDCl3) d 2.92-2.87 (m, 4H), 2.79 (s, 2H), 2.53 (s, 2H), 1.26 (s, 6H); MS (ESI+) m/z 207.0 (M+H)
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[H-].[Na+].CN(C)C=O.Cl[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[N+:24]([O-:26])=[O:25]>C(O)(=O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:1][C:2]2[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=2)=[C:17]([N+:24]([O-:26])=[O:25])[CH:18]=1
Reactant: Cn1ccnc1S
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(Sc2nccn2C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a mixture of 2-mercapto-1-methylimidazole (1.14 g, 10 mmoles), 0.6 of 60% sodium hydride in mineral oil and 20 ml of N,N-dimethylformamide was added 1.88 g (10 mmoles) of 4-chloro-3-nitroanisole. The mixture was stirred at room temperature for 0.5 hours and then heated at 90°-100° C. for 4 hours. After cooling in an icebath, 0.5 ml of acetic acid was added and the mixture was partitioned between dichloromethane and dilute sodium bicarbonate. The organics were concentrated on a steam bath to a small volume and the residue was chromatographed on silica gel using ethyl acetate as the eluent. The fractions containing the product were combined and concentrated to give 1.0 g (38%) of the product, mp 117°-120° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1.OS(O)(=O)=O.[CH3:16][CH2:17]O>>[CH2:16]([O:9][C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[N:4][CH:5]=1)=[O:10])[CH3:17]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cncc(Br)c1

Procedure:
A stirred mixture of 3-bromo-5-pyridine-carboxylic acid (10.1 g, 50 mmol) and H2SO4 (1.5 ml) in EtOH (150 ml) was refluxed for 6 hrs. After cooling, the solvent was removed by evaporation in vacuo. The residue was diluted with H2O (100 ml), basified with 5% NaHCO3 (aq) solution and extracted with ether (4×100 ml). The combined organic extracts were washed with saturated NaCl and dried over Na2SO4. Filtration and concentration in vacuo of the filtrate yielded 3-bromo-5-pyridine-carboxylic acid ethyl ester as an oil that solidified on standing: (9.8 g, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]2[C:17]=1[CH2:18][CH2:19][NH:20][CH:21]2[CH3:28]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:16]=4[O:15][CH3:14])[CH:21]3[CH3:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: COc1ccc2c(c1OC)CCNC2C
Product: COc1ccc2c(c1OC)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5,6-Dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(O)C.[BH4-].[Na+]>C(Cl)(Cl)Cl>[OH:3][CH:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)OCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(O)c1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
60.98 g (0.24 mol) of benzyl 4-acetylbenzoate (II-19), 100 ml of ethanol and 300 ml of chloroform were supplied into a four-necked flask equipped with a stirrer and a thermometer. Then 4.6 g (0.12 mol) of sodium borohydride was added at 15°-25° C., over a period of 10 minutes. The mixture was kept at the same temperature for 2 hours and the resulting reaction mixture was poured into ice-water and extracted twice with 200 ml of ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure to obtain 58.37 g (95% yield) of benzyl 4-(1-hydroxyethyl)phenylcarboxylate (III-19). nD25 =1.5682.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[SH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH2:18][C@@H:19]([CH3:29])[N:20]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:21][CH:22]=2)[N:16]=1.O(P(OC1C=CC=CC=1)O[C:39]1[C@H:45]([CH3:46])[C@H:44]2[N:41]([C:42](=[O:54])[C@@H:43]2[C@H:47]([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH3:48])[C:40]=1[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])C1C=CC=CC=1.C(#N)C>C1COCC1>[CH2:26]([O:25][C:23]([N:20]1[CH2:21][CH:22]=[C:17]([C:15]2[N:16]=[C:12]([S:11][C:39]3[C@H:45]([CH3:46])[C@H:44]4[N:41]([C:42](=[O:54])[C@@H:43]4[C@H:47]([O:49][Si:50]([CH3:51])([CH3:52])[CH3:53])[CH3:48])[C:40]=3[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[S:13][CH:14]=2)[CH2:18][C@H:19]1[CH3:29])=[O:24])[CH:27]=[CH2:28]
Reactant: C=CCOC(=O)N1CC=C(c2csc(S)n2)C[C@H]1C
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C(=O)OCC=C)[C@H](C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
A solution of lithium hexamethyldisilazide in THF (1M, 0.58 ml, 0.58 mmol) was added at 0–5° C. to a solution of allyl (2R)-4-(2-mercapto-1,3-thiazol-4-yl)-2-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (172 mg, 0.58 mmol) in THF (2.0 ml) and the mixture was stirred for 10 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 2.21 g, 1.2 mmol) and the solution was allowed to stand in a refrigerator for 16 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate: 1/4→1/3) to give allyl (4R,5S,6S)-3-[(4-{(2R)-1-[(allyloxy)carbonyl]-2-methyl-1,2,3,6-tetrahydro-4-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (137 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]=[CH:33][N:34]=[C:35]([O:38][CH:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:36]=2[N:37]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[CH:6][C:5]([C:28]2[CH:29]=[CH:30][C:31]3[N:32]=[CH:33][N:34]=[C:35]([O:38][CH:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[C:36]=3[N:37]=2)=[CH:4][N:3]=1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(OC4CCOCC4)c3n2)cnc1Cl)c1ccccc1
Temperature: 25 °C
Yield: 22.9 %

