Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[C:17]([Cl:26])[C:16]=2[Cl:27])(=[O:14])=[O:13])=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].C(C1C=CC(OCCCSC2C=CC(CC(OC)=O)=C(Cl)C=2Cl)=C(CCC)C=1O)(=O)C>>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[C:17]([Cl:26])[C:16]=2[Cl:27])(=[O:14])=[O:13])=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCS(=O)(=O)c2ccc(CC(=O)OC)c(Cl)c2Cl)ccc(C(C)=O)c1O
Agent: CCCc1c(OCCCSc2ccc(CC(=O)OC)c(Cl)c2Cl)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(CC(=O)O)c(Cl)c2Cl)ccc(C(C)=O)c1O

Procedure:
By following Step H of Example 1, but substituting the product of Step A of this example for the ester of Step G of Example 1, the title compound, mp 180°-181° C., was obtained.
Reaction SMILES: [Cl:1][C:2]1C=CC2SC(CCl)=NC=2[CH:12]=1.[C:13]([NH:21][NH2:22])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][CH2:2][C:12]1[O:20][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:21][N:22]=1
Reactant: NNC(=O)c1ccccc1
Reactant: ClCc1nc2cc(Cl)ccc2s1
Product: ClCc1nnc(-c2ccccc2)o1

Procedure:
2-Chloromethyl-5-phenyl-[1,3,4]oxadiazole was prepared similarly to 5-chloro-2-chloromethyl-benzothiazole using benzoic acid hydrazide as the reagent.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH:11]([OH:13])[CH3:12].[CH:14]1C=CC=CC=1.[OH-].[Na+].CI>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCOCC>[CH3:14][O:13][CH:11]([CH3:12])[C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(C)O
Reactant: c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Solvent: O
Product: COC(C)c1cc([N+](=O)[O-])ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(2'-methyl-5'-nitrophenyl)ethanol (0.9 g) is dissolved in 5 ml. of benzene and 0.8 g of 50% aqueous sodium hydroxide, ca 10 mg of tetrabutylammonium chloride, 5 ml of ether and 1.25 ml of methyl iodide is added. The reaction mixture is stirred at room temperature for 2 hours and heated at 30°-35° for 4 hours. An additional 1.0 ml of methyl iodide is added and the mixture stirred at room temperature for 22 hours. Thin layer chromatography indicates starting material remaining therefore 0.52 ml of 50% NaOH solution and 2.0 ml of methyl iodide are added and the mixture stirred at room temperature for 5 days. Water is added and the mixture extracted with ether. The organic layer is washed with water and brine. The solution is evaporated to dryness giving 0.97 g of oil which is purified by column chromatography to give pure material, mp 35°-37° C.
Reaction SMILES: CC(C)([O-])C.[K+].C1(S([CH2:16][C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][N:18]=2)(=O)=O)C=CC=CC=1.[N:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][C:36]#[N:37])=[CH:30][CH:29]=1>O1CCCC1>[C:22]1([C:20]2[N:21]=[C:17]3[CH:16]=[C:34]([C:31]4[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=4)[CH:35]=[C:36]([NH2:37])[N:18]3[N:19]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccc2)n1)c1ccccc1
Reactant: N#CC=Cc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To a boiling suspension of 78.8 g(0.70 mol) potassium tert-butoxide in 400 ml tetrahydrofuran was slowly added over a period of 5 hours a mixture of 70.1 g (0.23 mol) 3-benzenesulfonylmethyl-5-phenyl-1H-[1,2,4]triazole and 30.5 g (0.23 mol) 3-(4-pyridinyl)-2-propenenitrile in 800 ml tetrahydrofuran. Boiling was continued for 18 hours and then the mixture was cooled to room temperature. Evaporation of the solvent and chromatography on silicael with dichloromethane/methanol 95/5 gave 19.8 g (29%) 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine as yellow crystals with mp. 207-210° C., MS m/e (%):287 (M+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=[C:5]([CH:13]=[O:14])[CH:4]=1.[CH3:15][Mg]Cl>O1CCCC1>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=[C:5]([CH:13]([OH:14])[CH3:15])[CH:4]=1
Reactant: C[Mg]Cl
Reactant: COc1cc(C=O)cc2c1OCCO2
Solvent: C1CCOC1
Product: COc1cc(C(C)O)cc2c1OCCO2
Temperature: 0 °C

