Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1.N1C=CN=C1.CN(C)C=O>C(OCC)(=O)C>[Si:5]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.7 mL of t-butylchlorodiphenyl silane was added to the mixture of 5 g of 1-(4-hydroxyphenyl)-1-ethanone, 3 g of imidazole, and 70 mL of N,N-dimethylformamide, and stirred overnight at room temperature. The reaction mixture was added with 200 mL of ethyl acetate, washed with water and saturated brine in the subsequent order, and the obtained organic layer was dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to obtain 11.7 g of 1-(4-{[t-butyl(diphenyl)silyl]oxy}phenyl)-1-ethanone [79-1] as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]#[N:19])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:37][C:38]1[CH:39]=[C:40]([C:44]2[N:45]([CH3:49])[CH2:46][CH2:47][N:48]=2)[CH:41]=[CH:42][CH:43]=1>CS(C)=O>[CH3:49][N:45]1[CH2:46][CH2:47][N:48]=[C:44]1[C:40]1[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=1)[O:37][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]#[N:19])[CH:3]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(Oc2cc(Cl)nc(-c3ccccc3)n2)c1
Reactant: CN1CCN=C1c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CN1CCN=C1c1cccc(Oc2cc(Oc3cc(C#N)ccc3OCc3ccccc3)nc(-c3ccccc3)n2)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 37.6 %

Procedure:
To 3-[(6-chloro-2-phenylpyrimidin-4-yl)oxy]-4-(benzyloxy)benzonitrile (1.0 g, 2.4 mmol) in DMSO (12 mL) was added Cs2CO3 (0.8 g, 2.5 mmol) and 2-(3-hydroxyphenyl)-1-methylimidazoline (0.44 g, 2.5 mmol). After stirring in an oil bath at 50° C. for 24 hours, the reaction was partitioned with water and ethyl acetate. The layers were separated, washed with water and brine, dried (Na2SO4), and the solvent was removed in vacuo. The residue was chromatographed on silica gel with CH2CL2/MeOH/NH4OH (120/5/1) to give 0.5 g of 3-[(6-[3-(1-methylimidazolin-2-yl)phenoxy]-2-phenylpyrimidin-4-yl)oxy]-4-(benzyloxy)benzonitrile.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40]([N:18]([CH2:17][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1)=[O:41]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(-c2cccc(C#N)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2cccc(C#N)c2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 22 (386 mg, 0.86 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (238 mg, 1.03 mmol) using Method D to give the title compound.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1>O>[F:13][C:14]([F:24])([F:25])[C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH:21][C:2]2[N:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:17][CH:16]=1
Reactant: NOCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cccnc1Cl
Solvent: O
Product: CCOC(=O)c1cccnc1NOCc1ccc(C(F)(F)F)cc1
Temperature: 120 °C
Yield: 41 %

Procedure:
The mixture of ethyl 2-chloronicotinate (1.4 g, 7.54 mmol) and O-(4-(trifluoromethyl)benzyl)hydroxylamine (2.163 g, 11.31 mmol) was heated at 120° C. for 6 h. Reaction mixture was diluted with water and extracted with EtOAC. The organic layer was separated and distilled out to get crude product which was column purified using 15-20% EtOAc in hexane to get the titled compound in 41% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][OH:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]#[C:25][C:26]3[CH:40]=[CH:39][C:29]([O:30][CH2:31][CH2:32][NH:33][CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[C:28]([CH3:41])[CH:27]=3)=[N:22][CH:23]=2)=[CH:14][CH:13]=1>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]#[C:25][C:26]3[CH:40]=[CH:39][C:29]([O:30][CH2:31][CH2:32][N:33]([CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:8][CH2:9][OH:10])=[C:28]([CH3:41])[CH:27]=3)=[N:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCNC1CCCC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN(CCO)C1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
55 mg (0.40 mmol) of potassium carbonate and 28 μL (0.40 mmol) of 2-bromoethanol was added to a solution of 86.2 mg (0.20 mmol) of (2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclopentylamine in 2 mL of DMF and the mixture was stirred for 24 hours at RT. Another 55 mg (0.40 mmol) of potassium carbonate and 28 μL (0.40 mmol) of 2-bromoethanol were added and the mixture was stirred for 8 hours at 50° C. The reaction mixture was evaporated down in vacuo and the residue was taken up in DCM. The organic phase was washed with water, dried over sodium sulfate, and evaporated down in vacuo. The crude product was purified by MPLC (silica gel, EtOAc/MeOH 95:5) and then MPLC (Alox, cyc/EtOAc 8:2) and triturated with DIPE. Yield: 2.9 mg (3% of theoretical); C29H31ClN2O2 (M=475.021); calc.: molpeak (M+H)+: 475/477 (Cl); found: molpeak (M+H)+: 475/477 (Cl); Rf value: 0.26 (silica gel, EtOAc/MeOH 95:5)
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:3][CH2:2]1.S(Cl)([Cl:15])=O>>[CH:4]1([CH2:7][CH2:8][CH2:9][C:10]([Cl:15])=[O:12])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: O=C(O)CCCC1CCCCC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCCC1CCCCC1

