Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:25]([C:26](=[S:28])[NH2:27])[N:24]=[C:23]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])[S:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:44]1[C:49](=O)[CH2:48][CH2:47][N:46]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:45]1.CCN(C(C)C)C(C)C>C(O)C>[Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:25]([C:26]2[S:28][C:44]3[CH2:45][N:46]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:48][C:49]=3[N:27]=2)[N:24]=[C:23]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])[S:22]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3ccccc3)sc2C1
Reaction time: 8 h

Procedure:
To a solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide (0.500 g, 0.809 mmol) in mL of ethanol was added tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (0.338 g, 1.21 mmol) followed by DIEA (0.423 mL, 2.43 mmol). The mixture was allowed to stir overnight at reflux then treated with tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (200 mg) and stirred at reflux for a further 3 hours. The cooled mixture was partitioned between saturated NaHCO3 solution (50 mL) and EtOAc (50 mL) and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic phases were washed with brine (50 mL) dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (5-10% ethyl acetate/hexanes) to afford the desired product as a viscous yellow oil, 0.412 g, 64%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[F:10].[C:11]([S:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([S:15][C:16](=[O:21])[CH:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[F:10])[C:18](=[O:20])[CH3:19])([CH3:14])([CH3:12])[CH3:13]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC(=O)CC(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(F)cc1F)C(=O)SC(C)(C)C

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-2,4-difluorobenzene and 3-oxothiobutyric acid S-tert-butyl ester
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][S:4][C:5]1[CH:10]=[C:9]([C:11]2[C:12]([C:16]([F:19])([F:18])[F:17])=[N:13][NH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[CH:20]([F:22])[F:21].ClC1C=CC=C(C(OO)=[O:33])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:24][C:2]([F:1])([F:23])[CH2:3][S:4]([C:5]1[CH:10]=[C:9]([C:11]2[C:12]([C:16]([F:18])([F:19])[F:17])=[N:13][NH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[CH:20]([F:22])[F:21])=[O:33]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)c1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC(F)(F)F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=S(CC(F)(F)F)c1cc(-c2c[nH]nc2C(F)(F)F)ccc1C(F)F
Yield: 96.9 %

Procedure:
To 0.37 g (1.0 mmol) of [2-difluoromethyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluoroethyl sulfide (Compound No. V-295 of the present invention) in 5 ml of chloroform, 0.25 g (1.5 mmol) of m-chloroperbenzoic acid was added at 0° C. with stirring, and the reaction solution was stirred for 1 hour. The reaction solution was mixed with 10 ml of 10% aqueous sodium sulfite and stirred at room temperature for 10 minutes, and then 20 ml of chloroform was added. The chloroform layer was washed with 20 ml of saturated aqueous sodium hydrogen carbonate three times and dried over anhydrous magnesium sulfate, and the chloroform was distilled off under reduced pressure to obtain 0.38 g of [2-difluoromethyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluoroethyl sulfoxide (yield 97.4%) as a yellow dough (nD20 1.4909).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:25][CH:26]([OH:42])[CH2:27][N:28]3[CH2:33][CH2:32][N:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]#[N:41])[CH2:30][CH2:29]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(Cl)Cl>FC(F)(F)C(O)=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:10]3[CH2:9][NH:8][CH2:13][CH2:12][C:11]=3[N:14]([CH2:25][CH:26]([OH:42])[CH2:27][N:28]3[CH2:33][CH2:32][N:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]#[N:41])[CH2:30][CH2:29]3)[N:15]=2)=[CH:18][C:19]=1[CH3:24]
Reactant: Cc1cc(-c2nn(CC(O)CN3CCN(c4ccccc4C#N)CC3)c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2nn(CC(O)CN3CCN(c4ccccc4C#N)CC3)c3c2CNCC3)ccc1Cl
Reaction time: 2 h
Yield: 100.4 %

