Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH2:24](C([SnH3])=C(CCCC)CCCC)[CH2:25]CC>C1(C)C=CC=CC=1.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>[CH:15]1([N:7]2[C:8]3[C:3](=[C:2]([CH:24]=[CH2:25])[C:11]([F:12])=[C:10]([F:13])[C:9]=3[F:14])[C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6]2)[CH2:17][CH2:16]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(Br)c2c1=O
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1
Temperature: -18 °C

Procedure:
5.9 g of ethyl 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 6.7 g of tributylvinylstannane and 0.69 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 10 hours in 60 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is cooled to -18° C., and the solid which has precipitated is filtered off with suction, washed with toluene and dried. 4.46 of the title compound are obtained (88% of theory).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[SH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23].C([O-])(O)=O.[Na+]>ClCCl>[S:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][S:15][CH:6]1[C:5]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([OH:2])[CH:4]=1
Reactant: SCc1ccccc1S
Reactant: COc1cc(C=O)cc(O)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C2SCc3ccccc3S2)cc(O)c1OC
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
Hydrogen chloride gas was bubbled for three minutes at 22° C. through a solution of 3-hydroxy-4,5-dimethoxybenzaldehyde (0.55 g, 3.0 mmol) and 2-(mercaptomethyl)benzenethiol (0.52 g, 3.3 mmol) in dichloromethane (15 ml). After an additional 15 min., the reaction mixture was poured into saturated NaHCO3 (50 ml) and extracted with dichloromethane (2×75 ml). The combined organic layer was washed with brine (30 ml), dried (Na2SO4), filtered and concentrated providing a crude solid. This solid was triturated with hexane and then purified by flash chromatography using a gradient of hexanes (100%) up to hexanes (70%:30%). Concentration of the product containing fractions provided the above subtitle compound (0.76 g, 78%) as a white solid. 1H NMR (300 MHz, CDCl3, ppm) δ 3.84 (s, 3H), 3.90 (s, 3H), 3.94 (d, J=15 Hz, 1H), 4.00 (d, J=15 Hz, 1H), 5.42 (s, 1H), 5.89 (br s, 1H), 6.63 (d, J=2 Hz, 1H), 6.78 (d, J=2 Hz, 1H), 7.15-7.36 (m, 4H); 13C NMR (75 MHz, CDCl3, ppm) δ 34.3, 51.5, 56.0, 61.0, 104.1, 108.2, 126.4, 127.7, 128.5, 129.6, 135.2, 135.3, 135.5, 135.7, 149.4, 152.5; MS calculated for C16H16O3S2-H 319 observed 319.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C@H:16]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]4)[C@@H:17]3[CH2:28][CH2:29][CH2:30][N:31]=[N+:32]=[N-:33])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[Cl-].[NH4+]>O1CCCC1>[N:1]1([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C@H:16]3[CH2:20][CH2:19][N:18]([C@@H:21]4[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]4)[C@@H:17]3[CH2:28][CH2:29][CH2:30][N:31]=[N+:32]=[N-:33])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [N-]=[N+]=NCCC[C@@H]1[C@@H](Nc2nc(Cl)cc(N3CCCCCC3)n2)CCN1C1CCC(=O)CC1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCC[C@@H]1[C@@H](Nc2nc(Cl)cc(N3CCCCCC3)n2)CCN1[C@H]1CC[C@@H](O)CC1

Procedure:
The compound 45 (1.12 g), tetrahydrofuran (25 mL) and 1.02 mol/L L-Selectride (7.0 mL) were stirred at −78° C. for 1 hour. The reaction solution was added aqueous saturated ammonium chloride solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate:methanol=50:50:0→0:100:0→0:90:10) to obtain the title compound (237 mg) having the following physical properties.
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@H:7]2[N:8]=1)[CH3:2].[CH2:17]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCC>C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH2:17]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH:26][C@@H:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][C@H:7]1[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccccc1Cc1ccccc1
Reactant: CCOC1=N[C@@H]2CCc3ccccc3[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCC
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N[C@@H]1CCc2ccccc2[C@H]1Nc1ccccc1Cc1ccccc1
Temperature: 50 °C
Yield: 70.4 %

Procedure:
A solution of (±) cis-2-ethoxy-3a,4,5,9b-tetrahydronapth[2,1-d]oxazole (1.90 g, 8.76 mmol) in dry toluene (15 ml) was treated with 2-benzylaniline (1.60 g, 8.76 mmol) and a catalytic amount of p-toluenesulfonic acid (0.5 ml of an anhydrous 0.1M solution of p-toluenesulfonic acid in benzene). The mixture was heated at 50° C. for 1.5 h. The reaction was worked up as described in Preparation 5. Trituration with n-pentane afforded the title compound as a pale yellow solid (2.47 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]([C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[CH2:22][OH:23])=[CH:16][CH:15]=1)([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH:11]([C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[CH:22]=[O:23])=[CH:18][CH:19]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1ccc(/C=C/CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(/C=C/C=O)cc1

