Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:41][CH2:42][CH3:43])[CH2:5][N:6]([CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:7](=[O:31])[C@@H:8]([NH:20]C(=O)OCC1C=CC=CC=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH3:2]>CO.[Pd]>[NH2:20][C@@H:8]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[C:7]([N:6]([CH2:5][CH:4]([O:41][CH2:42][CH3:43])[O:3][CH2:1][CH3:2])[CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31]
Reactant: CCOC(CN(CCCc1ccccc1)C(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1)OCC
Agent: [Pd]
Solvent: CO
Product: CCOC(CN(CCCc1ccccc1)C(=O)[C@@H](N)Cc1cccc2ccccc12)OCC
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of (S)-benzyl 1-((2,2-diethoxyethyl) (3-phenylpropyl)amino)-3-(naphthalen-1-yl)-1-oxopropan-2-ylcarbamate (Compound XV-32) 21.4 g (36.8 mmol) in methanol 200 ml, 10% of palladium on carbon (8 g) was added, then the mixture was stirred at H2 atmosphere overnight. The mixture was filtered and the filtrate was evaporated to obtain the title compound 14.5 g (yield 88%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:12]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)#[N:36].CO>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C@H:12]([O:14][CH2:15][C:16]3([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[CH3:13])[CH:3]=2)=[CH:39][CH:38]=1)#[N:36]
Reactant: C[C@@H](OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc(C(F)(F)F)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(-c2ccc(C#N)cc2)cc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
(R)-tert-Butyl 4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (0.35 g, 0.65 mmol), 4-cyanophenylboronic acid (284 mg, 1.93 mmol), and tetrakis(triphenylphosphine) palladium(0) (75 mg, 0.07 mmol) were combined in dry tetrahydrofuran (5 mL) in a microwave tube and sealed. After flushing with nitrogen, 2.3 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and purified by flash chromatography on silica gel (15% ethyl acetate/hexanes) to afford 300 mg (82%) as an oil. LC/MS: tR=3.51 min, 565.23 (MH)+. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C)C=O.C(N(CC)CC)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:7]
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])c(O)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 57.3 %

Procedure:
To a solution of 3-hydroxy-4-nitrobenzoic acid (10.00 g) in dry N,N-dimethylformamide (150 ml), 1-ethyl-3- (3-dimethylaminopropyl ) carbodiimide hydrochloride (12.56 g) , 1-hydroxybenzotriazole (8.86 g) , triethylamine (7.18 g) , and morpholine (5.71 g) were added successively. A mixture was stirred at room temperature for 23 hours, and the solvent was evaporated in a bath at 80° C. under reduced pressure to a solution volume of approximately 100 ml. Ethyl acetate (400 ml) was added to the residue, and the mixture was washed with 1N HCl aqueous solution (100 ml), water (200 ml), saturated sodium carbonate aqueous solution (50 ml), and water (150 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated to obtain the compound ([3]-(32)-587) (7.89 g) as a yellow solid.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.N1C=CN=C1.[Br:22]C(Br)(Br)Br>C(Cl)Cl>[Br:22][CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCOC(CCO)C1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(CCBr)C1
Reaction time: 8 h
Yield: 95 %

Procedure:
To a 25 mL round-bottomed flask at 0° C. was added tert-butyl 2-(2-hydroxyethyl)morpholine-4-carboxylate (0.176 g, 0.762 mmol), DCM (4 mL), 1H-imidazole (0.104 g, 1.524 mmol), perbromomethane (0.379 g, 1.143 mmol), and triphenylphoshphine (0.190 g, 0.723 mmol). The mixture was stirred overnight slowly reaching room temperature. The yellow solution was further diluted with 50 mL of DCM, washed with water, brine, dried over sodium sulfate, and filtered. The crude product was then pushed through a plug of silica gel and the solvent was removed to give 213 mgs of a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (s, 9H), 1.94 (q, J=6.86 Hz, 1H), 2.56-2.66 (m, 1H), 2.76-2.91 (m, 1H), 3.35-3.47 (m, 4H), 3.50-3.61 (m, 1H), 3.68 (br. s., 1H), 3.74-3.86 (m, 2H).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:18].[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][Cl:23].C(=O)([O-])O.[Na+]>CO>[ClH:23].[ClH:18].[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][S:15][C:13]1[NH:14][C:10]2[CH:9]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=[CH:16][C:11]=2[N:12]=1
Reactant: CN(C)CCCl
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CN(C)CCSc1nc2ccc(Cc3ccccc3)cc2[nH]1
Yield: 84.8 %

