Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([F:32])[CH:26]=2)=[N:4][C:5]([N:8]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][C:19]([CH3:24])([CH3:23])[CH2:18]2)C(=O)OC(C)(C)C)=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([F:32])[CH:26]=2)=[N:4][C:5]([NH:8][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][C:19]([CH3:23])([CH3:24])[CH2:18]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CC1CCOC(C)(C)C1)c1ccc(Cl)c(-c2cc(F)ncc2Cl)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(CNc2ccc(Cl)c(-c3cc(F)ncc3Cl)n2)CCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3,5′-dichloro-2′-fluoro-2,4′-bipyridin-6-yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate (8 mg, 0.017 mmol), DCM (1 mL) and TFA (0.1 mL, 1.3 mmol) were combined in a 4 mL screw cap vial. The vial was capped and the reaction mixture was stirred at ambient temperature for 1 hour. The solvent was evaporated under vacuum and the residual material was converted to the free base using sodium bicarbonate. (5.8 mg, 91%). LCMS (m/z): 3484.2/386.1/388.2 (M+H), retention time=1.07 min.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19]O)=[N:17][CH:18]=1)([O-:12])=[O:11].C(N(CC)CC)C>C(Cl)Cl>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][O:5][S:2]([CH3:1])(=[O:4])=[O:3])=[N:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CO)nc1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc([N+](=O)[O-])cn1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Methanesulfonic anhydride (1.79 g, 10.3 mmol, 1.1 equiv) was added portionwise to a cold (5° C.) mixture of (5-nitro-pyridin-2-yl)-methanol (Step 112.4) (1.44 g, 9.4 mmol) and triethylamine (1.57 mL, 11.3 mmol, 1.2 equiv) in DCM (20 mL), under an argon atmosphere. The reaction mixture was allowed to stir for 0.5 h at 5° C., quenched with H2O and extracted with DCM. The organic phase was washed with H2O, dried (Na2SO4), filtered and concentrated to provide 2.16 g of the title compound as a brown solid: : ESI-MS: 231.1 [M−H]−; tR=2.85 min (System 1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][C:7]=1[CH3:8].[H-].[Na+].[CH3:28]I.Cl.O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:28])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CI
Reactant: COC(=O)c1c(Nc2ccc(C)c(C)c2)c2ccccc2c(=O)n1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(N(C)c2ccc(C)c(C)c2)c2ccccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of methyl 4-[(3,4-dimethylphenyl)amino]-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (2.03 g, 6.03 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (0.362 g, 9.05 mmol) followed by methyl iodide (5.66 mL, 91 mmol). The mixture was stirred at room temperature for 18 hours. 1M HCl/water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude product was purified on silica using EtOAc/hexanes 30-50% to provide the title compound as an off-white solid (2 g, 95%): 1H NMR (400 MHz, CDCl3) δ ppm 8.56-8.37 (m, 1 H), 8.03 (s, 1 H), 7.62-7.47 (m, 2 H), 6.93 (d, J=8.4 Hz, 1 H), 6.48 (d, J=2.3 Hz, 1 H), 6.40 (dd, J=2.5, 8.2 Hz, 1 H), 3.77 (s, 3 H), 3.57 (s, 3 H), 3.24 (s, 3 H), 3.04-2.95 (m, 2 H), 2.89 (s, 2 H), 2.17 (d, J=8.8 Hz, 6 H);); ES-LCMS: 351.3 (M+1).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].Br[CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33]>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[O:28][CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33]
Reactant: CCC(Br)CC
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OC(CC)CC)c2)n1

Procedure:
Using the compound obtained in Example 347 and 3-bromopentane, white powdery N-{2-[4-difluoromethoxy-3-(1-ethylpropoxy)phenyl]oxazol-4-ylmethyl}-2-ethoxybenzamide was obtained following the procedure of Example 348.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][CH2:18][CH2:19][N:20]3[C:24](=O)C4=CC=CC=C4[C:21]3=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.NN.Cl>C(O)C>[CH3:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][CH2:18][CH2:19][N:20]([CH3:24])[CH3:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1C=Cc1ccccc1C2=CCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc2c1C=Cc1ccccc1C2=CCCN(C)C

