Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].CO.C(N(CC)CC)C.ClC1C=C(Cl)C(Cl)=CC=1[O:26][C:27](=O)[CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C)C=O>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:27](=[O:26])[CH2:28][NH:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31]
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)CNC(=O)CNC(=O)OC(C)(C)C

Procedure:
Prepare a solution of 1.98 g. of glycine methyl ester hydrochloride in dimethylformamide containing 8 ml. of methanol and 1.42 g. of triethylamine. Cool and stir the solution while adding 5.0 g. of t-butoxycarbonylglycine-2,4,5-trichlorophenyl ester in 25 ml. of dimethylformamide. Stir the reaction mixture overnight, filter and evaporate the filtrate to dryness under reduced pressure. Chromatograph the residue on 150 g. of silica gel and collect the desired product which is eluted by an ethyl acetate:chloroform (1:9) mixture. Evaporate the eluate to dryness and crystallize from hexane to obtain the title product (m.p. 132°-135° C.).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][CH:14]3[CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[CH2:15]3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1>[OH-].[OH-].[Pd+2].CCO>[NH:16]1[CH2:15][CH:14]([O:13][C:8]2[C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[N:12][CH:11]=[CH:10][N:9]=2)[CH2:17]1
Reactant: O=C(OCc1ccccc1)N1CC(Oc2nccnc2C2=CCOCC2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: c1cnc(C2CCOCC2)c(OC2CNC2)n1
Reaction time: 20 h
Yield: 76.5 %

Procedure:
To a N2 purged round bottom flask was added benzyl 3-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)azetidine-1-carboxylate (see PREPARATION P28.2; 490 mg, 1.334 mmol), pearlman's catalyst (37.5 mg, 0.267 mmol) and EtOH (10 mL). A balloon of H2 was placed atop the round bottom flask. After 20 hours, the reaction was filtered through CELITE® and the cake was washed with EtOAc. The filtrate was concentrated in vacuo to give 2-(azetidin-3-yloxy)-3-(tetrahydro-2H-pyran-4-yl)pyrazine (240 mg, 1.020 mmol, 76% yield), as a tan residue. MS (ESI) m/z 236.1 (MH+).
Reaction SMILES: [CH3:1][N:2]([C:21]1[C:22]([O:31][CH3:32])=[N:23][C:24]([CH3:30])=[C:25]([C:27](=[O:29])[CH3:28])[CH:26]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:33][Mg]Br>O1CCCC1>[OH:29][C:27]([C:25]1[CH:26]=[C:21]([N:2]([CH3:1])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=3)[CH2:9][CH2:10]2)=[O:4])[C:22]([O:31][CH3:32])=[N:23][C:24]=1[CH3:30])([CH3:33])[CH3:28]
Reactant: C[Mg]Br
Reactant: COc1cc(OC)cc(N2CCN(C(=O)N(C)c3cc(C(C)=O)c(C)nc3OC)CC2)c1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(N2CCN(C(=O)N(C)c3cc(C(C)(C)O)c(C)nc3OC)CC2)c1
Yield: 92 %

Procedure:
1-[N-Methyl-N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(221 mg, 0.5 mmol) was dissolved in tetrahydrofuran(10 ml) and thereto methyl magnesium bromide(0.50 ml, 1.50 mmol). The resulting mixture was refluxed for 15 hrs, concentrated under the reduced pressure to remove used solvent, extracted with ethylacetate, filtered to dryness, and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][C:33]1([CH2:38][OH:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][C:33]2([CH2:38][OH:39])[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: NC1(CO)CCCC1
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NC2(CO)CCCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (1-aminocyclopentyl)methanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a cream-colored solid: 1H NMR (d6-DMSO) δ 10.32 (1H, s), 8.50 (1H, s), 7.74 (1H, s), 7.32 (2H, dd, J=8.5, 6 Hz), 7.12 (2H, t, J˜9 Hz), 5.12 (2H, s), 5.04 (1H, br), 4.11 (2H, s), 3.51 (2H, s), 3.12 (3H, s), 2.82 (3H, s), 1.91 (2H, m), 1.74 (4H, m), 1.56 (2H, m); HRMS calcd for C26H29FN4O5+H+: 497.2200. Found: 497.2200.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:4]=1[CH2:13]O.S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[Cl:17][CH2:13][C:4]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(C(F)(F)F)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cccc(C(F)(F)F)c1CCl
Temperature: 0 °C