Procedure:
In a 250 mL round-bottomed flask, 0.60 g (3.1 mmol) of 10 was dissolved in 15 mL of anhydrous tetrahydrofuran. The solution was cooled to 0° C. and treated with 1.1 mL (3.3 mmol) of 3M methyl magnesium chloride in THF. The reaction was stirred for a few minutes then quenched with a 1N HCl solution. The mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo to afford the alcohol 11.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:22]([C:23]([CH:25]3[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:33](=[O:42])[CH2:34][CH2:35][CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH2:27][CH2:26]3)=[O:24])[CH2:21][C:20]3[CH:19]=[N:18][N:17]([CH3:43])[C:16]=3[NH:15][C:14]=2[CH:44]=1>CN(C=O)C.C(N(CC)CC)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:22]([C:23]([CH:25]3[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:33](=[O:42])[CH2:34][CH2:35][CH:36]4[CH2:37][CH2:38][N:39]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:40][CH2:41]4)[CH2:27][CH2:26]3)=[O:24])[CH2:21][C:20]3[CH:19]=[N:18][N:17]([CH3:43])[C:16]=3[NH:15][C:14]=2[CH:44]=1
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)C1CCC(CNC(=O)CCC3CCNCC3)CC1)C2
Reactant: CCCCCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCN1CCC(CCC(=O)NCC2CCC(C(=O)N3Cc4cnn(C)c4Nc4cc(Cl)ccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-3-piperidin-4-yl-propionamide hydrochloride (Compound number 237) (2.57 mg, 0.005 mmol) in DMF (0.05 ml) and triethylamine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=597.6/599.6
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1.[Cl:12]Cl>C(Cl)(Cl)Cl>[Cl:12][C:5]1[C:6](=[O:9])[NH:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1
Reactant: ClCl
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Solvent: ClC(Cl)Cl
Product: O=c1[nH]cc(C(F)(F)F)cc1Cl

Procedure:
[A] 0.2 g of 5-trifluoromethyl-2-pyridone was dissolved in 20 ml of chloroform, and chlorine gas was pressed through the solution at 50° C. for 1 hour while stirring. After completion of the reaction, the chloroform was distilled off, and recrystallization was performed from a mixed solvent of toluene and n-hexane to obtain 0.15 g of the titled compound having a melting point of 144° to 147° C. The recrystallization was further repeated to obtain 0.09 g of the titled compound having a melting point of 165° to 166° C.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([NH:5][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A mixture of Pd(dba)2 (0.230 g, 0.400 mmol), (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene (0.374 g, 0.601 mmol) and toluene (40 mL) in a sealed tube was stirred for 30 min at room temperature before adding tert-butylamine (1.80 mL, 17.1 mmol), bromobenzene (1.60 mL, 15.2 mmol) and sodium tert-butoxide (2.01 g, 20.9 mmol). The reaction solution was flushed with Ar for 1 min. and was stirred for 24 h at 100° C. After cooling the reaction mixture to room temperature, Et2O (50 mL) was added. The reaction mixture was filtered through a pad of celite and was concentrated. Vacuum distillation of the crude mixture at 60° C. gave the desired product (1.876 g, 83.3%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.17 (t, J=7.9 Hz, 2 H), 6.83-6.69 (m, 3H), 3.37 (br. s, 1H), 1.35 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 147.1, 129.1, 118.6, 117.7, 51.7, 30.3. HRMS-ESI (m/z): [M+H]+ calcd for C10H15N, 150.1277. found, 150.1270.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH:20]1([C:23]([OH:29])([C:27]#[CH:28])[CH2:24][O:25][CH3:26])[CH2:22][CH2:21]1>CN(C)C=O.C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:28]#[C:27][C:23]([CH:20]1[CH2:22][CH2:21]1)([OH:29])[CH2:24][O:25][CH3:26])[N:5]=2
Reactant: C#CC(O)(COC)C1CC1
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC(O)(COC)C3CC3)nc21