Procedure:
9.2 g. of 1-methyl-5-(3-phthalimidopropylidene)-5H-dibenzo [a,d]cycloheptene are dissolved in 100 ml. of ethanol, treated with 1.2 g. of hydrazine hydrate and heated for 6 hours under reflux conditions. An excess of concentrated hydrochloric acid is added, and the mixture is heated for an additional hour under reflux conditions. The reaction mixture is filtered warm. The solid residue is washed with warm ethanol, and the residual ethanol portions are evaporated to dryness. The residue is taken up in ether. The ethereal solution is washed with dilute sodium hydroxide solution, dried and evaporated whereby 1-methyl-5-(3-aminopropylidene)-5H-dibenzo[a,d]cycloheptene remains behind as a thick oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:18]=3)=[C:15]3[N:10]([C:11](SC)=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH:42]1([NH2:47])[CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:18]=3)=[C:15]3[N:10]([C:11]([NH:47][CH:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3cccc(Cl)c3)nn12
Reactant: NC1CCCC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Clc1cccc(-c2nn3c(NC4CCCC4)nccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64.6 %

Procedure:
To a cold (0° C.) solution of 4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine (40 mg, 0.0915 mmol) in dichloromethane (3 mL) was added m-chloroperoxybenzoic acid (24 mg, 0.139 mmol). The reaction mixture was stirred 1.5 hours at 0° C. then diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration provided a crude oil which was heated in cyclopentylamine (2 mL, 20 mmol) at 85° C. in a sealed tube for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 to 3:1 hexanes:ethyl acetate) provided 2-(3-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]pyrimidin-7-amine (28 mg, 65%) as a beige solid. Rf 0.27 (3:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.09 (d, 1H), 7.78 (d, 1H), 7.71 (s, 1H), 7.51–7.35 (m, 4H), 6.41 (d, 1H), 6.30 (d, 1H), 5.15 (d, 1H), 4.53 (m, 1H), 4.29 (m, 1H), 2.20 (m, 2H), 2.04 (m, 2H), 1.83–1.50 (m, 12 H); MS m/z 474 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17]O)[CH:15]=3)[N:10]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS([Cl:37])(=O)=O.C(OCC)(=O)C>C(Cl)Cl>[Cl:37][CH2:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CO)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CCl)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under ice-cooling, to a solution of 3.0 g of tert-butyl 3-(3-fluorophenyl)-5-(hydroxymethyl)-1H-1-indazolecarboxylate in 30 ml methylene chloride were added 1.6 ml of triethylamine and 0.78 ml of methanesulfonyl chloride, and the mixture was stirred at room temperature for one day. To the reaction mixture was added 180 ml of ethyl acetate, and the mixture was sequentially washed with water, 1 N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (toluene), to give 2.74 g of the title compound as yellow crystals.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:15](OCC)(OCC)OCC>>[C:9]1([C:7]2[CH:6]=[CH:5][N:4]3[CH:15]=[N:2][N:1]=[C:3]3[N:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NNc1nccc(-c2ccccc2)n1
Reactant: CCOC(OCC)OCC
Product: c1ccc(-c2ccn3cnnc3n2)cc1

Procedure:
A mixture of 2.0 g. of 2-hydrazino-4-phenylpyrimidine and 25 ml. of triethyl orthoformate is refluxed for 6 hours. On cooling the desired compound is removed by filtration, m.p. 232°-234° C. [This compound is cited J. Chem. Soc. Japan, Ind. Chem. Sect. 58, 440 (1955) as having m.p. 192° C. No description or preparation procedures are given.]
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:28][NH:29]2)=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:35]4[CH2:36][CH2:37][N:32]([C:27]5[C:26]6[C:30](=[CH:31][C:23]([F:22])=[CH:24][CH:25]=6)[NH:29][N:28]=5)[CH2:33][CH2:34]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2n[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 6-fluoro-3-piperazin-1-yl-1H-indazole (Table No.1, SM 4) in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=506.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.C(Cl)C1C=CN=CC=1.CN(C)[CH:33]=[O:34]>>[C:33]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:8]=1)(=[O:34])[C:19]1[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reactant: c1ccncc1
Reactant: CN(C)C=O
Agent: Br
Agent: Cl
Agent: ClCc1ccncc1
Product: O=C(Nc1ccc(-c2c[nH]c(=O)cn2)cc1)c1ccncc1