Procedure:
50 g of 4-cyclohexanebutyric acid are refluxed for 4 hours in 160 ml of thionyl chloride. After evaporation of the excess thionyl chloride, the expected product is distilled off. b.p.=70-80° C. at 400 Pa.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10](=O)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].Cl.[NH2:22][NH:23][C:24]([NH2:26])=[NH:25]>Cl.C(O)C>[ClH:1].[C:24]([NH:23][N:22]=[C:10]([CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH:9]=[CH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[NH:25])[NH2:26]
Reactant: O=C(C=Cc1ccccc1Cl)C=Cc1ccccc1Cl
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: N=C(N)NN=C(C=Cc1ccccc1Cl)C=Cc1ccccc1Cl
Yield: 124.6 %

Procedure:
Following the general procedure of Example 1, 9.1 grams of 1,5-bis(2-chlorophenyl)-1,4-pentadien-3-one, 4 grams of amino-guanidine hydrochloride, 10 drops of concentrated hydrochloric acid and 250 ml. of ethanol, and employing a 6.5 hour reflux period, 7.4 grams of the title compound is obtained, melting at 243°-244° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[S:6].S(=O)(=O)(O)O.[CH3:22]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([O:7][CH3:22])=[S:6]
Reactant: CO
Reactant: Cc1cc(C(O)=S)ccc1-c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=S)c1ccc(-c2ccccc2)c(C)c1

Procedure:
A mixture was 85 g of 3-methyl-4-phenylthiobenzoic acid, 20 ml of concentrated sulfuric acid, and 1.2 liters of methanol was refluxed for 4 hours while stirring. After reaction, the reaction mixture was concentrated in vacuo, and 1.5 liters of ethyl acetate was added to the residue, and the mixture was washed with saturated brine (400 ml×3), and dried with anhydrous sodium sulfate, concentrated in vacuo, and methyl 3-methyl-4-phenylthiobenzoate was obtained (80.33 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:25])[CH2:16][NH:17]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:27]>O1CCOCC1.C(OCC)C>[ClH:27].[CH2:1]([O:8][C:9](=[O:26])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:25])[CH2:16][NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.4 %

Procedure:
N-t-butyloxycarbonylglycyl-L-proline benzylester (18.12 g, 50 mmole) was dissolved in 4N hydrochloric acid in dioxane (220 ml) solution, and stirred for 20 minutes at room temperature. The solvent was distilled off and the residue thus obtained was powdered in diethyl ether to obtain glycyl-L-proline benzylester hydrochloride (yield: 13.21 g; 88.4%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17]>O1CCOCC1.O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[CH:7]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Reactant: NCC(O)CO
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1c(NCC(O)CO)cc(Cl)cc1NCC(O)CO

