Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[Br:8][CH2:9][C:10](Cl)=[O:11].C(N(CC)CC)C>C(OCC)C>[Br:8][CH2:9][C:10]([O:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:11]
Reactant: O=C(Cl)CBr
Reactant: CC(O)CC(=O)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(CC(=O)O)OC(=O)CBr
Temperature: 5 °C
Yield: 70 %

Procedure:
5 g (0.048 mol) of 3-hydroxybutyric acid and 0.062 mol of bromoacetyl chloride were dissolved in 100 ml of diethyl ether. This solution was stirred in an ice bath, and while maintaining the solution at a level of not higher than 5° C., 20 ml of diethyl ether containing 5.35 g (0.053 mol) of triethylamine was dropwise added over a period of 30 minutes. After the dropwise addition, the mixture was stirred at room temperature for 10 hours. Then, triethylamine hydrochloride was filtered off from the reaction solution, and the filtrate was washed three times with distilled water. The ether solution thereby obtained was dried over anhydrous sodium sulfate, and then diethyl ether was distilled off. As a result, a slightly yellow desired compound was obtained in a yield of 70%.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36]1([CH2:42][S:43][C:44]2[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([CH2:42][S:43][C:44]2[CH:45]=[C:46]([C:2]3[CH:35]=[CH:34][C:5]([CH2:6][C:7]4[N:8]([C:20]5[CH:21]=[C:22]([N:26]6[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]6)[CH:23]=[CH:24][CH:25]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=5[Cl:19])[N:11]=4)=[CH:4][CH:3]=3)[CH:47]=[CH:48][CH:49]=2)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: OB(O)c1cccc(SCC2CCCCC2)c1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4cccc(SCC5CCCCC5)c4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (119 mg, 0.2 mmol) was treated as described in general procedure G using 3-(cyclohexylmethylsulfanyl)phenylboronic acid (100 mg, 0.4 mmol, prepared according to general procedure I) to give 5-{3-[2-(3′-cyclohexylmethylsulfanyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:40])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH:9]1[CH3:41])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]([NH:29][C:28]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][C:14]4[C:15]5[CH2:16][CH2:17][NH:8][CH:9]([CH3:41])[C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:27][CH:26]=3)[CH:22]=[CH:23]2)=[O:40])[CH:35]=[CH:34][CH:33]=1
Reactant: CC1c2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c2CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1NCCc2c(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)ncnc21

Procedure:
A solution od 8-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (217 mg, 0.38 mmol), DCM (5 mL), and TFA (5 mL) is stirred at rt for 2 h. At that point the solution is concentrated in vacuo and the residue is separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 468.1 (M+1); 1H NMR (400 MHz, DMSO-do) δ ppm 10.39 (s, 1H), 8.51 (s, 1H), 8.28 (d, J=9.1 Hz, 1H), 8.06-8.15 (m, 2H), 7.97 (d, J=8.6 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.43-7.53 (m, 2H), 7.13 (dd, J=9.0, 2.4 Hz, 1H), 6.80 (d, J=3.5 Hz, 1H), 4.19 (q, J=6.6 Hz, 1H), 3.34-3.42 (m, 1H), 3.08-3.20 (m, 1H), 2.88 (t, J=5.7 Hz, 2H), 1.49 (d, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[C:13]=1[OH:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:26].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[C:20]([F:26])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[C:13]=1[OH:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(C)ccc2c1O
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(F)c2cc(C)ccc2c1O

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(1-hydroxy-3,6-dimethylnaphthalen-2-yl)acetate (0.62 g, 1.9 mmol) in MeCN (14 mL) cooled to 0° C. was treated with SelectFluor® fluorinating reagent (0.66 g, 1.9 mmol). The cold bath was removed and after 90 minutes the reaction was quenched with pH 7 buffer solution. The aqueous layer was extracted with EtOAc and the combined organics washed with brine and dried over anhydrous MgSO4 and filtered. Following concentration in vacuo, the desired product was obtained via silica gel chromatography followed by preparatory HPLC to afford (S)-ethyl 2-tert-butoxy-2-(4-fluoro-1-hydroxy-3,6-dimethylnaphthalen-2-yl)acetate. LCMS-ESI− (m/z): [M−H]− calcd for C20H24O4F: 347.4. found: 347.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:15][CH3:16])=[C:4]([CH:8]=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH2:15][CH3:16])=[C:4]([CH:8]=[C:9]2[CH2:10][CH2:11][N:12]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CCc1c(Br)cccc1C=C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(=Cc2cccc(Br)c2CC)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.2 %