Procedure:
To a stirred solution of 5-(4-aminophenyl)-2-(1H)-pyrazinone hydrobromide (1.3 g) in dimethylformamide (20 ml) containing pyridine (1 ml) was added a solution of isonicotinyl chloride hydrochloride (1.3 g) in dimethylformamide (10 ml). The mixture was heated under reflux for 4 hours and evaporated to small volume. Water was added to the residue and the solid (1.0 g) was collected, washed with water, dilute sodium hydroxide solution (pH8), water and then dried to give the title compound m.p. 303°-308° C.
Reaction SMILES: [C:1]([C:7]1[CH:8]=[C:9]([O:13][CH2:14][C@@H:15]2[CH2:18][CH2:17][N:16]2C(OC(C)(C)C)=O)[CH:10]=[N:11][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C(Cl)[Cl:27]>C(O)(C(F)(F)F)=O>[ClH:27].[ClH:27].[C:1]([C:7]1[CH:8]=[C:9]([O:13][CH2:14][C@@H:15]2[CH2:18][CH2:17][NH:16]2)[CH:10]=[N:11][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: ClCCl
Reactant: CCCCC#Cc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCC#Cc1cncc(OC[C@@H]2CCN2)c1
Product: Cl
Yield: 96 %

Procedure:
A solution of 5-hexynyl-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 58a (102 mg, 0.26 mmol) in CH2Cl2 (2 mL) and TFA (1 mL) was stirred at room temperature for 3 hours. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with CHCl3:MeOH:NH4OH 10:1:0.1 to afford the free base of the title compound(73 mg, 96% yield). MS (CI/NH3) m/z 279 (M+H)+. 1HH NMR (CDCl3, 300 MHz) δ: 0.96 (t, J=7.0 Hz, 3H), 1.43-1.61 (m, 2H), 2.21-2.44 (m, 4H), 2.48 (t, J=7.5 Hz, 2H), 3.44-3.52 (m, 1H), 3.68-3.80 (m, 1H), 3.96-4.09 (m, 2H), 4.25-4.35 (m, 1H), 7.28 (d, J=3.0 Hz, 1H), 7.99 (d, J=3.0 Hz, 1H). The base was treated with HCl in EtOH to afford the hydrochloride salt (73 mg). mp 103-105° C. MS (CI/NH3) m/z 279 (M+H)+. 1H NMR (D2O, 300 MHz) δ 0.98 (t, J=7.4, 3H), 1.48-1.72 (m, 4H), 2.55-2.60 (m, 2H), 2.68-2.77 (m, 2H), 4.07-4.24 (m, 2H), 4.44-4.48 (m, 2H), 4.80-4.99 (m, 1H), 7.66 (d, J=2.7, 1H), 8.14 (d, J=3.1, 1H). Anal. Calcd for C15H19N2O.1.6 HCl: C, 53.44; H, 6.16; N, 8.31. Found: C, 53.81; H, 5.77; N, 8.43. [α]25D=−7.5° (c 0.2, MeOH).
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:9]([NH2:18])[N:8]=[C:7]([NH2:19])[N:6]=1)=O.Cl.[CH3:21][NH:22][OH:23]>>[CH3:2][C:3]([C:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:9]([NH2:18])[N:8]=[C:7]([NH2:19])[N:6]=1)=[N+:22]([CH3:21])[O-:23]
Reactant: CC(=O)c1nc(N)nc(N)c1-c1ccc(Cl)cc1
Reactant: CNO
Agent: Cl
Agent: [Na]
Product: CC(c1nc(N)nc(N)c1-c1ccc(Cl)cc1)=[N+](C)[O-]

Procedure:
To a solution of sodium metal (0.6 g.) in absolute alcohol (20 ml.) was added [2,6-diamino-5-(p-chlorophenyl)-4-pyrimidinyl] methyl ketone (2.0 g.) and N-methyl hydroxylamine hydrochloride (1.2 g.), and the mixture was refluxed together for 5 hours. After removal of ethanol, the residue was filtered and recrystallized from ethanol-chloroform to give α-methyl-α-[2,6-diamino-5-(p-chlorophenyl)-4-pyrimidinyl]-N-methylnitrone as a white solid, m.p. 306°-309° (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1>CC(N(C)C)=O>[N+:17]([C:16]1[C:11]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: N#Cc1ccc(N)nc1
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Nc2ncccc2[N+](=O)[O-])nc1
Temperature: 80 °C
Yield: 51 %