Procedure:
A mixture of 0.1 mole (22.6 g) of 2,4,6-trichloro nitrobenzene and 54.7 g of 3-amino-1,2-propanediol in 20 ml of dioxan was refluxed for 4 hours followed by evaporation of the dioxan under reduced pressure. The oil obtained was diluted in about 300 ml of water. The desired product was obtained using HPLC in two stages. About 200 ml of the aqueous solution of the product containing 3-amino-1,2-propanediol were injected onto a C18RD chromatographic column (Instrument: Waters Prep 500). The desired product was eluted using 35% methanol-65% water solution. After evaporation of the fractions containing the desired product, a dry extract was obtained which was recrystallized from 96° alcohol. The product melted at 146° C.
Reaction SMILES: C=O.[Cl-].[Mg+2].[Cl-].[Br:6][C:7]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:8]=1[OH:15].C[CH2:17][O:18]CC>C1COCC1>[Br:6][C:7]1[C:8]([OH:15])=[C:9]([CH:10]=[C:11]([S:13][CH3:14])[CH:12]=1)[CH:17]=[O:18]
Reactant: CCOCC
Reactant: CSc1ccc(O)c(Br)c1
Agent: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CSc1cc(Br)c(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Anhydrous paraformaldehyde (2.14 g) and anhydrous magnesium chloride (−10 mesh, 99.9%, 4.53 g) were suspended in anhydrous THF (120 mL) under nitrogen atmosphere. Freshly distilled TEA (6.7 mL) was added to the above suspended solution and stirred for 30 minutes. To the above mixture, a solution of 2-bromo-4-methylthiophenol (XXI, 5.22 g) in anhydrous THF (40 mL) was added. The resultant mixture was heated at gentle reflux and stirred for 6 h. After the mixture was cooled down to ambient temperature, ether (100 ml) was added. The organic layer was washed with 1N HCl (60 mL×3) and water (60 mL×3), and dried over MgSO4, filtered and solvent removed in vacuo. The mixture was recrystallized from hexane to afford the product (3.60 g, 61%) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:29](=[O:31])[NH2:30])=[C:15]([NH:17][C:18](=[O:28])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])[S:16][C:10]=2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:18]([NH:17][C:15]2[S:16][C:10]3[CH2:9][NH:8][CH2:13][CH2:12][C:11]=3[C:14]=2[C:29]([NH2:30])=[O:31])=[O:28])=[C:21]([F:27])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(NC(=O)Cc3ccc(Cl)cc3F)c2C(N)=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(NC(=O)Cc2ccc(Cl)cc2F)sc2c1CCNC2
Temperature: 25 °C

Procedure:
Starting material 19 (3.2 g, 22% content, 1.5 mmol) was dissolved in 25 ml dried DCM and trifluoro acetic acid (TFA, 8.0 ml, 104 mmol) was added. The reaction was stirred at ambient temperature for 30 Min. The solvent was reduced in vacuo and the crude product was purified at the Flashmaster (Method 1). The isolated product was not sufficiently pure and was therefore purified again at the prep. HPLC (Method 4). The pure fractions were combined and the solvent was reduced. The desired product 20 was thereby isolated as a brown solid (236 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10](=[CH:11][N:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]#C.BrCC[F:21].CN(C=O)C>>[Cl:1][C:2]1[N:3]=[C:4]2[C:10]([N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][CH2:16][F:21])=[CH:11][N:12]=1
Reactant: FCCBr
Reactant: C#CCN1CCC(=O)N(C)c2cnc(Cl)nc21
Solvent: CN(C)C=O
Product: CN1C(=O)CCN(CCF)c2nc(Cl)ncc21

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 154, on a 0.31 mmol scale, utilising 1-bromo-2-fluoroethane (Apollo Scientific; 235 mg, 1.44 mmol), as a white crystalline solid containing 0.6 equivalents of DMF (86 mg, 100%).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:27][C:28]([F:35])([F:34])[C:29]1[CH:33]=[CH:32][NH:31][N:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>CCOC(C)=O.[Cu]I>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([N:31]3[CH:32]=[CH:33][C:29]([C:28]([F:35])([F:34])[F:27])=[N:30]3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-n3ccc(C(F)(F)F)n3)cc2)C(=O)O1
Temperature: 130 °C
Yield: 42.7 %