Procedure:
To a solution of 4-[(3-bromo-2-ethylphenyl)methylidene]piperidine (D137) (0.53 g, 1.891 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added potassium carbonate (3.92 g, 28.4 mmol), followed by ethyl bromoacetate (0.190 mL, 1.702 mmol). The reaction solution was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over sodium sulphate, concentrated to afford ethyl {4-[(3-bromo-2-ethylphenyl)methylidene]-1-piperidinyl}acetate (D142) (0.693 g). MS (ES): C18H24BrNO2 requires 365.1. found 366.1 (M+H+).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12]([BH3-])#[N:13].[Na+]>CO>[NH2:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([NH:13][CH2:12][CH:2]2[CH2:3][CH2:4][CH2:8][CH2:9][CH2:10]2)[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(N)cc(C(=O)O)c1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Nc1cc(NCC2CCCCC2)cc(C(=O)O)c1

Procedure:
15.2 g. (0.1 mol) of 3,5-diaminobenzoic acid was placed in a 500 ml. round bottom flask to which 200 ml. of methanol was added. To the round bottom flask 11.22 g. (0.1 mol) of cyclohexane carboxyaldehyde was added. The solution was stirred for several minutes. While the solution stirred, 3.77 g. (0.06 mol) sodium cyanoborohydride was added slowly. After 5 hours the solution was filtered and then concentrated to dryness. The reaction mixture was dissolved in 200 ml. of 2M hydrochloric acid. The acid solution was extracted twice with 200 ml. ethyl acetate. The ethyl acetate solutions were combined and back washed with 200 ml. distilled water, and then dried over sodium sulfate. The solution was concentrated to dryness and 4.18 gm. of product was collected. The product was then purified by column chromatography using a solution of tetrahydrofuran/ethanol/water/ammonium hydroxide in the following ratio--10:3:1:0.04 as the eluent. Structural verification was obtained by carbon magnetic resonance, proton magnetic resonance and infra-red analysis.
Reaction SMILES: P(=O)(O)(O)[OH:2].CS([C:9]1[N:18]2[C:12]([CH2:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[CH:16]=[CH:17]2)=[N:11][N:10]=1)=O>O>[N:11]1[NH:10][C:9](=[O:2])[N:18]2[CH:17]=[CH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13][C:12]=12
Reactant: CS(=O)c1nnc2n1C=Cc1ccccc1C2
Reactant: O=P(O)(O)O
Solvent: O
Product: O=c1[nH]nc2n1C=Cc1ccccc1C2

Procedure:
To 3 ml of 80% phosphoric acid was added 0.245 g of 3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine and the mixture was heated on an oil bath at 130°-140° C. for 1 hour. Following addition of water, the crystals were collected by filtration and dried. By the above procedure was obtained 2,11-dihydro-3H-s-triazolo[3,4-b][3]benzazepin-3-one. Recrystallization from chloroform-methanol yielded colorless needles, m.p. 210°-211° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[O:12].[H-].[Na+].[CH3:15]I>CN(C=O)C.Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:15])[CH:6]=[C:5]2[CH:11]=[O:12]
Reactant: CI
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C=O)c2cc(F)ccc21
Temperature: 0 °C
Yield: 38.9 %

Procedure:
In DMF (100 ml) was dissolved 5-fluoroindol-3-carbaldehyde (5.17 g, 36.7 mmol). To the resulting solution was added sodium hydride (60% in oil, 1.39 g, 34.9 mmol) in portions under stirring at 0° C. After the reaction mixture was stirred at the same temperature for 1 hour, methyl iodide (4.57 ml, 73.4 mmol) was added thereto at 0° C. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured in 1N HCl, followed by extraction with ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was crystallized by adding thereto chloroform/hexane. The crystals thus precipitated were collected by filtration under reduced pressure and dried under reduced pressure to give 5-fluoro-1-methylindole-3-carbaldehyde (2.53 g, 39%) as a white crystalline powder.
Reaction SMILES: Cl.[F:2][C@H:3]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH:19]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([F:32])[CH:26]=2)[C:20]1=[O:33].CCN(C(C)C)C(C)C>CN(C=O)C>[F:2][C@H:3]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=2)[CH2:7][CH2:6][N:5]([CH:19]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([F:32])[CH:26]=3)[C:20]2=[O:33])[CH2:4]1
Reactant: COc1ccc([C@@H]2CCNC[C@H]2F)cc1F
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H]2CCN(C3CCN(Cc4ccc(C)c(F)c4)C3=O)C[C@H]2F)cc1F
Temperature: 120 °C
Yield: 126.1 %

