Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=O)([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1>C1COCC1.[Zn].[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]([C:15]([O:17][CH3:18])=[O:16])([C:11]([O:13][CH3:14])=[O:12])[CH2:19][C:20]=2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(CC(=O)c1ccc(F)cc1)(CC(=O)c1ccc(S(C)(=O)=O)cc1)C(=O)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)CC(c2ccc(F)cc2)=C(c2ccc(S(C)(=O)=O)cc2)C1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
To a vigorously stirred mixture of 50.4 g (771 mmol) of zinc dust in 640 mL of THF at -78° C. under an atmosphere of nitrogen was added dropwise 60.4 mL (551 mmol) of titanium(IV) chloride. The reaction was warmed to ambient temperature with a water bath and then stirred at reflux for 1 hour. To the resulting dark mixture under reflux was added a solution of 15 g (32.3 mmol) of dimethyl 2-[2-(4-fluorophenyl)-2-oxoethyl]-2-[2-[4-(methylsulfonyl)phenyl]-2-oxoethyl]propanedioate (prepared above) in 20 mL of THF. The resulting mixture was stirred at ambient temperature for 16 hours, filtered through a pad of celite, rinsed with ethyl acetate, and concentrated in vacuo. The residue was partitioned between water and ethyl acetate; the organic phase was washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica gel to give 6.26 g (44%) of 1-[2-(4-fluorophenyl)-4,4-dicarbomethoxycyclopenten-1-yl]-4-(methylsulfonyl)benzene which was identical to the material prepared in Step 8, Method A.
Reaction SMILES: [CH3:1][C:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[C:5]([CH3:16])[N:4]([C:17]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:20]=[CH:19][N:18]=2)[N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[CH:12][CH:13]=2)=[C:5]([CH3:16])[N:4]([C:17]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:20]=[CH:19][N:18]=2)[N:3]=1
Reactant: Cc1nn(-c2nccc(-c3ccccn3)n2)c(C)c1Oc1ccc(CO)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cc1nn(-c2nccc(-c3ccccn3)n2)c(C)c1Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of {4-[3,5-dimethyl-1-(4-pyridin-2-yl-pyrimidin-2-yl)-1H-pyrazol-4-yloxy]phenyl}-methanol (1.53 g, 4.10 mmol) in chloroform (80 mL) was added the Dess-Martin periodinane (2.36 g, 5.56 mmol). The reaction mixture was stirred at room temperature for 3 hours and then concentrated to provide a white paste. Flash chromatography over silica (methanol/methylene chloride) provided 1.37 g (90%) the product as a white solid. 1H NMR analysis was consistent with assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:15][CH2:16][C:17](Br)=[O:18]>C1(C)C=CC=CC=1>[Br:15][CH2:16][C:17]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:18]
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(CBr)Nc1ccc(Cl)cc1

Procedure:
To a solution of 5 g 4-Chloro-phenylamine and 1.5 mL pyridine in 30 mL toluene, 8 g bromo-acetyl bromide dissolved in 10 mL toluene were added dropwise under ice cooling. After 2 h the precipitate was isolated by filtration and recrystallized from toluene to yield a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]([CH:9]([CH3:11])[CH3:10])[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[O:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[N:19]1[CH2:28][CH:29]=O.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.C1COCC1>[O:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[N:19]1[CH2:28][CH2:29][NH:8][C@H:7]([CH:9]([CH3:10])[CH3:11])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:12]
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@@H](NCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.4 %