Procedure:
3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.26 g, 2.13 mmol) was dissolved in trifluoroacetic acid (3 mL) and CH2Cl2 (3 mL) and allowed to stir for 2 h. The reaction mixture was concentrated, taken up in EtOAc (50 mL) and washed with aqueous NaHCO3 (2×25 mL). The EtOAc layer was dried over Na2SO4 and concentrated to give 2-(4-{3-[3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile (1.05 g, 99%) as a yellow foam. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.27. MS (electrospray): m/z 491.2 (491.2, calculated for C27H31ClN6O, [M+H]+). 1H NMR (400 MHz, CDCl3): 9.8 (br s, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.50 (t, J=8.2 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.11 (t, J=8.2 Hz, 1H), 6.98 (d, J=8.2 Hz, 1H), 4.56 (brs, 1H), 4.12-4.32 (m, 4H), 2.98-3.51 (m, 13 H), 2.35 (s, 3H).
Reaction SMILES: [N:1]([CH:4]1[CH2:22][CH2:21][N:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:6]2[CH2:5]1)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[NH2:1][CH:4]1[CH2:22][CH2:21][N:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:6]2[CH2:5]1
Reactant: [N-]=[N+]=NC1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NC1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
4 g of 2-azido-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine (axial) is added to a suspension of 3 g of LiAlH4 in dry ether. The mixture obtained is heated for 1 hour, and after that cooled down. Then 12 ml of water are added to the mixture dropwise, whereby an inorganic precipitate is formed. The inorganic residue is removed by filtration after which the filtrate is evaporated to dryness.
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:11][C:12]([NH2:14])=[S:13]>C(O)C>[NH2:14][C:12]1[S:13][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH3:10])[N:11]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1C
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of ethyl 2-chloroacetoacetate (50 g, 0.30 mol, Aldrich) and thiourea (45.6 g, 0.60 mol) in 400 mL of absolute ethanol was heated to reflux. After refluxing overnight the reaction mixture was allowed to cool to room temperature and then concentrated to half the original volume in vacuo. The remaining ethanol solution was poured into H2O (1L) and made basic (pH 10) with 2N NaOH. An off-white solid precipitated immediately. The mixture was stirred for ~10 minutes and then the solid was removed by vacuum filtration and dried to give 54.75 g (98% yield) of the desired product as a white solid: 1H NMR (CDCl3) 67 5.5 (bs, 2H), 4.25 (q, 2H), 2.5 (s, 3H), 1.35 (t, 3H).
Reaction SMILES: [I-].Cl[C:3]1C=CC=C[N+:4]=1C.C(N(CC)CC)C.Cl.CN.[C:20]([NH:23][CH2:24][CH2:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH:28]=[C:27]1[C:37]([OH:39])=O)(=[O:22])[CH3:21]>ClCCl>[C:20]([NH:23][CH2:24][CH2:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH:28]=[C:27]1[C:37]([NH:4][CH3:3])=[O:39])(=[O:22])[CH3:21]
Reactant: C[n+]1ccccc1Cl
Reactant: COc1ccc2cc(C(=O)O)n(CCNC(C)=O)c2c1
Agent: CN
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc2ccc(OC)cc2n1CCNC(C)=O

Procedure:
Under nitrogen, add 0.12 g of 2-chloro-1-methylpyridinium iodide, 0.32 ml of triethylamine and 0.04 ml of methylamine hydrochloride in dichloromethane to a solution of 0.13 g of the compound obtained in Step C in 20 ml of dichloromethane and then heat at reflux for 14 hours. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous sodium chloride solution. Extract and dry the organic phase over sodium sulfate and then filter and evaporate. Purify the compound by column chromatography on silica gel using as eluant a 19/1 dichloromethane/ethanol mixture. After triturating in diisopropyl ether, the title compound is obtained in the form of a white solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:16][C:17]1[CH:18]=[C:19]([C:25]2([C:30]([F:33])([F:32])[F:31])[CH2:29][CH2:28][NH:27][CH2:26]2)[CH:20]=[C:21]([Cl:24])[C:22]=1[Cl:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([C:25]2([C:30]([F:33])([F:32])[F:31])[CH2:29][CH2:28][N:27]([C:2]3[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=3)[CH2:26]2)[CH:20]=[C:21]([Cl:24])[C:22]=1[Cl:23]
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 100 °C
Yield: 86.5 %