Procedure:
To a well stirred solution of 6-aminonicotinonitrile (0.631 g, 5.29 mmol) in dry DMA (10 ml), CS2CO3 (2.157 g, 6.62 mmol) and 2-chloro-3-nitropyridine (0.700 g, 4.415 mmol) were added and reaction mixture was heated at 80° C. under nitrogen atmosphere for 24 h. After completion the reaction mixture was cooled to room temperature, extracted with ethyl acetate (2×100 ml), combined organic layers washed with water (2×50 ml) and brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield 543 mg of the product.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH:28]1[CH2:31][CH:30]([C:32]([N:34]2[CH2:40][CH2:39][CH2:38][N:37]([CH:41]3[CH2:44][CH2:43][CH2:42]3)[CH2:36][CH2:35]2)=[O:33])[CH2:29]1>ClCCl.CN(C=O)C>[CH:41]1([N:37]2[CH2:38][CH2:39][CH2:40][N:34]([C:32]([CH:30]3[CH2:29][N:28]([C:10]([C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[CH:4][N:3]=[CH:2]5)=[CH:14][CH:13]=4)=[O:12])[CH2:31]3)=[O:33])[CH2:35][CH2:36]2)[CH2:44][CH2:43][CH2:42]1
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2ccnc2)cc1)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 4.3 %

Procedure:
To a solution of 4-(1H-imidazol-1-yl)benzoic acid (150 mg, 0.80 mmol) in dichloromethane (10 mL) cooled to 0° C. was added oxalyl chloride (1 mL). DMF (2 drops) was added and the mixture was stirred for 45 min at 0° C. and volatiles were then removed at reduced pressure. The residue was diluted with dichloromethane (20 mL), cooled to 0° C. and triethylamine (201 mg, 2.0 mmol) was added followed by 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (187 mg, 0.79 mmol). The resulting mixture was stirred at RT for 16 h before being diluted with more dichloromethane (50 mL) and quenched by addition of water (50 mL). The organic layer was then washed with saturated aqueous NaHCO3 (50 mL), dried (Na2SO4), filtered and concentrated at reduced pressure. Purification by silica FCC (using a gradient of eluents; 97:3 to 95:5 DCM/2M NH3 in MeOH) followed by purification by preparative HPLC (Method 2) gave the title compound (14 mg, 4% yield) as pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.C(N(CC)CC)C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>O1CCCC1>[C:30]([O:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1)(=[O:33])[CH:31]=[CH2:32]
Reactant: O=C1NCC(CO)O1
Reactant: C=CC(=O)Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCC1CNC(=O)O1

Procedure:
105 g (0.90 moles) of 5-hydroxymethyl-oxazolidin-2-one were placed into a one liter, three necked, round bottomed flask equipped with a paddle stirrer and thermometer. This was followed by 500 ml of tetrahydrofuran, 101 g (1.0 mol.) of triethylamine and 0.5 g of phenothiazine. Stirring was started as 90 g (1.0 mol.) of acryloyl chloride were added dropwise in such a way that the contents of the flask were maintained at 30° C. or less. When the addition was complete, the contents were stirred overnight at room temperature. The triethylamine hydrochloride was filtered and the solution was allowed to stand over NaHCO3 and Na2SO4. The solution was filtered, transferred to a one liter, round bottomed flask and placed on a rotoevaporator. The solution was concentrated by purging with a stream of air while rotating the flask. The resulting liquid was confirmed by 13C NMR to contain a mixture of the desired compound and unreacted starting material.
Reaction SMILES: [C:1]([C@@:4]1([OH:23])[C@@H:8]([CH:9]([C:11](=[O:13])[CH3:12])[OH:10])[O:7][C@@H:6]([N:14]2[CH:21]=[C:20]([Br:22])[C:18](=O)[NH:17][C:15]2=[O:16])[CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.C1(C)C=C(C)C=C(C)C=1S(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1.[NH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[OH:62]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:22][C:20]1[C:18]([NH:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[OH:62])=[N:17][C:15](=[O:16])[N:14]([CH:21]=1)[C@@H:6]1[O:7][C@H:8]([CH:9]([C:11](=[O:13])[CH3:12])[OH:10])[C@@:4]([C:1](=[O:3])[CH3:2])([OH:23])[CH2:5]1
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2cc(Br)c(=O)[nH]c2=O)C[C@@]1(O)C(C)=O
Reactant: Nc1ccccc1O
Agent: CN(C)c1ccncc1
Agent: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)C(O)[C@H]1O[C@@H](n2cc(Br)c(Nc3ccccc3O)nc2=O)C[C@@]1(O)C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3′,5′-diacetyl-5-bromo-2′-deoxyuridine (8.5 g; 21.7 mmol), methylene chloride (100 ml), triethylamine (8.8 g; 87 mmol) and DMAP (0.13 g) was added 2-mesitylsulfonyl chloride (9.5 g; 43.4 mmol). After stirring at room temperature for 18 h. DBU (6.6 g; 43.5 mmol) and 2-aminophenol (9.5 g; 87 mmol) were added and the solution was stirred for 1 hr. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate aq. solution. The organic layer was purified by flash column chromatography on silica gel to yield the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[NH:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.Cl[CH2:23][C:24](OCC)=[O:25].O>CN(C)C=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[C:5]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:4]3[NH:3][C:24](=[O:25])[CH2:23][N:8]3[N:7]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCl
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Cn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Reaction time: 0.5 h
Yield: 10.1 %