Procedure:
According to the method described in Example 2 g (25 mmoles) of 5-benzyl-benzimidazoline-2-thione, 4.32 g (30 mmoles) of 2-(dimethylamino)-ethylchloride hydrochloride and 2.55 g of sodium hydrogencarbonate are refluxed in methanol. The salt is filtered off, the filtrate is concentrated and treated with aqueous sodium hydroxide solution and dichloromethane. The organic phase is separated, concentrated and the salt is precipitated by adding hydrochloric ether. 8.15 g (84.8%) of 2-(2-dimethylaminoethylthio)-5-benzyl-benzimidazole dihydrochloride are obtained, which melts at 204° C. after recrystallization from isopropanol.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Br.[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[CH:35][C:36](=[O:39])[NH:37][N:38]=2)=[CH:29][CH:28]=1.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[CH:35][C:36](=[O:39])[NH:37][N:38]=3)=[CH:29][CH:28]=2)=[O:9])[CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: NCCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
868 mg of nicotinic acid, 954 mg of N-hydroxybenzotriazole and triethylamine (1.23 ml) were added to a dimethylformamide solution (50 ml) containing 2.0 g of 6-[4-(4-aminobutoxy)phenyl]pyridazin-3(2H)-one hydrobromide. 1.35 g of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide was added to the mixture at 0° C., and the resulting mixture was stirred at room temperature for 6 hours and then poured into ice water, and precipitated crystal was collected by filtration. The crystal was recrystallized from ethanol to obtain 1.75 g of 6-[4-(4-(pyridin-3-ylcarbonylamino)butoxy)phenyl]pyridazin-3(2H )-one.
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([CH2:15][C@@H:16]([NH:22][C:23]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[CH2:37][CH2:36][C:35]4[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=4[NH:33][C:32]3=[O:42])[CH2:27][CH2:26]2)=[O:24])[C:17]([O:19]CC)=[O:18])=[CH:7][C:6]=1[Cl:43]>O.C1COCC1.Cl>[NH2:4][C:5]1[C:10]([C:11]([F:13])([F:14])[F:12])=[CH:9][C:8]([CH2:15][C@@H:16]([NH:22][C:23]([N:25]2[CH2:26][CH2:27][CH:28]([N:31]3[CH2:37][CH2:36][C:35]4[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=4[NH:33][C:32]3=[O:42])[CH2:29][CH2:30]2)=[O:24])[C:17]([OH:19])=[O:18])=[CH:7][C:6]=1[Cl:43]
Reactant: CCOC(=O)[C@@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)NC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.64 g (15 mmol) lithium hydroxide hydrate in 100 mL water was added to a suspension of 6.0 g (10.31 mmol) ethyl (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionate in 50 mL THF. In each case 100 mL water and THF were again added to this suspension, and a solution formed after 5 min. This was stirred for 1 hour at RT, the THF was eliminated i.vac., the remainder was diluted with 100 mL water and 1 M aqueous hydrochloric acid solution was added dropwise while cooling with ice until an acid reaction was obtained. The precipitated substance was filtered, washed with water and dried in the air.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[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[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[CH:32]=1)=[O:30])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-isobutylamino-phenyl)-carbamic acid tert-butyl ester (Example J34) (313 mg, 1.0 mmol) and 3-(3-imidazol-1-yl-phenyl)-3-oxo-propionic acid tert-butyl ester (Example K26) (286 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (330 mg, 63%).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH2:23]O)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CO.Cl.[NH2:32][OH:33].C(=O)(O)[O-].[K+]>O>[CH3:27][Si:2]([CH3:28])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22]/[CH:23]=[N:32]/[OH:33])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: CCC(CCO)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCC(C/C=N/O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal (60 mg, 0.0002 mol) from Example 498, Step 2 in methanol (2 mL, 0.05 mol) was added hydroxylamine hydrochloride (16 mg, 0.00022 mol) and potassium bicarbonate (22 mg, 0.00022 mol). The reaction was stirred at room temperature for 2 h, water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give (1E)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal oxime as a semisolid residue (50 mg, 80%). LC/MS (M+H)+: m/z=415.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10](I)[N:9]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](I)[CH:23]=[CH:22][N:21]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:24]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:19])[CH:25]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(I)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-iodo-6-trifluoromethyl-pyrimidine (example A.3) (1.21 g, 3.15 mmol) and commercially available 2-chloro-4-iodo-pyridine [CAS No. 153034-86-7] (765 mg, 3.2 mmol) according to the general procedure IVc protocol a. Obtained as a light yellow solid (0.53 g, 45%). MS (ISP) 369.8 [(M+H)+]; mp 151° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:7]=1)(=[O:4])=[O:3].[CH:18](OC)(OC)[O:19][CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH:18]([O:19][CH3:20])[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:8]=2[CH:7]=1)(=[O:4])=[O:3]
Reactant: COC(OC)OC
Reactant: CC(C)(CO)c1cc(OS(C)(=O)=O)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC1OCC(C)(C)c2cc(OS(C)(=O)=O)ccc2O1
Yield: 79 %