Procedure:
(R)-6-Allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (20 mg, 0.048 mmol), 3-(trifluoromethyl)-1H-pyrazole (20 mg, 3 equiv.), CuI (1.4 mg, 15% mol), (1R,2R)-(−)-1,2-transcyclohexanediamine (2 mg, 30% mol), K3PO4 (20 mg, 2 equiv.) were mixed with dry toluene (2 mL) and heated in Microwave Oven for 1 h at 130° C. LC-MS found product peak. The mixture was diluted with EtOAc (8 mL), washed by water (2 mL), brine (3 mL) and dried over Na2SO4. After filtration and concentration, the residue was purified chromatography on a 4-g silica gel cartridge eluted with a gradient from 5 to 55% EtOAc in gexanes to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)ethyl)-1,3-oxazinan-2-one (9.7 mg, 43%) product. LC-MS Method 1 tR=2.05, min, m/z=474; 1H NMR (CDCl3) 7.86 (s, 1H), 7.43 (d, 2H), 7.26 (t, 2H), 7.01 (dd, 2H), 6.69 (d, 1H), 5.76-5.64 (m, 2H), 5.05 (dd, 2H), 2.95 (m, 1H), 2.65-2.51 (m, 2H), 1.54 (d, 3H).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[N:8]([C:9]2[C:10]3[CH:17]=[CH:16][S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[C@@H:7]([CH3:18])[CH2:6][N:5]([CH2:19][C:20](O)=[O:21])[CH2:4]1.[NH2:23][C:24]1[N:28]([CH3:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=1>>[CH3:2][C@H:3]1[N:8]([C:9]2[C:10]3[CH:17]=[CH:16][S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[C@@H:7]([CH3:18])[CH2:6][N:5]([CH2:19][C:20]([NH:23][C:24]2[N:28]([CH3:29])[C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[N:25]=2)=[O:21])[CH2:4]1
Reactant: Cn1c(N)nc2ccccc21
Reactant: C[C@@H]1CN(CC(=O)O)C[C@H](C)N1c1ncnc2sccc12
Agent: Cl
Product: C[C@@H]1CN(CC(=O)Nc2nc3ccccc3n2C)C[C@H](C)N1c1ncnc2sccc12

Procedure:
The title compound was prepared from the product of Example 9 step (ii) (0.2 g) and 2-amino-1-methyl-benzimidazole (0.14 g) by the method of Example 38 step (iv). Purification was by silica gel chromatography followed by recrystallisation from methanol. Yield 45 mg.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[CH:3]=[O:2])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)C1CCCN1C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1C=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3.5 g) in toluene (40 mL) at −78° C. was added dropwise diisobutylaluminium hydride (20 mL of a 1.5 M solution in toluene) maintaining the temperature below −65° C. The reaction mixture was stirred at −78° C. for 2 h and then quenched with methanol (10 mL). The mixture was then diluted with diethyl ether (50 mL), potassium sodium tartrate tetrahydrate was added and the mixture stirred vigorously for 20 min at room temperature. The two phases were then separated and the aqueous layer extracted with dichloromethane (2×50 mL). The combined organics were then washed with brine (100 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (2.687 g).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.Cl[CH2:21][C:22]1[NH:27][C:26](=[O:28])[NH:25][C:24](=[O:29])[CH:23]=1>CN(C=O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:21][C:22]2[NH:27][C:26](=[O:28])[NH:25][C:24](=[O:29])[CH:23]=2)=[CH:15][CH:14]=1
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Reactant: Fc1ccc(S)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1cc(CSc2ccc(F)cc2)[nH]c(=O)[nH]1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 55.2 %