Procedure:
(R)-Valine t-butyl ester (4.9 g; 28.28 mmol) was dissolved in methanol (100 ml). Acetic acid (1.62 ml; 28.28 mmol) and (1,3-dioxo-1,3-dihydroisoindol-2-yl)-acetaldehyde (5.40 g; 28.28 mmol) were added thereto. Then, sodium cyanoborohydride (1.95 g; 31.11 mmol) dissolved in THF (20 ml) was added. The mixture was stirred at RT for 6 h and then saturated NaHCO3 solution (200 ml) was added. Methanol was removed under reduced pressure, and the residue was extracted with EtOAc (3×; 100 ml). The combined organic phases were dried over MgSO4. Removal of the solvent under reduced pressure and purification of the residue by column chromatography (SiO′) resulted in t-butyl (R)-2-(2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethylamino)-3-methylbutyrate (6.60 g; 19.05 mmol). MS: 347.20 (M+H); Rt: 1.02 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:16]=[C:6]2[NH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:10](=[O:11])[N:5]2[N:4]=1.N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl>[C:23]([O:1][CH2:2][C:3]1[N:16]=[C:6]2[NH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:10](=[O:11])[N:5]2[N:4]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(=O)n2nc(CO)nc2[nH]1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(=O)n2nc(COC(C)=O)nc2[nH]1
Temperature: 55 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
Methyl 4,7-dihydro-2-(hydroxymethyl)-7-oxo-s-triazolo[1,5-a]pyrimidine-5-carboxylate (2.5 g) (11.1 mmol) are suspended in 20 ml of dichloromethane. After the addition of 1.76 g (22.3 mmol) of pyridine and 2.27 g (22.2 mmol) of acetic anhydride the mixture is stirred at 55° C. for 8 hours. The mixture is concentrated in a vacuum and the product is precipitated with diethyl ether. After recrystallization from methanol there are obtained 1.2 g of methyl 2-(acetoxymethyl)-4,7-dihydro-7-oxo-s-triazolo[1,5-a]pyrimidine-5-carboxylate as white crystals of melting point 260° C.
Reaction SMILES: CC1N=CC=CC=1C(N)=O.[C:11]([C:15]1[N:20]=[C:19]([Cl:21])[C:18]([CH:22]([NH2:24])[CH3:23])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[C:25]([C:27]1[C:32]2[N:33]([CH2:36][C:37](O)=[O:38])[CH:34]=[N:35][C:31]=2[CH:30]=[CH:29][CH:28]=1)#[N:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:11]([C:15]1[N:20]=[C:19]([Cl:21])[C:18]([CH:22]([NH:24][C:37](=[O:38])[CH2:36][N:33]2[C:32]3[C:27]([C:25]#[N:26])=[CH:28][CH:29]=[CH:30][C:31]=3[N:35]=[CH:34]2)[CH3:23])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: CC(N)c1ccc(C(C)(C)C)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ncccc1C(N)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)Cn1cnc2cccc(C#N)c21)c1ccc(C(C)(C)C)nc1Cl

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 2-methylnicotinamide, starting from [1-(6-tert-butyl-2-chloropyridin-3-yl)ethyl]amine (intermediate 26) (100 mg, 0.47 mmol), 7-cyanobenzimidazole-1-acetic acid (0.42 mmol), HATU (191 mg, 0.5 mmol) and DIPEA (182 μL, 1.41 mmol). The product was recovered by filtration following precipitation induced by the addition of water. Yield 111 mg, 67%. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.27 (s, 9 H), 1.38 (d, J=7.03 Hz, 3 H), 5.05-5.13 (m, 1 H), 5.21-5.32 (m, 2 H), 7.34 (dd, J=8.01, 7.62 Hz, 1 H), 7.43 (d, J=8.01 Hz, 1 H), 7.71 (dd, J=7.62, 0.98 Hz, 1 H), 7.86 (d, J=8.01 Hz, 1 H), 8.01 (dd, J=8.01, 0.98 Hz, 1 H), 8.34 (s, 1 H), 9.06 (d, J=7.23 Hz, 1 H). MS [MH+] calc. 396.1591 found 396.3.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:17][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(SCCCOCc3ccccc3)nc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Br-]
Agent: [Zn+2]
Product: c1ccc(COCCCSc2ncc(C3CCNCC3OCc3ccc4ccccc4c3)cn2)cc1

Procedure:
In an analogous manner to that described in Example 125 (h), from tert-butyl (3RS,4RS)-4-[2-(3-benzyloxy-propylsulphanyl)-pyrimidin-5-yl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate by cleavage of the BOC group by means of anhydrous zinc bromide there was obtained 2-(3-benzyloxy-propylsulphanyl)-5-[(3RS,4RS)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-pyrimidine in in the form of an amorphous, colourless solid; MS: 500 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([O:13][C:14]3[C:15]4[O:23][CH:22]=[CH:21][C:16]=4[CH:17]=[N:18][C:19]=3[NH2:20])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:24]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([O:13][C:14]4[C:15]5[O:23][CH:22]=[CH:21][C:16]=5[CH:17]=[N:18][C:19]=4[NH2:20])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(Cl)nn12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(-c3ccccc3)nn12

