Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][CH2:22]Cl>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH2:20][O:21][CH3:22])=[C:6]([Br:12])[CH:5]=1
Reactant: COCCl
Reactant: COC(=O)c1cc(F)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COCOc1c(F)cc(C(=O)OC)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of 3-bromo-5-fluoro-4-hydroxybenzoic acid methyl ester (637 mg) in acetone (7 mL) were added potassium carbonate (708 mg) and chloromethyl methyl ether (412 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1, v/v) to give the title compound (608 mg).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])(=O)=O.[CH3:14][C:15]1([CH3:42])[NH:27][CH:26]([C:28]2[C:33]([F:34])=[CH:32][C:31](/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])=[CH:30][C:29]=2[F:41])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:34][C:33]1[CH:32]=[C:31](/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])[CH:30]=[C:29]([F:41])[C:28]=1[CH:26]1[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][C:15]([CH3:14])([CH3:42])[N:27]1[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: COC(=O)/C=C/c1cc(F)c(C2NC(C)(C)Cc3c2[nH]c2ccccc32)c(F)c1
Reactant: C[C@H](CF)COS(=O)(=O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1cc(F)c(C2c3[nH]c4ccccc4c3CC(C)(C)N2C[C@H](C)CF)c(F)c1
Reaction time: 24 h
Yield: 56.5 %

Procedure:
(S)-3-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 3, preparation of starting materials) (0.339 g, 1.51 mmol) was added to a solution of (E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate (0.3 g, 0.76 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.458 ml, 2.65 mmol) in 1,4-dioxane (2 ml). The stirring was continued for 24 hours then the volatiles were removed under vacuum and the crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in heptane. Pre fractions were evaporated to dryness to afford (E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (0.202 g, 36%) as a white solid. The material was combined with another batch (0.36 g) and purified by preparative HPLC (Chiralpak IA column, 20 μm silica, 20 mm diameter, 250 mm length), Heptane:IPA 70:30 at 80 ml/min (4 injections). Fractions containing the desired compounds were evaporated to yield (E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1, first eluted, 217 mg) and (E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-fluoro-2-methylpropyl-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 2, second eluted, 165 mg). Analysis was done on Chiralpak IA column, 5 μm silica, 4.6 mm diameter, 50 mm length, Heptane:IPA 70:30 at 2 ml/min. 1H NMR (400 MHz, DMSO, 30° C.) δ 0.50 (3H, d), 1.02 (3H, s), 1.30 (3H, s), 2.11 (1H, dd), 2.62 (2H, d), 2.80 (1H, d), 2.99 (1H, dd), 3.74 (3H, s), 4.09-4.23 (1H, m), 4.29 (1H, d), 5.09 (1H, s), 6.81 (1H, d), 6.97 (2H, dt), 7.16 (1H, d), 7.39 (1H, d), 7.53 (2H, d), 7.64 (1H, d), 10.44 (1H, s). m/z: ES+ [M+H]+ 471.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C@@H:3]2[CH2:7][CH2:8][O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C@@H:2]12.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([N:4]1[CH2:5][CH2:6][O:1][C@@H:2]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][C@@H:3]12)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)OCC[C@H]1NCCO[C@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCO[C@@H]2c3ccccc3OCC[C@H]21
Reaction time: 8 h

Procedure:
To a stirred solution of 2.41 g of trans-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine, prepared in accordance with Example 2, and 3.5 ml of triethylamine dissolved in 50 ml of methylene chloride is added dropwise a solution of 0.85 ml of acetyl chloride dissolved in 25 ml of methylene chloride. The mixture is stirred overnight, washed with a dilute hydrochloric acid solution and dried over anhydrous magnesium sulfate. The volatiles are removed by evaporation leaving an oil which yields the compound trans-4-acetyl-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine having a mp. of 97°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([N:18]=COC)=[C:16]([S:22]([C:24]([F:27])([F:26])[F:25])=[O:23])[C:15]([C:28]2[N:32]=[CH:31][O:30][N:29]=2)=[N:14]1.Cl.O.C(=O)([O-])O.[Na+]>CC(C)=O>[NH2:18][C:17]1[N:13]([C:3]2[C:4]([Cl:12])=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=2[Cl:1])[N:14]=[C:15]([C:28]2[N:32]=[CH:31][O:30][N:29]=2)[C:16]=1[S:22]([C:24]([F:27])([F:26])[F:25])=[O:23]
Reactant: COC=Nc1c(S(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Nc1c(S(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
1-(2,6-Dichloro-4-trifluoromethylphenyl)-5-methoxymethylideneamino-3-(1,2,4-oxadiazol-3-yl)-4-trifluoromethylsulfinylpyrazole (151 mg, 0.29 mmol) was dissolved in 5 ml of acetone and 1.2 N hydrochloric acid (0.12 ml, 0.14 mmol) was added, and then the mixture was stirred at room temperature. Seven hours after stirring, 1.2 N hydrochloric acid (0.12 ml, 0.14 mmol) was further added, followed by stirring at room temperature for 3 days. Furthermore, 1.2 N hydrochloric acid (0.12 ml, 0.14 mmol) was added, followed by heating to 50° C. and stirring for another 9 hours. After 5 ml of water and 2 ml of an aqueous saturated sodium hydrogencarbonate solution were added, acetone was distilled off and extracted with 40 ml ethyl acetate. The ethyl acetate layer was washed twice with 30 ml of an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 136 mg (0.29 mmol) of the title compound as a yellowish crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[O:6][CH2:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][CH:11]1[CH2:24][C:25]([O:27]C)=[O:26])=[O:9].CO.O.O.[OH-].[Li+]>C(OCC)(=O)C>[CH3:35][O:34][C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:31]=1[O:32][CH3:33])[O:6][CH2:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][CH:11]1[CH2:24][C:25]([OH:27])=[O:26])=[O:9]
Reactant: COC(=O)CC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1cc(OC)c(OC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(OCC(=O)N2CCN(Cc3ccc(F)cc3)CC2CC(=O)O)cc(OC)c1OC
Yield: 30 %

Procedure:
To a solution of 1-((3,4,5-trimethoxyphenoxy)methyl)carbonyl-2-(methoxycarbonyl)methyl-4-(4-fluorobenzyl)piperazine (0.20 g, 0.42 mmol) in a methanol/water solution (20 mL, 3:1) was added lithium hydroxide, monohydrate (0.40 mL, 9.5 mmol). The resultant mixture was stirred at ambient temperature for 30 min. At that time HPLC analysis showed complete conversion had occurred. The mixture was poured into ethyl acetate and washed sequentially with an aqueous acetic acid/water solution (pH<4), water, and brine. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to afford 0.060 g of 1-((3,4,5-trimethoxyphenoxy)methyl)carbonyl-2-(carboxy)methyl-4-(4-fluorobenzyl)piperazine as a white solid; NMR (CDCl3) 7.4 (m, 2), 7.1 (m, 2), 6.2 (m, 2), 5.1 (m, 1), 4.7 (m, 3), 4.0 (m, 2), 3.8 (d, 9), 3.3-3.1 (m, 4), 2.6 (m, 2), 2.4 (m, 2) ppm, MS (ESI) 476.