Procedure:
A mixture of N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzene sulfonamide (0.114 g, 0.290 mmol) (Intermediate 5), 6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine (Intermediate 1) (0.070 g, 0.263 mmol), 1 N aq. sodium bicarbonate (0.527 ml, 0.527 mmol) and PdCl2(dppf)-CH2Cl2Adduct (22.0 mg, 2.60 μmol) in dioxane (1.5 ml) was subjected to microwave irradiation for 1 hour at 110° C. The reaction mixture was cooled to room temperature, filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=2:1) to give N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (0.030 g, 23%) as a yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 1.75-1.98 (2H, m), 2.12-2.26 (2H, m), 3.55-3.72 (2H, m), 3.90-4.05 (2H, m), 5.58-5.72 (1H, m), 7.50-7.70 (3H, m), 7.85 (1H, d, J=7.6 Hz), 8.45 (1H, d, J=8.4 Hz), 8.58-8.72 (2H, m), 8.87 (1H, s), 9.04 (1H, br s), 10.55 (1H, s). m/z=498.09 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1B(O)O>>[Br:8][C:6]1[CH:5]=[C:4]([OH:9])[CH:3]=[C:2]([C:17]2[CH:16]=[C:15]([F:18])[CH:14]=[CH:13][C:12]=2[O:11][CH3:10])[CH:7]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Oc1cc(Br)cc(Br)c1
Product: COc1ccc(F)cc1-c1cc(O)cc(Br)c1

Procedure:
Example 54 was synthesized in 4 steps from 3-,5-dibromophenol. 2-Methoxy-5-fluorophenyl boronic acid was reacted as described above, step 1. In this manner was isolated 5-bromo-5′-fluoro-2′-methoxy-biphenyl-3-ol, which was then reacted with 3-fluorophenyl boronic reacted as described above, Step 2. In this manner, 3,5″-difluoro-2″-methoxy-[1,1′;3′,1″]terphenyl-5′-ol was obtained.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[C:8]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].S([O-])([O-])(=O)=O.O[NH3+:26].O[NH3+]>O>[C:8]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:26])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: [NH3+]O
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc(C#N)cc1
Temperature: 100 °C

Procedure:
With stirring (20 rpm), a turbine dryer is charged at room temperature with 1800 parts by weight of anhydrous sodium sulfate, 365 parts by weight of 4-tert-butylbenzaldehyde and 194 parts by weight of hydroxylammonium sulfate. Following evacuation to 25 mbar, the mixture is heated to 100° C. and stirred at this temperature for 2 hours. It is subsequently heated at 125° C. for 40 minutes, during which about 82 parts by weight of water are removed by distillation. The distillation of the nitrile is then initiated and controlled by successive reduction of the pressure to 10 mbar and raising of the jacket temperature to 170° C. 300 parts by weight of 4-tert-butylbenzonitrile are obtained with an outstanding purity of ~98-99% (HPLC), along with 18 parts by weight of a less pure fraction.
Reaction SMILES: N.[Na].[C:3](#[N:5])[CH3:4].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]#[N:12]>O1CCCC1.CCOCC>[NH2:12][C:11]([C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)=[CH:4][C:3]#[N:5]
Reactant: CC#N
Reactant: N#Cc1cccs1
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CC=C(N)c1cccs1
Reaction time: 0.5 h

Procedure:
About 100 ml. of ammonia is condensed in the reaction flask and a small piece of sodium is added, giving a blue color. The color is discharged with ferric chloride and 2.7 g. of sodium is added. When the blue color disappears, 4.91 ml. of acetonitrile in 10 ml. of ether is added. The reaction is cooled in a dry ice-acetone bath and 9.28 g. of 2-thiophenecarbonitrile in 25 ml. of tetrahydrofuran is added dropwise. Cooling is continued for 30 minutes, then the ammonia and solvent are allowed to evaporate. A 50 ml. portion of water is added and the mixture is extracted with methylene chloride. The methylene chloride extracts are dried over sodium sulfate and then passed through Magnesol. Hexanes are added and the filtrate is evaporated on a steam bath to an oil. The oil is dry column chromatographed on silica gel, eluting with methylene chloride. The fraction containing the desired product is taken up in methylene chloride, passed through Magnesol and the filtrate is evaporated on a steam bath with the addition of hexanes until an oil comes out. Cooling and seeding gives the desired product as crystals, mp. 50°-45° C.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6]1)(=[O:3])[CH3:2].[BH4-].[Na+].C[OH:25]>>[C:1]([NH:4][CH:5]1[CH:11]([OH:25])[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1Cc2ccccc2OC(c2ccccc2)C1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CC(=O)NC1CC(c2ccccc2)Oc2ccccc2C1O
Reaction time: 5 h
Yield: 28 %

Procedure:
797 mg (2.70 m moles) of 4-acetamido-2-phenyl-2,3,4,5-tetrahydro-1-benzoxepin (compound R3a of Reference Example) was dissolved in 50% methanol, 411 mg (10.8 m moles) of sodium borohydride was added to the solution at -50° C. to -20° C., and the whole was stirred for 5 hours. The reaction mixture was concentrated, and ice water was added to the concentrate. The mixture was extracted with methylene chloride, and the extract was washed with water and dried with anhydrous magnesium sulfate. After filtrating off the magnesium sulfate, the filtrate was concentrated to obtain a residue, which was then applied to a silica gel column, and eluted with a mixture of methylene chloride/methanol (98:2) to obtain stereoisomers R4a (22.5 mg; yield 28.0%) and R4b (485 mg; yield 60.4%) of the desired compound.