Procedure:
A suspension of 0.47 g (1.68 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide in a mixture of 8.4 ml of dimethylformamide and 3 ml of triethylamine is placed in a 10 ml microwave tube. This suspension is sparged with argon for 10 minutes and then 0.433 g of (±)-2-cyclopropyl-1-methoxybut-3-yn-2-ol (3.09 mmol), 0.032 g of CuI (0.17 mmol) and 0.059 g of bis(triphenylphosphine) palladium(II)dichloride (0.08 mmol) are successively added.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].O>CN(C=O)C>[N+:24]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnccc1Oc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 107.8 %

Procedure:
To a solution of 5-hydroxyindole (7.45 g) in 100 ml of DMF was added K2CO3 (10.4 g). This mixture was stirred for 10 minutes at room temperature and then a solution of 4-chloro-3-nitropyridine (11.89 g) in 50 ml DMF was added dropwise. The reaction was allowed to proceed for 24 hours at room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl solution and dried over MgSO4. After filtration, the solvent was evaporated to yield an oil (15.4 g). This material was eluted with 5% ethyl acetate/DCM on a silica gel column via HPLC. The desired fractions were concentrated to yield a solid, 1.35 g, m.p. 182°-184° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CS(O[CH:22]([CH3:42])[CH2:23][N:24]1[C:32]2[N:31]=[C:30]([NH2:33])[N:29]3[N:34]=[C:35]([C:37]4[O:38][CH:39]=[CH:40][CH:41]=4)[N:36]=[C:28]3[C:27]=2[CH:26]=[CH:25]1)(=O)=O>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:12][CH2:13][N:14]([CH:22]([CH3:42])[CH2:23][N:24]2[C:32]3[N:31]=[C:30]([NH2:33])[N:29]4[N:34]=[C:35]([C:37]5[O:38][CH:39]=[CH:40][CH:41]=5)[N:36]=[C:28]4[C:27]=3[CH:26]=[CH:25]2)[CH2:15][CH2:16]1
Reactant: CC(Cn1ccc2c1nc(N)n1nc(-c3ccco3)nc21)OS(C)(=O)=O
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Cn1ccc2c1nc(N)n1nc(-c3ccco3)nc21)N1CCN(c2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (13.0 mg, 60 wt % in mineral oil, 0.3 mmol) in 2.0 mL of anhydrous DMF is added 2,4-difluorophenylpiperazine (63 mg, 0.32 mmol). After stirring the solution at RT for 15 min, a solution of 1-(5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)propan-2-yl methanesulfonate (80 mg, 0.21 mmol) in 1.5 mL of anhydrous DMF is added. The reaction is stirred at RT under N2 for 12 h. However, very little of product formation is seen by LC/MS. The reaction is then heated at 100° C. for 12 h to complete the reaction as detected by LC/MS. The crude reaction mixture is purified by chromatography to afford 7-(2-(4-(2,4-difluorophenyl)piperazin-1-yl)propyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: 1H NMR (400 MHz, CD2Cl2) δ 1.05 (d, 3H, J=6.83 Hz), 2.62-272 (m, 2H), 2.83-3.05 (m, 8H), 3.13-3.22 (m, 1H), 4.10 (dd, 1H, J=14.06 Hz and 6.64 Hz), 4.27 (dd, 1H, J=13.96 Hz and 7.52 Hz), 6.61 (dd, 1H, J=3.51 Hz and 1.76 Hz), 6.73 (d, 1H, J=3.51 Hz), 6.76-6.96 (m, 4H), 7.00 (d, 1H, J=3.32 Hz), 7.22 (dd, 1H, J=3.51 Hz and 0.78 Hz), 7.63 (dd, 1H, J=1.76 HZ and 0.78 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2([CH3:18])[NH:13][C:12](=[O:14])[CH2:11][N:10]3[N:15]=[CH:16][CH:17]=[C:9]23)[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][CH:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:3]=[C:4]([C:8]3([CH3:18])[NH:13][C:12](=[O:14])[CH2:11][N:10]4[N:15]=[CH:16][CH:17]=[C:9]34)[CH:5]=[CH:6][CH:7]=2)[CH:24]=[N:25][CH:26]=1
Reactant: CC1(c2cccc(Cl)c2)NC(=O)Cn2nccc21
Reactant: COc1cncc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cncc(-c2cccc(C3(C)NC(=O)Cn4nccc43)c2)c1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
Palladium(II) acetate (0.022 g, 0.097 mmol) was added to a stirred suspension of rac-4-(3-chloro-phenyl)-4-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazin-6-one (0.17 g, 0.65 mmol), 5-methoxypyridine-3-boronic acid (0.15 g, 0.97 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.080 g, 0.195 mmol) and potassium phosphate (0.28 g, 1.30 mmol) in toluene (2 mL) and EtOH (0.2 mL) at room temperature and under nitrogen. The mixture was stirred at 150° C. for 30 minutes under microwave irradiation. Then the mixture was filtered through diatomaceous earth and washed with AcOEt. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel; AcOEt). The desired fractions were collected and concentrated in vacuo to yield rac-4-[3-(5-methoxy-pyridin-3-yl)-phenyl]-4-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazin-6-one (0.11 g, 51% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:12]=3[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:10](=[O:29])[NH:9]2)=[C:4]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:3]=1.O.[CH3:35][N:36](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:29]=[C:10]1[NH:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]#[N:36])=[CH:3][C:4]=2[S:30]([CH3:33])(=[O:31])=[O:32])[C:17]2[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:12]=2[N:11]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[CH:20]=1
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)c1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Temperature: 110 °C