Procedure:
Into a 50-mL round-bottom flask, was placed [2-methoxy-6-(trifluoromethyl)phenyl]methanol (1.0 g, 4.85 mmol, 1.00 equiv), chloroform (10.0 g). This was followed by the addition of thionyl chloride (1.73 g, 14.54 mmol, 3.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at 30° C. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×15 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.2 g (crude) of 2-(chloromethyl)-1-methoxy-3-(trifluoromethyl)benzene as yellow oil. This residue could be used for the next step directly.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=2)=[CH:4][C:3]=1[CH3:19].[S-:20][C:21]#[N:22].[NH4+].BrBr>C(O)(=O)C>[NH2:22][C:21]1[S:20][C:18]2[CH:17]=[C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=3)[CH:4]=[C:3]([CH3:19])[C:2]=2[N:1]=1
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(C)c2)ccn1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: CNC(=O)c1cc(Oc2cc(C)c3nc(N)sc3c2)ccn1

Procedure:
To the solution of 4-(4-amino-3-methylphenoxy)-N-methylpicolinamide (25 mg, 0.097 mmol, 1.0 eq) in 1 mL of cold acetic acid was added ammonium thiocyanate (11 mg, 0.145 mmol, 1.5 eq). After stirring for a few minutes, bromine (6 μL, 0.116 mmol, 1.2 eq) was injected dropwise and reaction stirred at room temperature for 3 hours. Thereafter, reaction was quenched with NaHCO3 saturated solution (ca. 10 mL) and extracted with ethyl acetate (ca. 25 mL×3), combined organic extracts were dried over sodium sulfate and condensed under reduced pressure to give sufficiently pure crude product which was carried to next step without further purification. LC/MS (m/z) [315.1] (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH:14]1[CH2:16][CH2:15]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[O:10])[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: NCC1CC1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(Cl)nc1C(=O)NCC1CC1
Reaction time: 16 h
Yield: 27.6 %

Procedure:
6-Chloro-3-methylpyridine-2-carboxylic acid (595 mg, 3.47 mmol), aminomethylcyclopropane (356 μL, 4.16 mmol), EDC.HCl (1.46 g, 7.63 mmol), HOBN (1.54 g, 8.67 mmol) and NEM (1.10 mL, 8.67 mmol) were dissolved in DCM (30 mL) and stirred for 16 h. The reaction mixture was washed with sat aq NaHCO3 (30 mL), 1M aq HCl (30 mL), brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (215 mg, 28%) as a yellow solid. LCMS (ES+): 225.5 [MH]+.
Reaction SMILES: [CH3:1][CH:2]([NH:14][C:15]1[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[H][H].[ClH:25]>[Pd]>[ClH:25].[CH3:1][CH:2]([NH:14][C:15]1[NH:20][CH:19]([CH3:21])[CH2:18][CH:17]([CH3:22])[N:16]=1)[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][CH:9]=1
Reactant: Cc1cc(C)nc(NC(C)Cc2ccc(C(C)(C)C)cc2)n1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: CC1CC(C)NC(NC(C)Cc2ccc(C(C)(C)C)cc2)=N1

Procedure:
A solution of the 2-(1-methyl-2-[4-t-butylphenyl]ethyl)amino-4,6-dimethylpyrimidine (1.24 g, 4.18 mmol) obtained in (iii) in 0.5M ethanolic hydrogen chloride (100 ml) was hydrogenated at about 3 atmospheres in the presence of 10% palladium on charcoal catalyst (320 mg) until hydrogen uptake had ceased. The solution was then filtered to remove the catalyst and the filtrate evaporated. Addition of dichloromethane (20 ml) and evaporation afforded 1.08 g 2-(1-methyl-2-[4-t-butylphenyl]ethyl)amino-4,6-dimethyl-3,4,5,6-tetrahydropyrimidine hydrochloride (in hemi-hydrate form) as an off-white foam, m.pt., 40°-45° C. M+ (--HCl) found: 301.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[OH:10].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C.C(OCC)C.[I-].[Na+]>[CH2:11]([O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[F:1])[CH:6]=[O:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)c(O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)O
Product: O=Cc1ccc(F)c(OCc2ccccc2)c1
Yield: 86.8 %