Procedure:
Ethyl 2-chloro-4-(trifluoromethyl)-1,3-thiazole-5-carboxylate (1.4 g) [see J. Het. Chem., 22, 1621 (1985)], 3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidine (1.7 g), and potassium carbonate (0.8 g) were added to N,N-dimethylformamide (50 mL), followed by heating at 100° C. for five hours. After cooling, the reaction solution was poured over ice water, and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (2.5 g, 86%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1)=O.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.[BH4-].[Na+]>CO>[C:24]1([CH2:23][N:20]2[CH2:21][CH2:22][CH:17]([NH:16][CH2:1][C:3]3[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=3)[CH2:18][CH2:19]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)C(=O)Nc1ncccc1C=O
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(=O)Nc1ncccc1CNC1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 8.2 g (0.0398 mol) of N-(3-formyl-2-pyridinyl)-2,2-dimethylpropanamide and 7.6 g (0.04 mol) of 4-amino-1-(phenylmethyl)piperidine in 80 ml of methanol was combined in batches with a total of 1.7 g (0.045 mol) of sodium borohydride and refluxed for a total of 24 hours. The solvent was removed in vacuo, the residue was distributed between water and ethyl acetate. The organic phase was dried over sodium sulphate and freed from solvent. The residue was triturated with diisopropylether and suction filtered. 6.0 g (39.6% of theory) of colourless crystals of melting point 138° C. were obtained.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH2:13][C:7]1([CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[C:6]2=[N:17]S(C(C)(C)C)=O.CCOCC>O1CCOCC1>[Br:2][C:3]1[CH:4]=[C:5]2[C:14]([CH2:13][C:7]3([C:6]2=[NH:17])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:15][CH:16]=1
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCOCC2
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N=C1c2cc(Br)ccc2CC12CCOCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HCl (4M in 1,4-dioxane) (0.683 mL, 2.73 mmol) was added to a solution of N-(5-bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-3(1H)-ylidene)-2-methylpropane-2-sulfinamide (Example 25 Step 1, 105 mg, 0.27 mmol) in anhydrous 1,4-dioxane (1 mL) and the resulting mixture was stirred under a nitrogen atmosphere at r.t. overnight. Et2O (3 mL) was added, the precipitate was filtered off, washed with Et2O and then dissolved in DCM (5 mL) and sat. aq. NaHCO3 (5 mL). The mixture was poured into a phase separator, the organic layer was collected and concentrated to give the title compound that was used in the next step without any further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][N:14]([CH2:16][CH2:17]Cl)[CH3:15].Cl>CS(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:17][CH2:16][N:14]([CH3:15])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CN(CCCl)CCCl
Reactant: N#CCc1ccc(I)cc1
Agent: Cl
Solvent: CS(C)=O
Product: CN1CCC(C#N)(c2ccc(I)cc2)CC1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To a solution of 4-iodophenylacetonitrile (10 g, 41.1 mmol) in anhydrous DMSO (20 mL) was added NaNH2 (4.8 g, 123.3 mmol, 3 eq.) in one portion. The temperature of the reaction was maintained at 20° C. using a water bath. The mixture was stirred at 20° C. for 20 min to give a deep red solution then a solution of bis-(2-chloro-ethyl)-methyl-amine.HCl salt (7.92 g, 41.1 mmol, 1 eq.) in anhydrous DMSO (20 mL) was added in a drop-wise fashion. The resulting mixture was stirred at room temperature for 16 h then partitioned between EtOAc (250 mL) and H2O (250 mL). The organic layer was separated and washed with H2O (3×100 mL) and saturated brine (100 mL) then dried over Na2SO4, filtered and concentrated by rotary evaporation. The crude product was purified by flash column chromatography by eluting with 10% MeOH/EtOAc to yield 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carbonitrile as a brownish solid (7.6 g, 23.43 mmol, 57%). 1H NMR (300 MHz, CD3OD): δ 7.89 (d, 2H), 7.43 (d, 2H), 3.13 (d, 2H), 2.58 (td, 2H), 2.50 (s, 3H), 2.24 (m, 4H).
Reaction SMILES: C(OCC)(=O)C.C([O:14][C:15]1[CH:16]=[C:17]([CH:37]=[CH:38][C:39]=1[O:40]CC1C=CC=CC=1)[C:18]1[O:19][C:20]2[C:25]([C:26](=[O:28])[CH:27]=1)=[C:24]([O:29][CH3:30])[C:23]([O:31][CH3:32])=[C:22]([O:33][CH3:34])[C:21]=2[O:35][CH3:36])C1C=CC=CC=1>[Pd].CO>[OH:14][C:15]1[CH:16]=[C:17]([CH:37]=[CH:38][C:39]=1[OH:40])[C:18]1[O:19][C:20]2[C:25]([C:26](=[O:28])[CH:27]=1)=[C:24]([O:29][CH3:30])[C:23]([O:31][CH3:32])=[C:22]([O:33][CH3:34])[C:21]=2[O:35][CH3:36]
Reactant: COc1c(OC)c(OC)c2c(=O)cc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)oc2c1OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1c(OC)c(OC)c2c(=O)cc(-c3ccc(O)c(O)c3)oc2c1OC