Procedure:
To a suspension of sodium hydride (288 mg) in N,N-dimethylformamide (20 ml) was added dropwise a solution of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (1.524 g) in N,N-dimethylformamide (5 ml) with ice cooling. The mixture was stirred for 30 minutes and to the mixture was added a solution of ethyl chloroacetate (883 mg) in N,N-dimethylformamide (5 ml). After stirring of the mixture for 1 hour at ambient temperature, the reaction mixture was poured into water and the separated oil was extracted with dichloromethane. The extract was washed with brine, dried and concentrated in vacuo. The residue was dissolved in a solution of sodium (138 mg) in ethanol (5 ml) and the solution was refluxed for 1 hour. The reaction mixture was cooled, poured into water and neutralized with diluted hydrochloric acid. The separated oil was extracted with dichloromethane and the extract was washed with brine, dried and concentrated in vacuo. The residue was crystallized from ethanol to yield 2,3-dihydro-6-(4-fluorophenyl)-2-oxo-7-(pyridin-4-yl)-1H-imidazo[1,2-b]pyrazole (178 mg).
Reaction SMILES: [C:1]([S:5]([NH:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.I[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[CH2:20]([C:11]1[S:10][C:9]([NH:8][S:5]([C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:7])=[O:6])=[CH:13][CH:12]=1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(C)(C)S(=O)(=O)Nc1cccs1
Reactant: CCCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCc1ccc(NS(=O)(=O)C(C)(C)C)s1
Temperature: -20 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 2-(t-butylsulfonamido)thiophene (3.42 g, 15.6 mmol) in anhydrous THF coole to -78° C. under N2 was added 2.5M n-BuLi (15.6 mL, 2.5 equiv). The reaction was warmed to -20° C. over 3.5 h After stirring at -20° C. for an addional h, iodopentane (2.4 mL, 1.2 equiv) was added. The ice bath was removed and the reaction was stirred at rt overnight. The next day the reaction was quenched with sat'd NH4Cl solution and the THF was removed in vacuo. The residue was extracted with Et2O/EtOAc and washed with water and brine. The organic was dried over anhydrous MgSO4 and concentrated in vacuo. The product was purified by flash chromatography on a silica column eluting with Hex/EtOAc (15:1). Removal of the solvent afforded 2.72 g (60%) of the titled compound as a yellow oil. Rf=0.4 (6:1 Hex/EtOAc).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][SH:17])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:12]([O:14][C:15]([C:16]1[S:17][C:2]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=2[CH:4]=1)=[O:18])[CH3:13]
Reactant: CCOC(=O)CS
Reactant: COc1ccc(F)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OC)ccc2s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A solution of 2-fluoro-5-methoxy-benzaldehyde (4.35 g, 28.2 mmol) in DMF (30 mL) is added mercapto-acetic acid ethyl ester (3.71 mL, 33.9 mmol) and K2CO3 (7.86 g, 57.0 mmol). The resulting suspension is stirred at 80° C. for 60 min and quenched with water (300 mL). The mixture is extracted with EtOAc (2×200 mL), and the organic layer is dried over Na2SO4, concentrated, and purified by silica gel column chromatography (10% EtOAc/Hex), to give the title compound as an oil (4.40 g, 66%).