Procedure:
Under an atmosphere of argon, a mixture of 4-(4-bromo-2-(methylsulfonyl)phenyl)-1-(3-(trifluoromethyl)phenyl)-3,4,7,8-tetrahydroquinazoline-2,5(1H,6H)-dione (intermediate 34), zinc cyanide (22 mg, 0.191 mmol) and tetrakis(triphenylphosphine)-palladium(O) (17 mg, 15 pot) in N,N-dimethylformamide (1 mL) is heated at 110° C. over night. Water is added and the mixture is filtered. The precipitate is purifed by flash chromatography on silica (gradient cyclohexane/ethyl acetate 80:20 to 50:50). Yield: 47 mg; ESI mass spectrum [M+H]+=490; Retention time HPLC: 0.98 min (Z012_S04).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[N:6][CH:7]=1.C([Li])(C)(C)C.CN(C)[CH:24]=[O:25].[Cl-].[NH4+]>O1CCCC1>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:5]1[N:6]=[CH:7][C:2]([CH:24]=[O:25])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Fc1ccccc1CNc1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc(NCc2ccccc2F)nc1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 93.7 %

Procedure:
In a round bottom flask, (5-bromo-pyridin-2-yl)-(2-fluoro-benzyl)-amine (40, 3.90 g, 13.9 mmol) was combined with 60.0 mL of tetrahydrofuran at −78° C. under nitrogen and tert-butyllithium (5.57 mL, 2.50 M in hexane) was added over 5 minutes. After 30 minutes additional tert-butyllithium (17.1 mL, 1.7 M in hexane) was added over 5 minutes. After 25 minutes, N,N-dimethylformamide (2.6 mL, 34 mmol) was added and the mixture was stirred for 70 minutes at −78° C., then allowed to warm up to room temperature for 1 hour. The reaction was poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic portion was dried with sodium sulfate, filtered and filtrate concentrated under vacuum to provide the desired compound (41, 3.0 g), which was used in the next step without further purification.
Reaction SMILES: C(N[C:6]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)(=[O:11])=[O:10])=[O:7])CCC.C(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([N:8]=[C:6]=[O:7])(=[O:10])=[O:11]
Reactant: CCCCNC(=O)NS(=O)(=O)c1ccccn1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1ccccn1

Procedure:
To 125 ml of dry xylene is added with stirring 20.7 g of N-(butylcarbamoyl)-2-pyridinesulfonamide. This solution is heated to reflux, and phosgene is added until no further uptake of this gas is observed. It is then cooled, filtered and the solvent is removed in vacuo to yield 2-pyridinesulfonylisocyanate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[CH:2].Br[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1>C(N(CC)CC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)=[CH:13][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: C#Cc1cncc(OC)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c([N+](=O)[O-])c2)c1
Yield: 43.3 %