Procedure:
A mixture of (3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine hydrochloride (30 mg, 0.11 mmol, from step G), 3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (54 mg, 0.19 mmol, intermediate 6,) and DIPEA (0.02 mL, 0.11 mmol) in DMF (3 mL) was heated to 120° C. for 90 min in a microwave reactor. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure to obtain 60 mg of 3-((3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)-pyrrolidin-2-one (diastereomeric pair), which was used in the next step without purification. LCMS (Method P) RT=1.12 min, m/z 433 (M+H+).
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:9])[CH2:7][OH:8].Br[CH2:11][CH:12]=[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>C1(C)C=CC=CC=1>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:12][CH2:11][O:8][CH2:7][CH2:6][OH:9])[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(C(=CCBr)c2ccccc2C)c1
Reactant: OCCO
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: COc1cccc(C(=CCOCCO)c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of n-butyllithium in hexanes (32.2 ml, 2.5 M) was added dropwise under a nitrogen atmosphere to ethylene glycol (60 ml) at 10° C. When addition was complete the mixture was stirred for 0.5 h at room temperature. A solution of 3-bromo-1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propene (24.4 g, 77 mmol) in toluene (50 ml) was added and the reaction mixture was stirred at room temperature for 4 days and at 65° C. for 6 h. The solvent was evaporated in vacuo, water (250 ml) was added and the mixture was extracted with ethyl acetate (2×200+100 ml). The combined organic phases was dried over magnesium sulphate and the solvent was evaporated in vacuo. Flash chromatography of the residue on silica gel (320 g) using a mixture of cyclohexane and ethyl acetate gradient as eluent provided 16.6 g (72%) of 2-(3-(3-methoxyphenyl)-3-(2-methylphenyl)-2-propen-1-yloxy)ethanol.
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH2:7][C:8]1[C:9]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[C:10]2[C:14](=[C:15]([CH3:19])[C:16]=1[O:17][CH3:18])[CH2:13][O:12][C:11]2=[O:20])[CH:4]=[O:5])[CH3:2].[Li+].[BH4-]>CO.C1COCC1>[OH:5][CH2:4][C:3]([CH2:1][CH3:2])=[CH:6][CH2:7][C:8]1[C:9]([O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])=[C:10]2[C:14]([CH2:13][O:12][C:11]2=[O:20])=[C:15]([CH3:19])[C:16]=1[O:17][CH3:18]
Reactant: CCC(C=O)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 73.2 %

Procedure:
A solution of 2-ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal (1.3 g, 3.30 mmol) in methanol (10 mL) and THF (10 mL) was cooled to 0° C. A solution of CeCl3 (8.25 mL, 0.4M, MeOH: H2O, 9:1) was added, followed by LiBH4 (1.66 mL, 3.30 mmol of a 2M solution in THF). The ice bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for an additional 40 minutes whereupon TLC indicated complete consumption of starting aldehyde. The reaction was worked up by addition of aqueous 1N HCl and the product was extracted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 948 mg (73%) of the product as colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 1.07 (t, 3H), 1.20 (dd, 2H, J=7, 8 Hz), 2.13 (s, 3H), 2.38-2.50 (m, 2H), 3.77 (s, 3H), 3.99 (s, 2H), 4.27 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H), 5.34 (t, J=7.2 Hz, 1H) ppm.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH2:12].C(N(CC)CC)C.[Cl:26][CH2:27][C:28]1[N:32]=[C:31](Cl)[S:30][N:29]=1>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:12][C:31]1[S:30][N:29]=[C:28]([CH2:27][Cl:26])[N:32]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(C)C
Reactant: ClCc1nsc(Cl)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)Nc1nc(CCl)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.3 %

Procedure:
A solution of N-L-leucyl-L-proline methyl ester hydrochloride (2.22 g, 8 mmol) and triethylamine (2.8 mL, 20 mmol) in DMF (50 mL) was stirred at room temperature for 15 min. Then, a solution of 3-chloromethyl-5-chloro-[1,2,4]thiadiazole (0.34 g, 2 mmol) in DMF (10 mL) and tetra-butylammonium bromide (100 mg) were added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with water and extracted into ethyl acetate. The organic layer was washed with a saturated ammonium chloride solution, brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a mixture of hexane and ethyl acetate (7/3, 6/4 and 1/1) afforded N-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl ester as a white foam, 0.49 g, 65.3% yield. 1H-NMR (CDCl3) δ 7.56 (d, J=8.2 Hz, 1H, NHCH), 4.78 (m, 1H, NHCH), 4.60 (dd, J=8.5, 4.6 Hz, 1H, CHCO2), 4.46 (s, 2H, CH2Cl), 4.09 (m, 1H), 3.69-3.73 (m, 1H), 3.74 (s, 3H, OMe), 2.25-2.30 (m, 1H), 1.68-2.11 (m, 6H), 0.99-1.03 (2d, 6H, 2Me); MS (m/z) 375 (M++1), 357 305, 246, 218,162,150, 130.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:22])[CH2:20]Cl)=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:23][C:24](=[O:35])[C@:25]([O:31]C(=O)C)([CH3:30])[C:26]([F:29])([F:28])[F:27]>O.CC(C)=O>[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:22])[CH2:20][N:2]([CH3:3])[CH3:1])=[CH:16][CH:17]=2)[CH:8]=[CH:7][C:6]=1[NH:23][C:24](=[O:35])[C@:25]([OH:31])([CH3:30])[C:26]([F:28])([F:29])[F:27]
Reactant: CNC
Reactant: CC(=O)O[C@](C)(C(=O)Nc1ccc(Sc2ccc(NC(=O)CCl)cc2)cc1Cl)C(F)(F)F
Solvent: O
Solvent: CC(C)=O
Product: CN(C)CC(=O)Nc1ccc(Sc2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1