Procedure:
Following General Procedure H, oxalyl chloride (9.5 ml, 19.0 mmol, 2M in CH2Cl2), DMSO (1.8 ml, 25.3 mmol), (E)-3-(4-isopropylphenyl)prop-2-en-1-ol (Compound 109, 2.2 g, 12.6 mmol) and triethylamine (7.1 ml, 50.7 mmol) in CH2Cl2 (100 ml) were reacted to obtain the title compound as an oil.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.[NH2:60][C@H:61]([C:67]1[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=1)[CH2:62][C:63]([O:65][CH3:66])=[O:64]>CN1C(=O)CCC1.CCOC(C)=O>[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([NH:60][C@H:61]([C:67]2[CH:68]=[CH:69][C:70]([Cl:73])=[CH:71][CH:72]=2)[CH2:62][C:63]([O:65][CH3:66])=[O:64])=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:26])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: COC(=O)C[C@H](N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 82.3 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (1.157 g, 3.04 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (1 g, 2.77 mmol) and N,N-diisopropylethylamine (1.006 mL, 6.09 mmol) in NMP (10 mL) at 20° C. The resulting solution was stirred at 20° C. for 5 minutes. (S)-methyl 3-amino-3-(4-chlorophenyl)propanoate (hydrochloride) (Intermediate 20) (0.692 g, 2.77 mmol) was then added to the solution and stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with water (2×50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford (S)-methyl 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (1.27 g, 82%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) δ 1.40 (9H, s), 1.99 (2H, s), 2.04-2.07 (2H, m), 2.79-2.84 (2H, m), 3.56 (3H, s), 3.60-3.66 (1H, m), 3.67-3.70 (1H, m), 4.20 (2H, t), 5.20-5.26 (1H, m), 6.73 (1H, d), 7.13 (1H, s), 7.27 (1H, t), 7.35 (4H, q), 8.14 (1H, d), 8.21 (1H, s), 11.98 (1H, s). m/z (ESI+) (M+H)+=557; HPLC tR=2.12 min.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Cl[CH2:10][CH2:11][NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].CCCCCC>CN(C)C=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:10][CH2:11][NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCOC(=O)NCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)NCCOc1ccc(O)cc1
Temperature: 25 °C

Procedure:
A mixture of hydroquinone (11.0 g, 100.0 mmol), ethyl 2-chloroethylcarbamate (7.6 g, 50.0 mmol) and potassium carbonate (13.8 g, 100.0 mmol) in 100 ml of dimethylformamide (DMF) is heated at 80° for 20 hours. After cooling to RT, the reaction mixture is poured into ice water and hexane, and the hexane layer is discarded to remove the bis ether by-product. The aqueous layer is then extracted with ether (3X) and the combined ether layers are washed with water, followed with brine, and dried over calcium sulfate. The solvent is removed and the residue is diluted with chloroform to precipitate out the excess hydroquinone. Following filtration, the filtrate is collected and rotoevaporated to give ethyl N-[2-(4-hydroxyphenoxy)ethyl]carbamate, a solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:36])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[CH:34]=[N:33][CH:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:36])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CNc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3cncn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-(isobutyl-amino)-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M129) (0.39 g, 0.74 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light orange solid (270 mg, 89%).
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=O)[CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=[CH:11][CH:12]=1>CO>[Br:6][C:7]1[CH:8]=[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(CCN1CCCC1)Nc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CO
Product: Brc1cccc(NCCCN2CCCC2)c1
Reaction time: 8 h

Procedure:
A 1M solution of BH3 in tetrahydrofuran (10 ml, 10 mmol) was added dropwise to N-(3-bromo-phenyl)-3-pyrrolidin-1-yl-propionamide (0.3 g, 1 mmol) and the solution was stirred overnight at reflux then subsequently hydrolysed by slow addition of excess of methanol and refluxing for a further 2 hours. The solvent was removed under reduced pressure and aqueous ammonium chloride was added. The aqueous phase was extracted twice with ethyl acetate and the organics were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was dissolved in methanol and loaded onto an SCX cartridge, which was washed with methanol and the product subsequently eluted with 2M ammonia in methanol. Removal of all solvents under rotary evaporation gave the desired product. Yield 0.23 g, 82%. LCMS method: 2, RT: 2.71 min; MI: 283-285 [M+1].
Reaction SMILES: [ClH:1].[OH:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:12]=[CH:13][C:14]([N+:16]([O-])=O)=[CH:15][C:7]=2[CH2:6]1>C(O)C.[Pd]>[ClH:1].[OH:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:7]=2[CH2:6]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CN(CCO)CCC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)CN(CCO)CCC2
Reaction time: 2 h
Yield: 126.4 %