Procedure:
Sequentially add 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (400 mg, 3.0 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.100 g, 0.14 mmol) and copper (I) iodide (53 mg, 0.28 mmol) to a solution of 4-bromo-1-fluoro-2-nitrobenzene (616 mg, 2.8 mmol) in triethyl amine (6 mL) and heat for 2 h at 60° C. Add additional 3-ethynyl-5-methoxypyridine (100 mg, 0.75 mmol) and continue heating for 1 h. Concentrate and purify the residue by silica gel chromatography, eluting with 30:70 to 40:60 ethyl acetate:hexanes, to give the title compound as a pale yellow solid (330 mg, 43%).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].C([O-])([O-])=O.[K+].[K+].C([O:18][C:19](=[O:22])[CH2:20][SH:21])(C)(C)C>CC#N>[O:7]=[C:3]1[CH:2]([S:21][CH2:20][C:19]([OH:22])=[O:18])[CH2:6][CH2:5][O:4]1
Reactant: O=C1OCCC1Br
Reactant: CC(C)(C)OC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)CSC1CCOC1=O
Yield: 133.8 %

Procedure:
To a solution of 3-bromo-dihydro-furan-2-one (16 g, 97.6 mmol) in 300 mL of CH3CN was added K2CO3 (20 g, 146 mmol), followed by mercapto-acetic acid tert-butyl ester (14.5 g, 98 mmol). The reaction mixture was refluxed for 2 hrs and cooled. The mixture was filtered and the filtrate was concentrated. The residue was redissolved in 300 mL of EtOAc and the resulting solution was washed with 1N HCl (100 mL*2). The organic layer was dried over MaSO4, filtered andconcentrated to afford the ter-butyl ester title compound (23 g). 16 g of the ester was dissolved in 250 ml of HCl-MeOH (4M) and stirred at 25° C. for 4 hrs. The reaction mixture was concentrated below 45° C. in vacuum. The residue was purified by column chromatography (EtOAc) to afford 7 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=[O:15])=[C:12]([Br:16])[N:11]([CH:17]([CH3:19])[CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([OH:15])[C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[C:12]([Br:16])[N:11]([CH:17]([CH3:19])[CH3:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)n1nc(OCc2ccccc2)c(C=O)c1Br
Reactant: COc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2c(OCc3ccccc3)nn(C(C)C)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Benzyloxy-5-bromo-4-formyl-1-isopropyl-1H-pyrazole (0.7 g) was dissolved in tetrahydrofuran (5 mL), and a solution of 4-methoxyphenyl magnesium bromide in tetrahydrofuran (0.5 mL/L, 4.3 mL) was added to the stirred solution. The mixture was stirred at room temperature for 1 hour. A small amount of a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was purified by column chromatography on aminopropylated silica gel (eluent:tetrahydrofuran) to give the title compound (0.6 g).
Reaction SMILES: CCN(CC)CC.[C:8]1([CH:14]=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH2:17]([O:19][C:20]([C:22]1[N:23]=[C:24]2[CH2:29][NH:28][CH2:27][CH2:26][N:25]2[CH:30]=1)=[O:21])[CH3:18].[BH3-]C#N.[Na+]>CCO>[CH2:17]([O:19][C:20]([C:22]1[N:23]=[C:24]2[CH2:29][N:28]([CH2:14][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:27][CH2:26][N:25]2[CH:30]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cn2c(n1)CNCC2
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn2c(n1)CN(Cc1ccccc1)CC2
Reaction time: 3 h

Procedure:
Et3N (6.27 mL), PhCHO (4.92 mL) were added successively to the EtOH (81 mL) solution of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester, hydrochloride (9.47 g) at room temperature and stirred for 3 h under a nitrogen atmosphere. Then NaBH3CN (2.97 g) was added to the reaction mixture and stirred for 19 h. The mixture was filtered through a pad of Celite and diluted with CH2Cl2 and washed with 50% K2CO3 aq. The organic layer was dried (K2CO3) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with CHCl3-acetone (1/0˜9/1) and CHCl3-MeOH (19/1˜9/1). The titled compound was obtained as pale yellow crystals (4.16 g, 36%).