Procedure:
DBU (4.02 mL, 26.91 mmol) was added to 4-fluorobenzenethiol (3.45 g, 26.91 mmol), in DMF (90 mL) at RT. The resulting solution was stirred at 20° C. for 15 minutes. 6-(Chloromethyl)-1H-pyrimidine-2,4-dione (2.88 g, 17.94 mmol) was then added and the reaction stirred for 4 hours. The reaction mixture was concentrated and diluted with DCM (100 mL), and washed with water (100 mL). The aqueous layer was acidified with 2M hydrochloric acid to give a white solid which was filtered and washed with water then dried under vacuum to give desired product (2.5 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1([CH2:13][CH3:14])[CH2:10][CH2:9][CH:8]=[C:7]([Br:11])[C:6]1=[O:12].[CH2:16]([Mg]Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.[Br-].[Zn+2].[Br-]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1([CH2:13][CH3:14])[CH2:10][CH2:9][CH:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]([Br:11])[C:6]1=[O:12]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCC1(CC(=O)OC)CCC=C(Br)C1=O
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCC1(CC(=O)OC)CCC(Cc2ccccc2)C(Br)C1=O
Reaction time: 0.08 h

Procedure:
A solution of 3-bromo-1-ethyl-2-oxocyclohex-3-eneacetic acid methyl ester (10 g, 36.3 mmol, as prepared in Example 1) and copper (I) bromide-dimethyl sulfide complex (3.63 mmol, 746 mg) in 107 mL of dry tetrahydrofuran was stirred at 0° C. under nitrogen and treated with anhydrous zinc bromide (36.3 mmol, 8.17 g). After 5 minutes, the mixture was treated dropwise with 36.3 mmol of benzylmagnesium chloride (18.2 mL of 2M in THF). After 45 minutes, another 8 mmol of benzylmagnesium chloride were added followed by 350 mg of copper (I) bromide-dimethyl sulfide complex and then another 16 mmol of benzylmagnesium chloride. The reaction was quenched with 150 mL of 1M HCl and extracted with 4×50 mL of ether. The extracts were conbined, dried over magnesium sulfate, and concentrated affording 3-bromo-1-ethyl-2-oxo-4-(phenylmethyl)cyclohexaneacetic acid methyl ester. This was then stirred in a solution of 74 mL of N,N-dimethylformamide and 35 mL of water and treated with 109 mmol (18.96 g) of sodium dithionite. The mixture was heated at 55° C. under nitrogen for 20 minutes, poured into 200 mL of water and extracted with 4×100 mL of 1:1 ether-petroleum ether. The extracts were combined, washed with 100 mL of water and 100 mL of saturated sodium bicarbonate (aq), dried over magnesium sulfate, and concentrated affording 10.48 g (36.3 mmol, 100% crude yield) of product as a pale yellow oil. Analysis by capillary GC demonstrated a 4.41:1 ratio of diastereomers, with the cis isomer predominating. The reduction of the intermediate 3-bromo-1-ethyl- 2-oxo-4-(phenylmethyl)cyclohexaneacetic acid methyl ester to the title compound can also be carried out as described in Example 3.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][O-:12].[Na+].C(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:12][CH3:11])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1C#N
Yield: 79.6 %

Procedure:
In a 1 L round-bottomed flask, 53.94 g (270 mmol) of 4-bromo-2-fluorobenzonitrile was dissolved in 500 mL of THF. Sodium methoxide (21.99 g, 407 mmol) was added and the mixture was heated to reflux until TLC (SiO2: CH2Cl2) showed complete consumption of starting material. The mixture was poured into 1N HCl and the THF was evaporated in vacuo. The remaining mixture was extracted with diethyl ether. The extract was dried (MgSO4) and filtered over a plug of silica gel. The plug was eluted with CH2Cl2 and the filtrate was evaporated in vacuo to afford 45.56 g (80%) of the product as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.42 (d, 1H), 7.17 (dd, 1H), 7.14 (d, 1H), 3.95 (s, 3H).
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[N:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=1>>[CH3:17][C:2]1[N:20]2[CH:21]=[CH:22][C:23]([CH3:25])=[N:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1
Reactant: Cc1ccnc(N)n1
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Product: Cc1ccn2c(C)c(-c3ccc4c(c3)NC(=O)C(C)O4)nc2n1
Yield: 41.9 %

Procedure:
6-(3,7-Dimethylimidazo[1,2-a]pyrimidin-2-yl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.3 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.0 g) and 2-amino-4-methyl-pyrimidine (3.3 g). mp. 298° C. (dec.).