Procedure:
To a solution of 2-(2-hydroxyethyl)-8 nitro-2,3,4,5-tetrahydro-1H-2-benzazapine hydrochloride (1.51 g, 5.54 mmol) in ethanol (100 ml) was added 10% Pd-C (0.2 g) and the solution was hydrogenated at 50 psi for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give an oil. Evaporation with absolute ethanol gave 2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-2-benzazapin-8-amine hydrochloride as an amorphous solid (1.70 g, 110%) which was used without further purification. A solution of this salt (1.64 g, corrected to 1.50 g, 5.37 mmol) and S-methyl-2-thiophenethiocarboximide hydroiodide (1.91 g, 6.71 mmol) in N-methylpyrrolidinone (8.0 ml) was heated at 45° C. for 6 h. The reaction mixture was poured into water, basified, and extracted with dichloromethane. The dried (magnesium sulfate) organic phase was concentrated to give an oil. Column chromatography on silica gel, using 2% methanol in chloroform saturated with ammonia to 10% methanol in chloroform as agent, gave a yellow oil (1.69 g, 100%). This oil (1.02 g, 3.23 mmol) was dissolved in ethanol and fumaric acid (0.82 g, 7.91 mmol) was added and the solution was heated at reflux for 0.5 h. Upon cooling, the product was collected to give the monofumarate salt (0.68 g), m.p. 172-4° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH2:20][C:21](=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl.O>[C:14]1([CH2:13][C:12](=[O:11])[CH2:20][C:21](=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCCCCCCCCCC(=O)CC(O)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCCCCCCCCC(=O)CC(=O)Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.03 h

Procedure:
To a cold (-60° C.), stirred solution of oxalyl chloride (32 mL, 0.37 mol) in dichloromethane (980 mL) was added over 10 minutes a solution of dimethylsulfoxide (52 mL, 0.73 mol) in CH2Cl2 (450 mL). Stirred 2 minutes. To the mixture was added a solution of (±)-2-hydroxy-1-phenyl-4-hexadecanone (105.6 g, 0.3176 mol) in CH2Cl2 (900 mL) over 17 minutes. Stirred 20 minutes. To the mixture was added triethylamine (230 mL, 1.65 mol) over 5 minutes. Stirred 5 minutes. The mixture was allowed to warm to -20° C. and water (1 L) was added. Stirred 30 minutes. The organic layer was washed (1M HCl and saturated NaCl), dried (Na2SO4), and rotoevaporated to an oil. The oil was chromatographed on silica gel using petroleum ether-acetone (45:1) to give a pale yellow oil; yield 67.6 g (64.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:11]=[C:12]=[S:13])=[CH:5][CH:4]=1.[ClH:23]>C(OCC)C>[Cl:23][C:12]1[S:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:11]=1
Reactant: COc1ccc(C(=O)C(N=C=S)c2ccc(OC)cc2)cc1
Reactant: Cl
Solvent: CCOCC
Product: COc1ccc(-c2nc(Cl)sc2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
10 g of the 1,2-bis-(p-methoxyphenyl)-2-isothiocyanoethanone so obtained are suspended in 150 ml of diethyl ether and, while stirring, the suspension is cooled to 15°-20°. Gaseous hydrogen chloride is then introduced slowly at such a rate that the reaction temperature does not exceed 20°. After about 45 minutes a clear, yellowish solution is obtained. It is maintained at 15° and a little hydrogen chloride is introduced for a further 7 hours, the solution is left to stand overnight at 15°, poured onto 300 ml of ice, the diethyl ether is removed by distillation, and the crystalline precipitate is filtered with suction, then washed twice with water and sucked dry on a suction filter. The crude product is recrystallised from 100 ml of hexane. 2-Chloro-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 92°-94° is obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]2[NH:29][C:30]1[S:31][C:32]2[CH:38]=[C:37]([NH2:39])[CH:36]=[CH:35][C:33]=2[N:34]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]2[NH:29][C:30]1[S:31][C:32]2[CH:38]=[C:37]([NH:39][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=3)[CH:36]=[CH:35][C:33]=2[N:34]=1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)c5cccc(OC(F)(F)F)c5)cc4s3)c2cc1OC