Procedure:
54 mg of 4-fluoro-3-hydroxybenzaldehyde was dissolved in 2 ml of 2-propanol, and 73 mg of benzyl chloride, 80 mg of potassium carbonate and 5 mg of sodium iodide were added to the solution. The mixture was heated under reflux for 7 hours with stirring. The reaction mixture was diluted with ethyl ether, and the inorganic salts were removed by filtration. The filtrate was evaporated under reduced pressure, and purified by silica gel column chromatography (Wakogel C-200, 5 g; eluting solvent: hexane/ethyl acetate=20/1), and then recrystallized from chloroform/hexane to give 77 mg of 3-benzyloxy-4-fluorobenzaldehyde as colorless needles having a melting point of 68° to 69° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][C:12]2[CH:13]=[N:14][C:15]([Cl:19])=[CH:16][C:17]=2[NH2:18])[CH:7]=[N:6][CH:5]=1.[CH3:21]C([O-])(C)C.[K+].CI>CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[N:18]([CH3:21])[C:17]3[CH:16]=[C:15]([Cl:19])[N:14]=[CH:13][C:12]=3[CH:11]=2)[CH:7]=[N:6][CH:5]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1cncc(C#Cc2cnc(Cl)cc2N)c1
Agent: [K+]
Solvent: CI
Solvent: CN1CCCC1=O
Product: COC(=O)c1cncc(-c2cc3cnc(Cl)cc3n2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-(4-amino-6-chloro-pyridin-3-ylethynyl)-nicotinic acid methyl ester (0.950 mg, 3.30 μmol) in NMP (15 mL) was added KOtBu (1.112 mg, 9.91 μmol) and the reaction was left to stir overnight at room temperature. The reaction was cooled to 0° C. and methyl iodide (0.619 μl, 9.91 μmol) was added. The reaction mixture was stirred for 30 min. The reaction was quenched with water and extracted with ethyl acetate twice. The combined organic layer was washed with water thrice, dried over sodium sulfate and concentrated in vacuo to afford desired product 5-(6-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-nicotinic acid methyl ester as a brown color oil which was taken onto next step without further purification. ESI-MS: m/z 302.0 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)=O.[C:22]([CH2:30][C:31](=O)[CH3:32])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:13]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:4]=3)[N:1]=[C:31]([CH3:32])[C:30]=2[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:29])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1cccc(Cl)c1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1nc2ccc(OC(F)(F)F)cc2c(-c2cccc(Cl)c2)c1C(=O)c1ccccc1
Yield: 57 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(3-chloro-phenyl)-methanone [example A7] and benzoylacetone according to the procedure of example 1, except that the solvent was isopropanol, and heptane/ethyl acetate (1:2) was used. Yield: 57%; MS: m/z=441 (M).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)C(CCCN3CCC(C4C=C(NC(=O)C(C)C)C=CC=4)CC3)=C2C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:45](OC)[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:55]=[C:56]([NH:60][C:61](=[O:65])[CH:62]([CH3:64])[CH3:63])[CH:57]=[CH:58][CH:59]=2)[CH2:50][CH2:49]1.Cl.C1(N(C2C=CC=CC=2)N)C=CC=CC=1>>[CH3:63][CH:62]([CH3:64])[C:61]([NH:60][C:56]1[CH:57]=[CH:58][CH:59]=[C:54]([CH:51]2[CH2:52][CH2:53][N:48]([CH2:47][C:46]3[C:2]4[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:7]([C:15]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:45]=3)[CH2:49][CH2:50]2)[CH:55]=1)=[O:65]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1
Reactant: COC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)OC
Agent: Cl
Agent: NN(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cn(-c4ccccc4)c4ccccc34)CC2)c1
Yield: 56 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[3-(1,2-diphenyl-1H-indol-3- yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide, N-{3-[1-(3,3-dimethoxypropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (15.2 mg, 0.0436 mmol) and 1,1-diphenylhydrazine hydrochloride (11.6 mg, 0.0524 mmol) provided 2-methyl-N-(3-{1-[(1-phenyl-1H-indol-3-yl)methyl]-4-piperidinyl}phenyl)propanamide (11 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, 1H, J=7.8 Hz), 7.57 (d, 1H, J=7.7 Hz), 7.54-7.47 (m, 4H), 7.43-7.32 (m, 4H), 7.25-7.16 (m, 4H), 6.95 (d, 1H, J=7.8 Hz), 3.87 (s, 2H), 2.53-2.47 (m, 2H), 2.21 (dt, 2H, J=3.0, 10.5 Hz), 2.12-1.77 (m, 6H), 1.24 (d, 6H, J=6.9 Hz); ESMS m/e: 451.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[C:3]=1[F:10].[CH3:11][N:12](C=O)C.[C-]#N.[Na+]>O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:11]#[N:12])=[C:3]([F:10])[C:4]=1[F:9]
Reactant: Nc1ccc(Br)c(F)c1F
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(N)c(F)c1F
Yield: 55 %