Procedure:
Into 200 ml. of a mixed solvent of ethyl acetate and methanol at a ratio of 1:1 was dissolved 1.11 g. of 3',4'-bis(benzyloxy)-5,6,7,8-tetramethoxyflavone and added 0.2 to 0.3 g. of 10% palladium-charcoal. The resulting mixture was mixed with shaking in a stream of H2 gas until H2 absorption was completed. After filtering out the catalyst, the obtained filtrate was concentrated. The residue was recrystallized from methanol to give 0.74 g. (97% of the theoretical amount) of the desired compound being a colorless prismatic crystal.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Brc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 85.7 %

Procedure:
In a flask, 25 g of benzyl bromide, 36.4 g of 4-bromo-4'-hydroxybiphenyl, 40.4 g of potassium carbonate, and 300 ml of 2-butanone were placed, and stirred under reflux for 6 hours. The reaction solution was poured into water, and an organic layer was extracted with toluene. After the toluene layer was washed with water and dried over sodium sulfate anhydrous, the solvent was distilled away. The residue was recrystallized from acetone to give 42.5 g of 4-bromo-4'-benzyloxybiphenyl (Y: 85.8%). The purity of the compound thus obtained was 99.0% by GC.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:18]([CH3:37])[CH:17]=2)([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:8][C:9]=1[CH3:10])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:33]([Si:30]([CH3:32])([CH3:31])[O:29][CH:24]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]([C:7]2[S:6][C:5]([CH2:3][OH:2])=[C:9]([CH3:10])[CH:8]=2)([CH2:12][CH3:13])[CH2:14][CH3:15])=[CH:17][C:18]=1[CH3:37])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)OC)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(CO)s1
Temperature: 25 °C
Yield: 100.6 %

Procedure:
To a 0° C. solution of 5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-carboxylic acid methyl ester (0.94 g, 1.71 mmol) and THF (50 mL)is added LAH (71 mg, 1.89 mmol). The mixture is stirred for 10 m, warmed to RT and stirred for 2 h. The reaction is quenched with H2O (70 ul), 15% NaOH (70 uL) and H2O (210 uL) and diluted with EtOAc (50 mL). The mixture is filtered through diatomaceous earth and concentrated to give the title compound (0.89 g, 1.72 mmol, 100%). 1H NMR (CDC3), B 0.07 (s, 3H), 0.12 (s, 3H), 0.72 (t, J=7.4 Hz, 6H), 0.91 (s, 9H), 0.98 (s, 9H), 2.01-2.14 (m, 4H), 2.19 (s, 3H), 2.21 (s, 3H), 3.68 (dd, J=5.3, 3.4 Hz, 1H), 3.86 (dd, J=9.0, 5.3 Hz, 1H), 3.98 (dd, J=9.0, 3.4 Hz, 1H), 4.67 (s, 22H), 6.54 (s, 1H), 6.67 (d, J=8.1 Hz, 1H), 7.00-7.06 (m, 2H). LC/MS (m/z): calcd for C30H50O3SSi M+: 518.9; found: 518.0.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([C:17]3[N:18]([CH3:22])[N:19]=[CH:20][CH:21]=3)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[CH3:22][N:18]1[C:17]([C:15]2[CH:14]=[CH:13][C:9]3[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=3[CH:16]=2)=[CH:21][CH:20]=[N:19]1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(-c3ccnn3C)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CNCCc2cc(-c3ccnn3C)ccc21
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A solution of N-trifluoroacetyl-7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (48 mg, 0.14 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and the solution stirred overnight at 20 C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and the solvent evaporated. Flash chromatography (0-15% MeOH in CH2Cl2, silica) resulted in 30 mg of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.48 (s, 1 H), 7.21 (m, 2 H), 7.13 (s, 1 H), 6.27 (s, 1 H), 3.89 (s, 3 H), 3.3−2.9 (m, 9 H), 2.79 (dd, J=7, 14 Hz, 1 H), 1.40 (d, J=8 Hz, 3 H). MS calculated for C15H19N3+H: 242, observed: 242.
Reaction SMILES: [Cl:1][C:2]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]([Cl:19])[C:3]=1[NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:21]([S:23]Cl)=[O:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]([Cl:19])[C:3]=1[NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]1[O:8][C:21](=[O:22])[S:23][N:9]=1
Reactant: O=C(Cl)SCl
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(N)=O)c1Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2nsc(=O)o2)c1Cl
Reaction time: 1 h