Reaction SMILES: [H-].[K+].[CH2:3]([O:5][C:6](=[O:15])[CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=2)[N:20]=[CH:19][C:18]=1[C:28]#[N:29]>CCCCCC.O1CCCC1>[CH2:3]([O:5][C:6](=[O:15])[C:7]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=2)[N:20]=[CH:19][C:18]=1[C:28]#[N:29])([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(CC)(C(=O)OCC)c1c(C#N)cnc2ccc(I)cc12
Reaction time: 0.17 h
Yield: 83.8 %

Procedure:
Potassium hydride (35% oil dispersion, 220 mg, 1.91 mmol) was washed with newly opened hexane for two times under Argon. Then anhydrous tetrahydrofuran (55 mL) was added, followed by addition of 2-ethyl-malonic acid diethyl ester (480 mg, 2.54 mmol). The reaction mixture was stirred at about room temperature for 10 min. Then 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c, 200 mg, 0.64 mmol) in anhydrous tetrahydrofuran (3 mL) was added to the above reaction mixture, and then reaction continued at room temperature for another 30 min. The reaction was quenched with ice water, and then extracted with ethyl acetate. The organic layers were collected, washed with brain, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 20% ethyl acetate in hexane in 25 min) afforded 2-(3-cyano-6-iodo-quinolin-4-yl)-2-ethyl-malonic acid diethyl ester (250 mg, 85%) as colorless viscous oil. LC-MS m/e 467 (MH+).
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=O.[CH3:7][N:8](C)C=O.[N:12]1[CH:17]=[CH:16][CH:15]=CC=1.O>C(OCC)(=O)C>[C:17]([C:16]1[CH:15]=[CH:2][C:1]([Cl:6])=[CH:7][N:8]=1)#[N:12]
Reactant: c1ccncc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(Cl)cn1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Oxalyl chloride (18.1 ml, 207 mmol) is added slowly to dimethylformamide cooled to −25° C. The resulting mixture is cooled to −45° C. and 2-carboxamido-5-chloropyridine (25 g, 160 mmol) is added portionwise. The reaction stirred for 30 minutes and pyridine (14.2 ml, 176 mmol) is added. The reaction stirred for 5 hours, 20 minutes and is poured into 1.5 L of water and 1 L of ethyl acetate is added. The phases are separated and the aqueous layer is extracted with 100 ml of ethyl acetate. The combined organics are washed with water (850 ml and 350 ml), saturated aqueous sodium chloride (100 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give 19.95 g (92%) of 2-cyano-5-chloropyridine which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([C@@H:13]3[O:21][C@H:20]([CH2:22][O:23]C(=O)C4C=CC=CC=4)[C@@H:19]([CH3:32])[C@H:14]3[O:15]C(=O)C)[C:4]=2[N:5]=[CH:6][N:7]=1.N.[OH:34]O>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]([NH2:12])=[O:34])=[CH:9][N:8]([C@@H:13]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([CH3:32])[C@H:14]3[OH:15])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OO
Reactant: CC(=O)O[C@@H]1[C@H](C)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cc(C#N)c2c(N)ncnc21
Agent: N
Product: C[C@H]1[C@@H](O)[C@H](n2cc(C(N)=O)c3c(N)ncnc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the compound from Step B (51 mg, 0.12 mmol), ethanolic ammonia (5 mL, saturated at 0° C.), aqueous ammonia (5 mL, 30%) and aqueous hydrogen peroxide (1 mL, 35%) was stirred room temperature for 8 h. The solution was evaporated and the residue purified on silica gel column with a solvent system of CH2Cl2MeOH: 10/1 to give the title compound as a white solid (28 mg). 1H-MNR (CD3OD): δ 1.12 (d, 3H, J=6.8 Hz), 2.40 (m, 1H), 3.76 (dd, 1H, J1=12.8 Hz, J2=4.0 Hz), 3.94–4.04 (m, 2H), 4.33 (d, 1H, J=5.4 Hz), 6.13 (s, 1H), 8.11 (s, 1H), 8.16 (s, 1H).