Procedure:
4-Hydroxy-3-(2-hydroxy-1,1-dimethylethyl)phenyl methanesulphonate (10.4 parts) (from Example 1) was reacted with trimethyl orthoformate (127 parts) in the presence of p-toluenesulphonic acid (0.05 parts) as in Example 20 to produce 4,5-dihydro-2-methoxy-5,5-dimethyl-1,3-benzodioxepin-7-yl methanesulphonate (9.5 parts, 79% yield) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:35])=[C:32]([CH:34]=1)[NH2:33].C[Al](C)C>>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:35])=[C:32]([NH:33][C:19](=[O:20])[C:18]2[CH:23]=[CH:24][C:15]([N:11]3[C:12](=[O:14])[NH:13][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10]3)=[CH:16][C:17]=2[O:25][CH3:26])[CH:34]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Cc1ccc(Cl)cc1N
Agent: C[Al](C)C
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cc(Cl)ccc1C
Yield: 45 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 5-chloro-2-methyl aniline (0.057 g, 0.39 mmol) and trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.057 g of desired product. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 4.05 (s, 3H), 7.13 (d, J=9.9 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.49 (t, 1H), 7.59 (d, 1H), 7.61-7.75 (m, 2H), 7.84 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 8.19 (s, 1H), 9.94 (br s, 1H), 12.83 (br s, 1H); MS (m/z): 487.11 [M]+.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[CH2:8]([N:11]([CH3:36])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)=O)=[C:21]([NH:34][CH3:35])[CH:20]=1)[CH:9]=[CH2:10].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:8]([N:11]([CH3:36])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:22]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=3)=[N:5][C:6](=[O:7])[N:34]2[CH3:35])=[CH:23][CH:24]=1)[CH:9]=[CH2:10]
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(NC)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCN(C)CCCCCCOc1ccc2c(-c3ccc(Br)cc3)nc(=O)n(C)c2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 0.16 ml of chlorosulphonyl isocyanate in 0.8 ml of methylene chloride is added dropwise at 0° C. to a solution of 0.69 g of [4-[6-(allyl-methyl-amino)-hexyloxy]-2-methylamino-phenyl]-(4-bromo-phenyl)-methanone in 4 ml of methylene chloride. After 3 hrs. at room temperature the mixture is again cooled to 0° C. and 0.8 ml of chlorosulphonyl isocyanate in 0.5 ml of methylene chloride is added dropwise. After 1 hr. at room temperature the mixture is worked-up with saturated sodium bicarbonate solution/methylene chloride and purified over silica gel with methylene chloride/methanol/25% aqueous ammonium hydroxide (95:5:0.5). There is obtained 0.26 g of 7-[6-(allyl-methyl-amino)-hexyloxy]-4-(4-bromo-phenyl)-1-methyl-1H-quinazolin-2-one, MS: m/e 484 (M+H+, 1 Br).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Cl.CCN(CC)CC.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:20](=[O:21])[CH2:19][Cl:18]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of L-proline methyl ester.HCl (8.04 g, 43 mmol) in CH2Cl2 (86.0 ml) at 0° C. was added NEt3 (12.0 mL, 86 mmol), followed by chloroacetyl chloride (1.1 equiv, 3.72 g, 47 mmol) dropwise via syringe. The reaction mixture was allowed to warm to room temperature with stirring. After 16 h, the mixture was diluted with sat. aqueous NaHCO3 and the organic layer was removed. The aqueous portion was extracted with CH2Cl2 (25 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford N-chloroacetyl-L-proline methyl ester as a light brown oil (7.85 g, 38 mmol). A portion of the resulting oil (5.25 g, 26 mmol) was dissolved in butanone (51 mL) at RT and NaN3 (3.67 g, 51 mmol) was added in one portion. The reaction vessel was fitted with a reflux condenser and the heterogenous mixture was heated at 80° C. for 20 h. The resulting mixture was cooled to room temperature, filtered and concentrated in vacuo to afford N-azidoacetyl-L-proline methyl ester as a light red oil (5.37 g, 25 mmol). A portion of the oil (1.97 g, 9 mmol) was dissolved in anhydrous PhMe (38 mL) and PPh3 (2.55 g, 10 mmol) was added in one portion. After gas evolution steadied, the reaction mixture was heated at 90° C. for 20 h. The reaction mixture was concentrated in vacuo and triturated with a 1:1 mixture of Et2O/hexanes in order to remove the desired diketopiperazine product from the bulk of phosphine oxide byproduct. The trituration solution was concentrated and the resulting residue was purified by flash column chromatography on silica gel (elution: 1% MeOH to 10% MeOH in 1:1 EtOAc/PhMe+1% NEt3). The resulting diketopiperazine lactim ether product, (S)-1-methoxy-6,7,8,8a-tetrahydropyrrolo[1,2-a]pyrazin-4(3H)-one (13), (1.43 g, 8 mmol, 80% yield, 3 steps) was obtained as a light yellow oil: TLC (60% EtOAc in hexane), Rf: 0.20 (CAM); [α]D25=+102 (c 2.07, CH2Cl2); IR (film): 2951, 2984, 2889, 2360, 2107, 1685, 1457, 1322, 1263, 1022, 751, 673, 625, 573 cm−1; 1H NMR (400 MHz, CDCl3) 4.21 (dd, J=9.5 Hz, 1.6 Hz, 1H), 4.11 (d, J=4.9 Hz, 1H) 4.03 (m, 1H), 3.68 (s, 3H), 3.65 (m, 1H) 3.47 (m, 1H), 2.25 (m, 1H), 2.03 (m, 1H), 1.83 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 166.4, 161.8, 56.5, 53.3, 52.3, 44.2, 29.3, 22.2; Exact mass calcd for C8H12N2O2 [M+Na+], 191.0791. Found 191.0790.
Reaction SMILES: [NH2:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]1=[NH:17].[CH:18]([O-])([O-])OCC>>[CH2:12]([N:4]1[C:5]2[N:6]=[CH:7][NH:8][C:9]=2[C:10](=[O:11])[N:2]2[N:1]=[CH:18][N:17]=[C:3]12)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOC([O-])[O-]
Reactant: CCCCCn1c(=N)n(N)c(=O)c2[nH]cnc21
Product: CCCCCn1c2nc[nH]c2c(=O)n2ncnc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 20.3 %