Procedure:
To a 90° C. solution of 2-(2,6-dichloro-3-methylanilino)benzamide (2.300 g, 7.79 mmols) [prepared according to Juby, J. Med. Chem., 11, 111 (1968)] in 40 mL of toluene is added chlorocarbonylsulfenyl chloride (1.300 mL, 15.38 mmols). Heating is continued at 90° C. for 1 hour. The solution is concentrated in vacuo and purified by flash chromatography, eluting with 10:1 hexane:diethyl ether providing 280 mg (10%) of 5-[2-[(2,6-dichloro-3-methylphenyl]amino]phenyl]-1,3,4-oxathiazol-2-one as a white solid; mp 135°-137° C.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([Li])[N:3]=[CH:2]1.[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[CH:13]=[N:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH3:8]>>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[CH:13]([NH:14][C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)[C:4]1[N:3]=[CH:2][O:1][CH:5]=1)[CH3:8]
Reactant: [Li]c1cocn1
Reactant: CCOc1cccc(C=Nc2ccncc2)c1
Product: CCOc1cccc(C(Nc2ccncc2)c2cocn2)c1

Procedure:
The title compund is prepared in a similar manner to Examples 5,6 and 7 from 4-oxazolyl lithium (obtained from 4-bromooxazole and butyl lithium) and 4-(m-ethoxybenzylideneamino)pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[C:18]1([CH2:24][N:25]([CH2:37][CH:38]=[CH2:39])[C:26](=[O:36])[CH2:27][NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[N:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]3[C:26](=[O:36])[N:25]([CH2:24][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:37][CH:38]3[CH2:39]2)=[CH:12][CH:11]=1
Reactant: C=CCN(Cc1ccccc1)C(=O)CNCc1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C1C2C(CC(c3ccc(OCc4ccccc4F)cc3)N2Cc2ccccc2)CN1Cc1ccccc1
Temperature: 120 °C
Reaction time: 72 h
Yield: 49.6 %

Procedure:
A solution of 4-{[(2-fluorophenyl)methyl]oxy}benzaldehyde (D92, 920 mg, 4.0 mmol), prepared by an analogous procedure to that described hereinabove, N1,N2-bis(phenylmethyl)-N1-2-propen-1-ylglycinamide (D90, 588 mg, 2.0 mmol) and DIPEA (0.68 ml, 4.0 mmol) in dry toluene (8 ml) were stirred at 120° C. for 72 h. After the reaction was terminated, it was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The residue was purified via flash chromatography affording the title compound (503 mg, 50%) as a racemate. Rf (cyclohexanes:ethyl acetate 1:1): 0.57.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:11]2[N:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH:12]=2)[CH:7]=[CH:8][C:9]=1[F:10].C(N(CC)CC)C.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>C(Cl)Cl>[F:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[CH:12]=[C:13]([NH:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[N:14]=[C:15]([O:17][CH3:18])[N:16]=2)=[CH:5][C:4]=1[CH2:3][NH:2][C:40](=[O:41])[CH2:39][O:38][CH3:37]
Reactant: COCC(=O)Cl
Reactant: COc1ccc(CCNc2cc(-c3ccc(F)c(CN)c3)nc(OC)n2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)NCc1cc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)ccc1F
Reaction time: 15 h

Procedure:
A solution of [6-(3-aminomethyl-4-fluoro-phenyl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [200 mg, 0.52 mmol, see example 27] and triethylamine (264 mg, 2.61 mmol) in DCM (5 mL) is treated with methoxyacetyl chloride (114 mg, 1.1 mmol) at 0° C. After 15 hours at 4° C. in a refrigerator, the mixture is quenched with water (10 mL) filtered through Chem-Elut. The filtrate is concentrated, and subjected to chromatography on silica gel eluting with 10% MeOH in DCM to give N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-2-methoxy-acetamide, which is treated with saturated solution of hydrogen chloride in EtOAc followed by lyophilization to afford N-(2-Fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-2-methoxy-acetamide hydrochloride [190 mg, 74%, Example 28]. LCMS: RT=2.35 minutes, MS: 455 (M+H). IC50=9 nM