Reaction SMILES: C(O[N:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:16]=[C:17]([C:21]([NH:23][CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[O:22])[CH:18]=[CH:19][CH:20]=1)C.[NH2:33][NH:34][C:35](=O)[CH2:36][N:37]([CH3:39])[CH3:38].C[O-].[Na+]>CO>[CH3:38][N:37]([CH2:36][C:35]1[N:4]=[C:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH:24]3[CH2:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:32]3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[NH:33][N:34]=1)[CH3:39]
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)NC4Cc5ccccc5C4)c3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)NC5Cc6ccccc6C5)c4)c3c2)n1

Procedure:
The title compound was prepared according to the procedure of Example 367 C using (3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)-N-indan-2-ylcarboxamide.2HCl (360 mg, 0.72 mmol), N-amino-2-(dimethylamino) acetamide (254 mg, 2.17 mmol) and sodium methoxide (415 μL of a 25% w/w in methanol) in anhydrous methanol (4.0 mL) with a reaction time of 48 h. Purification of the residue by preparatory TLC using 50% ethyl acetate in methanol gave the desired product which was further purified by precipitation from methanol and ethyl acetate with hexanes and ethyl ether to give the title compound (86 mg, 25% yield) as a colorless powder 1H NMR (DMSO-d6) δ 13.9 (br s, 1H), 13.4 (br s, 1H), 8.85 (d, 1H), 8.6 (br s, 1H), 8.45 (s, 1H), 8.1-8.0 (m, 2H), 7.7-7.6 (m, 2H), 7.3-7.1 (m, 4H), 4.8-4.7 (m, 1H), 3.6 (br s, 2H), 3.25 (dd, 2H), 3.0 (dd, 2H), 2.2 (s, 6H); ES-MS (m/z) 478 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[CH:21][C:6]2[N:7]=[C:8]([NH2:20])[C:9]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:10]=3[NH:11][C:5]=2[CH:4]=1.[CH3:23][O:24][CH2:25][CH2:26][CH2:27][C@H:28]1[CH2:33]N[CH2:31][CH2:30][NH:29]1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.CS(C)=O>[F:2][C:3]1[CH:22]=[CH:21][C:6]2[N:7]=[C:8]([N:20]3[CH2:31][CH2:30][NH:29][C@@H:28]([CH2:27][CH2:26][CH2:25][O:24][CH3:23])[CH2:33]3)[C:9]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:10]=3[NH:11][C:5]=2[CH:4]=1
Reactant: NC1=Nc2ccc(F)cc2Nc2ccc(C(F)(F)F)cc21
Reactant: COCCC[C@H]1CNCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3ccc(C(F)(F)F)cc32)CCN1
Temperature: 110 °C
Reaction time: 24 h
Yield: 51.2 %

Procedure:
Combine 7-fluoro-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (0.399 g, 1.20 mmol), (S)-2-(3-methoxy-propyl)-piperazine (0.381 g, 2.41 mmol), and diisopropylethyl amine (0.21 mL, 1.20 mmol) in a mixture of toluene (4.5 mL) and dimethylsulfoxide (1.5 mL) and stir at 110° C. for 24 hours. Evaporate the mixture then purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 7% 2N ammonia-methanol in dichloromethane gives (s)-7-fluoro-11-[3-(3-methoxy-propyl)-piperazin-1-yl]-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine (0.268 g, 0.614 mmol, 51%) as a yellow oil. Mass spectrum (APCI): m/z=437.2 (M+1).