Procedure:
A stirred mixture of the crude 4-bromo-2,3-difluoroaniline, 36 g of cuprous cyanide and 908 mL of DMF is heated 7 hours at reflux under an N2 atmosphere. After cooling, 900 mL of 10% aqueous NaCN is added and 45 minutes later 2 L of H2O. The black solution is extracted three times with CH2Cl2 (total volume 4 L). The CH2CL2 extract is washed with H2O, saturated NaHCO3 and H2O (500 mL of each) and then stripped in vacuo. The resulting black oil is purified by dry-column chromatography on silica gel using CH2CL2 as eluent. There is obtained 31.17 g (55% overall yield) of 4-amino-2,3-difluorobenzonitrile, m.p. 108°-110° C., with the expected ion at 156 in the mass spectrum and consistent NMR and IR spectral data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[C:27]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)#[N:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:33]2[CH:34]=[CH:35][C:30]([CH2:29][C:27]#[N:28])=[CH:31][CH:32]=2)=[CH:20][CH:19]=1)[CH3:9]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Reactant: N#CCc1ccc(B(O)O)cc1
Product: Cc1noc(-c2ccc(-c3ccc(CC#N)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl

Procedure:
Prepared as described in Example 36, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and 4-cyanomethylphenylboronic acid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:14])[CH2:11][NH:12][CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C@@H:22]([C:24]([OH:26])=[O:25])[NH2:23])[CH:16]=1.[C:27]1([CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CN(C)C=O.C(#N)C>[CH2:2]([O:9][C:10](=[O:14])[CH2:11][NH:12][CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:33]([S:34]([NH:23][C@H:22]([C:24]([OH:26])=[O:25])[CH2:21][C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)(=[O:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N[C@@H](Cc1cccnc1)C(=O)O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: CNCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(O)[C@H](Cc1cccnc1)NS(=O)(=O)Cc1ccccc1
Yield: 25.7 %

Procedure:
The title compound was prepared under the same manner as described in Example 58, using 2.44 g (6.7 mmole) of the compound of Example 57 in 10 mL of dry dimethylformamide and 25 mL acetonitrile, alphatoluenesulfonyl chloride (1.9 g, 10.1 mmole), and triethylamine (5 mL, 34 mmole). This afforded 0.86 g (27% yield) of the title compound as a brownish-yellow foam. Rf=0.45 (1:9 methanol:dichloromethane).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccccn3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M3) (253 mg, 0.466 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (66 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([N+:20]([O-])=O)[C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)[CH2:4][CH2:3]1>CO.[Pd]>[O:23]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH2:20])[C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: O=[N+]([O-])c1cc(N2CCS(=O)(=O)CC2)cnc1N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(N2CCS(=O)(=O)CC2)cnc1N1CCOCC1