Procedure:
Dimethylamine (0.17 ml of a 40% solution in water) was added to a solution of (R)-N-{2-chloro-4-[4-(2-chloroacetylamino)phenylsulphanyl]phenyl}-2-acetoxy-2-methyl-3,3,3-trifluoropropanamide (Method 19) (0.25 g) in acetone (1.5 ml). After 24 hours volatile material was removed by evaporation and the residue was dissolved in ethyl acetate, washed with water, and the organic layer was poured onto a Varian Chem Elut column. Elution with ethyl acetate gave the title compound (0.25 g) as a foam. NMR: 1.6 (s, 3H), 3.1 (s, 2H), 3.3 (s, 6H), 7.2 (d, 1H), 7.3 (s, 1H), 7.4 (d, 2H), 7.7 (m, 3H), 7.9 (d, 1H), 9.7 (s, 1H) 9.9 (s, 1H); MS (ESP−): 474.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]>>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:26]=1[O:27][CH3:28]
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: COc1cc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc(OC)c1OC

Procedure:
The title compound was prepared from the product of Example 65A and 3,4,5-trimethoxyphenylboronic acid according to General Method B: 1H NMR (500 MHz, CDCl3) δ ppm 8.16 (s, 2 H), 7.03 (s, 1 H), 6.73 (s, 2 H), 4.1 (s, 1 H), 3.91 (s, 9H.), 3.73-3.37 (m, 5 H), 3.05-3.00 (m, 4 H), 2.27-2.17 (m, 5 H); LC-MS Method D (ESI+) m/z 396.0 (M+H)+, retention time 1.32 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[OH:12])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[C:6]=1[OH:12])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)ccc1O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
5-Bromo-2-hydroxy-benzoic acid ethyl ester (40 g, 214 mmol) is suspended in sulfuric acid (200 mL) and the reaction cooled to zero in an ice bath. The reaction is equipped with an overhead stirrer and then the nitric acid (20 mL) in sulfuric acid (40 mL) is added dropwise to the solution over the course of 30 minutes. After the addition the ice bath is removed and the reaction warmed to room temperature. The reaction is stirred at room temperature for 16 hours. When complete the reaction is poured onto crushed ice and the resulting yellow solid is collected by vacuum filtration and washed with ice cold water. The solid dried in vacuum over overnight to give the 45 g (91%) of title compound that is used without further purification. LCMS (ESMS): m/z 291.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[O:27]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:25][C:26](=[O:27])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)c1ccccn1

Procedure:
150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 578.71 mg (1.77 mmol) of cesium carbonate, 199.40 mg (0.709 mmol) of 2-bromo-1-pyrid-2-ylethanone hydrobromide and 10 mL of acetonitrile were used in the reaction. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 0% B, t 15 min 50% B, t 25 min 70% B), 218 mg of (8S)-2-chloro-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:40](Cl)(=[O:43])[CH2:41][CH3:42].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH3:39])[CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:40](=[O:43])[CH2:41][CH3:42])=[CH:7][CH:6]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:38])[C:30]=2[CH:31]=1
Reactant: CCC(=O)Cl
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2ccc(N)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1ccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)cc1
Reaction time: 0.25 h
Yield: 16.7 %

Procedure:
To a solution of N-[1-(4′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (85 mg, 0.15 mmol) in dichloromethane (2 mL) was added propanoyl chloride (15.6 mg, 0.17 mmol). Triethylamine (30 mg, 0.30 mmol) was added, and the resultant mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by Gilson preparative HPLC (Xterra Prep RP, 30×100 mm, 45 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 25 to 55% over 15 min, UV detection at 214 nm) to give 15.7 mg (17%) of the title compound as an off white solid. MS (ES) m/e 625.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[F:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([F:28])[CH:27]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=3)[CH2:34][CH2:33]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 78 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.