Reaction SMILES: [CH2:1]([OH:5])[CH:2]=[CH:3][CH3:4].[CH2:6]=[C:7]1O[C:9](=[O:10])[CH2:8]1.[O:12]1CCCC1>C(OCC)C.C([O-])(=O)C.[Na+]>[C:1]([O:10][CH2:9]/[CH:8]=[CH:7]/[CH3:6])(=[O:5])[CH2:2][C:3]([CH3:4])=[O:12]
Reactant: C1CCOC1
Reactant: C=C1CC(=O)O1
Reactant: CC=CCO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: C/C=C/COC(=O)CC(C)=O
Temperature: 25 °C
Yield: 83 %

Procedure:
To a refluxing solution of crotyl alcohol (21.5 mL, 252 mmol) and sodium acetate (1.24 g, 15.12mmol) in anhydrous tetrahydrofuran (70 mL) under nitrogen, a solution of diketene (21.34 mL, 277.1 mmol) in anhydrous tetrahydrofuran (30 mL) was. added dropwise over a period of 1 hour. The reaction mixture was heated at reflux for an additional 30 min upon completion of the addition. Then, the reaction mixture was cooled to room temperature and diluted with diethyl ether (300 mL). The resulting solution was washed with a saturated aqueous sodium chloride. solution (2×50 mL) and organic layer. dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The brown residue was purified by column chromatography using a mixture 5:1 of hexane and diethyl ether as eluent to afford 33.0 g (83% yield) of trans-2-buten-1-yl acetoacetate as a colorless liquid.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[NH:6][C:5]1=[O:15])([CH3:3])[CH3:2].[OH-].[Na+].[Br:18]Br.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH:1]([N:4]1[C:9](=[O:10])[C:8]([Br:18])=[C:7]([C:11]([F:12])([F:14])[F:13])[NH:6][C:5]1=[O:15])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)cc(C(F)(F)F)[nH]c1=O
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)n1c(=O)[nH]c(C(F)(F)F)c(Br)c1=O

Procedure:
3-isopropyl-6-(trifluoromethyl)uracil as prepared in Example 1 (7.4 g., 0.033 mole) was dissolved in a mixture of 0.5N NaOH (0.04 mole) and chloroform (15 ml.). A solution of bromine (5.89 g., .036 mole) in 25 ml. chloroform was added in portions with stirring. After the addition was complete, the reaction mixture was stirred for one-half hour before discharging the bromine color with sodium bisulfite. The layers were separated, and the aqueous layer extracted with fresh chloroform. The combined chloroform extracts were washed with water and then evaporated to dryness leaving 10.1 g. (100%) of white solid residue. One recrystallization from benzene gave a product with a melting point of 146°-150°C. The analytical sample melted at 149°-150°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1.C(N(CC)CC)C.O>C(O)CCC>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([N:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)[N:7]=1.[Cl:1][C:2]1[N:7]=[C:6]([N:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Clc1cc(-c2ccccc2)nc(Cl)n1
Reactant: OC1CCNCC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Solvent: O
Product: OC1CCN(c2cc(-c3ccccc3)nc(Cl)n2)CC1
Product: OC1CCN(c2nc(Cl)cc(-c3ccccc3)n2)CC1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A mixture of compound, 2,4-dichloro-6-phenyl-pyrimidine (13 g, 57.77 mmol), piperidin-4-ol (2.9 g, 28.88 mmol) and triethylamine (32.14 mL, 231.11 mmol) in butanol (110 mL) was stirred at 120° C. for 12 hours under nitrogen atmosphere. The reaction mixture was then poured into water (250 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were collected, combined, washed with water (50 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum. The residue thus obtained was purified by column chromatography using ethyl acetate-petroleum ether to give the two compounds, 1-(4-chloro-6-phenyl-pyrimidin-2-yl)-piperidin-4-ol and 1-(2-chloro-6-phenyl-pyrimidin-4-yl)-piperidin-4-ol in ratio 1:4 (overall yield: 51%).
Reaction SMILES: [CH:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:5](=[O:8])[CH2:6]Br)([CH3:3])[CH3:2].[C:17]1(N)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:5](=[O:8])[CH2:6][NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CNc2ccccc2)C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
A mixture of N-Isopropyl-N-(4-methoxy-phenyl) bromoacetamide (257.6 g, 924 mmol), 1,2-phenylene diamine (100 g, 924 mmol) and potassium carbonate (128 g, 924 mmol) in DMF (1200 mL) is stirred at 0° C. for 2 h and then allowed to stir at RT for 20 h. The reaction mixture is filtered through celite and the filtrate concentrated in vacuo The resultant residue is dissolved in EtOAc (1200 mL), washed with water (3×200 mL), brine (200 mL), dried (MgSO4) and concentrated in vacuo. After removal of about 70% of the solvent a precipitate formed which is removed by filtration and washed with cold EtOAc and dried to afford the desired product (67.1 g) as a beige solid. The combined filtrates were concentrated in vacuo to afford a dark oil (88 g). Two recrystallisations from ethanol afforded a second batch (29.6 g) of the desired product as a beige solid: 1H NMR (300 MHz, DMSO-d6), δ7.22 (m, 2H), 7.05 (m, 2H), 6.47 (m, 1H), 6.34 (m, 2H), 5.95 (m, 1H), 4.81 (m., 1H, J=6.8), 4.59 (dt, 1H, J=27.2, 6.1), 4.4 (s, 2H), 3.77 (s, 3H), 3.30 (s, 2H), 0.96 (d, 6H, J=6.8).