Procedure:
A solution of 4-[5-(1,1-dioxidothiomorpholin-4-yl)-3-nitropyridin-2-yl]morpholine (180 mg, 0.53 mmol) in MeOH (100 mL) was reduced using a continuous flow hydrogenation reactor (flow rate: 1 mL/min, 10% mol Pd/C, temperature 35° C., H2 pressure: 20 bar) to give 5-(1,1-dioxidothiomorpholin-4-yl)-2-morpholin-4-ylpyridin-3-amine.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][C:5]([NH2:8])([CH3:7])[CH3:6].[OH-].[Na+].[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:13]=1[CH:14]=O>C(Cl)Cl>[Cl:2][CH2:3][CH2:4][C:5]([N:8]=[CH:14][C:13]1[C:12]([Cl:11])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20])([CH3:7])[CH3:6]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CC(C)(N)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(CCCl)N=Cc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
13.3 g (84.0 mmol) of 3-chloro-1,1-dimethyl propylamine-hydrochloride were added to 84.0 mL sodium hydroxide solution (1 M) at 0° C. with vigorous stirring. The reaction mixture was stirred for 30 min at 0° C. and then combined with 50 mL methylene chloride. The phases were separated and the aqueous phase was twice extracted with 35 mL methylene chloride. The combined organic phases were dried over magnesium sulphate and at ambient temperature combined with 14.2 g (81.0 mmol) of 2,6-dichlorobenzaldehyde with stirring. The reaction mixture was stirred for 18 h at ambient temperature, dried again with magnesium sulphate and the solvent was removed. 22.3 g (80.0 mmol, 99%) (3-chloro-1,1-dimethylpropyl)-(2,6-dichlorobenzylidene)-amine were obtained as a yellowish oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CS[C:17](=[NH:22])[NH:18][N+:19]([O-:21])=[O:20]>>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]([NH:18][N+:19]([O-:21])=[O:20])=[NH:22])[N:9]=1)[CH3:1]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Product: CN(C)Cc1nc(CSCCNC(=N)N[N+](=O)[O-])cs1

Procedure:
Following the above procedure, 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine was reacted with S-methyl N-nitroisothiourea to yield N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-nitroguanidine. The compound was purified by chromatography (silica-ethyl acetate/methanol), and melted at 104°-105.5° C. after recrystallization from ethyl acetate.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>CC(O)=O>[Br:1][C:10]1[CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc(C=O)cc2)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
Bromine (8.2 mL, 0.160 mol) in 40 mL of glacial HOAc was added under nitrogen dropwise over 30 minutes to a solution of 4′-methoxy-1,1′-biphenyl-4-carbaldehyde (31.0g, 0.146 mol), prepared in the previous step, in 500 mL of glacial HOAc at room temperature. After the addition the reaction was stirred at room temperature for 16 h. During the reaction a solid precipitated. The solid can be collected by filtration. If by TLC starting material remains in either the solid or filtrate the solid can be redissolved and additional bromine added until the reaction is complete. When the reaction is complete by TLC, water is added and the solid present is collected by filtration to give 3′-bromo-4′-methoxy-1,1′-biphenyl-4-carbaldehyde (40.8 g, 96%) as a white solid, MS (ESI) m/z 290. Elemental Analysis for C14H11BrO2. Calc'd: C, 57.76; H, 3.81; N, 0.00. Found: C, 57.30; H, 3.61; N, 0.00.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.Cl[C:17]1[C:18]2[CH:25]=[CH:24][N:23]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:19]=2[N:20]=[CH:21][N:22]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[S:26]([N:23]1[C:19]2[N:20]=[CH:21][N:22]=[C:17]([NH:1][CH:2]3[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]3)[C:18]=2[CH:25]=[CH:24]1)([C:29]1[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=1)(=[O:27])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCCCC(N)C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1
Temperature: 90 °C
Yield: 61.3 %

Procedure:
To a solution of tert-butyl 3-aminoazepane-1-carboxylate (1 g, 4.7 mmol), 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3.1 g, 5.1 mmol) in DMF (10 mL) was added DIEA (1.2 mL, 7.0 mmol) and the reaction mixture was heated to 90° C. for 3 h. The reaction was cooled to rt and diluted with ice cooled water (50 mL). The mixture was extracted with EtOAc (3×100 mL), the EtOAc layers were combined, dried over Na2SO4 and evaporated in vacuo to give the crude product that was purified by column chromatography (silica gel, gradient 0-20% EtOAc hexane) to afford the titled intermediate (1.4 g, 89%). LC-MS: m/z [M+1]=486.