Procedure:
N-[2-(6,7-Dimethoxyquinazolin-4-ylamino)-benzothiazol-6-yl]-3-trifluoromethoxybenzamide was prepared from 3-trifluoromethoxybenzoyl chloride (19 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 48 mg, 88 μmol, 78%). LC/ESI-MS: m/z=542 [M+H]+; m/z=540 [M−H]−; Rt=3.72 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][C@H:4]([N:8]([CH3:15])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:50][C:51]1[CH:56]=[CH:55][C:54]([CH:57]([C:64]2[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=2)[N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)=[CH:53][CH:52]=1>CN(C=O)C.C(OCC)C>[F:70][C:67]1[CH:66]=[CH:65][C:64]([CH:57]([C:54]2[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=2)[N:58]2[CH2:59][CH2:60][N:61]([C:5](=[O:7])[C@@H:4]([N:8]([CH3:15])[CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[CH2:3][CH:2]([CH3:1])[CH3:16])[CH2:62][CH2:63]2)=[CH:69][CH:68]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)N(C)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
(S)-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid (0.200 g, 0.873 mmol, Example 27, Step A) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N,-diisopropylethylamine (0.304 mL, 1.75 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.331 g, 0.873 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.252 g, 0.873 mmol) was then added. After stirring for, sequentially, 15 minutes at 0° C. and 40 minutes at ambient temperature, reaction mixture was mixed with 50 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (50% EtOAc in hexane) to provide 0.326 g (75%) of the pure titled compound as a white foam: mp 56-65° C. APCI-MS m/z 500.3 (MH+).
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].[CH3:15][N:16]=[C:17]=[O:18]>C1(C)C(C)=CC=CC=1>[CH3:15][NH:16][C:17](=[O:18])[O:10][CH:7]1[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4][C:3]([CH2:1][CH3:2])([CH3:14])[CH:8]1[CH3:9]
Reactant: CN=C=O
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1
Solvent: Cc1ccccc1C
Product: CCC1(C)CC(OC(=O)NC)C(C)C(C)(CC)N1
Yield: 97.2 %

Procedure:
4.0 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidinol (Compound 1) and 1.7 g of methyl isocyanate were dissolved in 6 ml of xylene and the solution was refluxed by heating for 3.5 hours. Xylene and excess methyl isocyanate were distilled off under reduced pressure. The residue was purified by column chromatography on silica gel ("60F 254", available from Merck & Co.) using a 4 : 1 by volume mixture of chloroform and methanol as eluent. The product was then distilled under reduced pressure, giving 5.0 g of Compound 66 as a pale yellow liquid (bp 145°-149° C./1.4 mmHg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]([C:29]2[CH:30]=[C:31]([O:39][CH3:40])[C:32]3[O:37][CH2:36][O:35][CH2:34][C:33]=3[CH:38]=2)[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)[CH:12]=[CH:11][C:10]=1[C:41]#[N:42])(C)(C)C.ClCCl.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[NH:42]=[C:41]1[C:10]2[C:9](=[CH:14][C:13]([NH:15][CH:16]([C:29]3[CH:30]=[C:31]([O:39][CH3:40])[C:32]4[O:37][CH2:36][O:35][CH2:34][C:33]=4[CH:38]=3)[C:17]3[NH:21][C:20](=[O:22])[N:19]([C:23]4[N:24]=[CH:25][CH:26]=[CH:27][N:28]=4)[N:18]=3)=[CH:12][CH:11]=2)[CH2:8][NH:7]1
Reactant: COc1cc(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C(Nc2ccc3c(c2)CNC3=N)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To a mixture of (2-cyano-5-{[(8-methoxy-4H-benzo[1,3]-dioxin-6-yl)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}benzyl)carbamic acid t-butyl ester (83 mg) and dichloromethane (3.0 mL) there was added TFA (0.3 mL), and the mixture was stirred at room temperature for 2 hours. Toluene (10 mL) was added to the mixture, and the solvent in the mixture was distilled off. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile/water mixed solvent, 0.1% acetic acid) to obtain the target compound (33.8 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]1([CH3:14])[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1>>[CH2:6]([NH2:1])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:13][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:7][CH3:14]
Reactant: Cc1ccccc1C
Reactant: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCN
Yield: 1052.7 %

Procedure:
A mixture of 39.4 g of the solid obtained in Intermediate Preparatory Example 5, 26.9 g of n-octadecylamine, 1.5 g of pyridine, and 100 g of xylene was stirred at a temperature of 120° C. for 5 hours. After cooling, the mixture was charged to 1.0 liter of methanol over 15 min with stirring and the stirring was continued for a further 1 hour. The deposited solid was collected by filtering and dried under reduced pressure, to obtain 57 g of a pale whitish yellow solid.