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.[C:16]([C:18]1[CH:29]=[CH:28][C:21]([C:22](N(OC)C)=[O:23])=[CH:20][CH:19]=1)#[N:17]>C1COCC1>[CH3:5][C:4]([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])([CH3:8])[C:6]#[C:7][C:22]([C:21]1[CH:28]=[CH:29][C:18]([C:16]#[N:17])=[CH:19][CH:20]=1)=[O:23]
Reactant: CON(C)C(=O)c1ccc(C#N)cc1
Reactant: C#CC(C)(C)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1ccc(C#N)cc1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 133.1 %

Procedure:
To a −78° C. stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy)silane (3.3 g, 20.00 mmol) in dry THF (45 mL), n-BuLi (4.1 mL, 9.00 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at −78° C., and then a solution of 4-cyano-N-methoxy-N-methylbenzamide (2.0 g, 10.00 mmol) in dry THF (15 mL) was added to the reaction mixture and stirring was continued for an additional 1 h at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 15% EtOAc in hexanes to afford 4-(4-methyl-4-(trimethylsilyloxy) pent-2-ynoyl)benzonitrile (3.8 g, 68%) as a yellow oil.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:27][N:28]1[C:32]([CH3:33])=[C:31]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([C:41]3[C:46]([C:47]4[CH:52]=[CH:51][C:50]([CH2:53]O)=[CH:49][CH:48]=4)=[N:45][CH:44]=[CH:43][N:42]=3)[CH2:37][CH2:36]2)[CH:30]=[N:29]1.N(C(OCC)=O)=NC(OCC)=O.C(Cl)[Cl:68]>>[ClH:68].[CH3:27][N:28]1[C:32]([CH3:33])=[C:31]([CH2:34][N:35]2[CH2:36][CH2:37][N:38]([C:41]3[C:46]([C:47]4[CH:48]=[CH:49][C:50]([CH2:53][N:5]5[C:4](=[O:6])[CH2:3][CH2:2][C:1]5=[O:7])=[CH:51][CH:52]=4)=[N:45][CH:44]=[CH:43][N:42]=3)[CH2:39][CH2:40]2)[CH:30]=[N:29]1
Reactant: Cc1c(CN2CCN(c3nccnc3-c3ccc(CO)cc3)CC2)cnn1C
Reactant: O=C1CCC(=O)N1
Reactant: ClCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(CN4C(=O)CCC4=O)cc3)CC2)cnn1C
Product: Cl

Procedure:
Dissolve succinimide (99 mg, 1.0 mmol) in dry DCM (5 mL) under nitrogen. Add triphenylphosphine (408 mg, 1.5 mmol) and stir for 20 min. at room temperature. Add {4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-phenyl}-methanol (378 mg, 1.0 mmol) and diethyl azodicarboxylate (0.19 mL, 1.1 mmol) and stir for 20 hr. Add water (10 mL), extract with DCM (2×5 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®, concentrate and purify by SCX-2® chromatography washing with methanol then eluting with 2 M ammonia in methanol. Further purify (silica gel chromatography, eluting with 0:100 to 5:95 methanol:DCM), to give the free base as a light yellow oil. Purify again by low pH reverse phase HPLC, and form the free base by passing through an SCX-2® ion exchange cartridge washing with methanol then eluting with 3.5 M ammonia in methanol. Dissolve the oil in acetonitrile and convert to the hydrochloride salt by adding 2 M aq HCl solution. Add water and lyophilize to give the title compound as a yellow powder (127 mg, 26%). MS (ES): m/z=460 [M+H]+.