Procedure:
The mixture of 1-amino-2-imino-3-pentyl-1,2,3,7-tetrahydro-6H-purin-6-one (0.10 g, 0.4 mmol) and ethyl orthoformate (5 mL, 30 mmol) was stirred at 100° C. for 6 hours. The reaction mixture was concentrated and purified by preparative LCMS to yield the desired product (20 mg, 20%). LCMS calculated for C11H15N6O (M+H): 247.1. found: 247.1.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:10][C:11]([F:13])([F:12])[CH:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1)[OH:8]
Reactant: Cc1ccc(C=O)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C(F)(F)F)cc1
Yield: 125.3 %

Procedure:
According to Reference Example 8-12, by use of p-tolualdehyde (500 μL, 4.24 mmol), (trifluoromethyl)trimethylsilane (752 μL, 5.09 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 424 μL, 0.424 mmol) and tetrahydrofuran (10 mL), the mixture was stirred and reacted at room temperature for 30 minutes. Thus, 4-(2,2,2-trifluoro-1-hydroxyethyl)toluene (Compound DE) (1.01 g, yield: quantitative) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[C:12]([CH2:17][NH2:18])(=[O:16])[CH:13]([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][CH2:17][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(=O)CNC(=O)c1ccc(Cl)cc1
Yield: 99 %

Procedure:
4.5 g of 4-chlorobenzoyl chloride are added dropwise to a mixture of 4 g of isobutyrylmethylamine hydrochloride, 9.8 g of sodium bicarbonate, 200 ml of ethyl acetate and 100 ml of water at 5° C. to 10° C. under stirring. The mixture is further stirred at room temperature for 3 hours. The ethyl acetate layer is collected, and said layer is washed with water, dried and then condensed under reduced pressure to remove solvent. 6.1 g of N-(4-chlorobenzoyl)isobutyrylmethylamine are obtained. Yield: 87.5%.
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][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(C(F)(F)F)cc21
Product: CC1c2cc(C(F)(F)F)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Yield: 18 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.