Procedure:
A mixture of 7-[(S)-1-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethoxy]furo[3,2-c]pyridine-6-ylamine (15.0 mg, 0.045 mmol), phenylboronic acid (11.1 mg, 0.091 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (18.8 mg, 0.136 mmol) and 4:1 dioxane:water (2 mL) was heated in a microwave reactor at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=2.10 (d, J=6.8 Hz, 3H), 6.55 (q, J=6.6 Hz, 1H), 6.77 (d, J=2.5 Hz, 1H), 7.48-7.56 (m, 3H), 7.59 (d, J=2.3 Hz, 1H), 7.76 (d, J=9.6 Hz, 1H), 7.80-7.85 (m, 2H), 8.05 (s, 1H), 8.21 (d, J=9.6 Hz, 1H). MS (ES+): m/z 373.09 (100) [MH+]. HPLC: tR=2.28 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:20][CH:19]3[CH2:21][CH2:22][CH2:23][CH:18]3[CH:17]2[CH2:24][OH:25])=[O:15])=[CH:4][CH:3]=1.Cl[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[O:25][CH2:24][CH:17]1[CH:18]2[CH2:23][CH2:22][CH2:21][CH:19]2[CH2:20][N:16]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:15]
Reactant: Clc1nc2ccccc2o1
Reactant: Cc1nc(C(=O)N2CC3CCCC3C2CO)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CC3CCCC3C2COc2nc3ccccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared following the same general protocol as described for Example 80 using (5-(4-fluorophenyl)-2-methylthiazol-4-yl)(1-(hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone and 2-chlorobenzoxazole. MS (ESI) 478.2 (M+H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:34]=[CH:33][C:25]([CH2:26][N:27]([CH3:32])[CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.CN.[CH2:37]([N:39](CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>O1CCCC1.C(OCC)(=O)C.C(Cl)Cl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]([CH3:32])[CH2:28][C:29]([NH:39][CH3:37])=[O:30])=[CH:33][CH:34]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCN(CC)CC
Reactant: CN(CC(=O)O)Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Agent: CN
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)CN(C)Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
A mixture of the compound (70 mg) obtained in Example 30, 2N methylamine in tetrahydrofuran solution (0.65 ml), triethylamine (59 mg), bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (39 mg) and methylene chloride (5 ml) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated is under reduced pressure. The residue was purified by column chromatography [developing solvent:ethyl acetate-methanol (10:1, volume ratio)] and recrystallized from ethyl acetate-hexane (1:1, volume ratio) to give the title compound (14 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[NH2:15])[CH3:2].[Cl:16][C:17]1[C:18]([C:27]([F:30])([F:29])[F:28])=[N:19][N:20]([CH2:23][C:24](O)=[O:25])[C:21]=1[CH3:22].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:16][C:17]1[C:18]([C:27]([F:29])([F:28])[F:30])=[N:19][N:20]([CH2:23][C:24]([NH:15][C:4]2[CH:5]=[N:6][N:7]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[C:3]=2[CH2:1][CH3:2])=[O:25])[C:21]=1[CH3:22]
Reactant: CCc1c(N)cnn1-c1ccc(F)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(NC(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 5-ethyl-1-(4-fluorophenyl)pyrazol-4-amine (0.02 g, 0.1 mmol) in DMF (1.0 mL) was added 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]acetic acid (0.024 g, 0.10 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.045 g, 0.12 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water, and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.015 g, 0.035 mmol, 35%). 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.92 (s, 1H), 7.40-7.31 (m, 2H), 7.17 (dd, J=8.9, 8.1 Hz, 2H), 4.93 (s, 2H), 2.56 (q, J=7.6 Hz, 2H), 2.39 (s, 3H), 1.01 (t, J=7.6 Hz, 3H); MS: (ES) m/z calculated for C18H16ClF4N5O [M+H]+ 430.1, found 430.0.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[CH3:8].C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCCCCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:8][C:3]1[S:4][C:5]([Cl:7])=[CH:6][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1sc(Cl)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Cl)c(CBr)s1
Temperature: 0 °C
Yield: 55.3 %

Procedure:
A solution of 3,5-Dichloro-2-methyl-thiophene (1.3 grams, 7.8 mmole), NBS (1.4 grams, 7.8 mmole) and benzoyl peroxide (0.065 g) in carbon tetrachloride (40 ml) was refluxed for 18 hours. The mixture was cooled to 0° C., diluted with 40 ml hexane and filtered. The filtrate was concentrated to an oil which was purified via flash chromatography on silica using hexane as eluent to give an oil (1.06 g). MW 245.95; MS (m/e) 246 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Br:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.Br[CH2:12][C:13](=[C:15]([C:18]#[N:19])[C:16]#[N:17])[CH3:14]>C(O)(C)C.O1CCCC1>[NH2:19][C:18]1[N:8]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([Br:10])=[CH:5][C:6]=2[Br:9])[CH:12]=[C:13]([CH3:14])[C:15]=1[C:16]#[N:17]
Reactant: Nc1c(Cl)cc(Br)cc1Br
Reactant: CC(CBr)=C(C#N)C#N
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1cn(-c2c(Cl)cc(Br)cc2Br)c(N)c1C#N
Yield: 26.3 %

Procedure:
A mixture of 5.3 g of 6-chloro-2,4-dibromoaniline and 3.5 g of 2-(2-bromo-1-methylethylidene)malononitrile was dissolved in a mixed solution of 10 ml of isopropanol and 10 ml of tetrahydrofuran. The reaction mixture was heated for 2 hours while being concentrated at 120° C. Water was poured into the reaction mixture. The reaction mixture was extracted with chloroform. The organic layer was ;washed with a saturated aqueous solution of sodium hydrogencarbonate and was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure and was allowed to stand for crystallization to yield 1.9 g of 2-amino-4-methyl-1-(2,4-dibromo-6-chlorophenyl)pyrrole-3-carbonitrile.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=[C:10]([C:11]([O:13]C)=O)[C:4]=2[O:3]1.[CH2:19]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][NH2:29])[CH:20]([CH3:22])[CH3:21].O>C(O)COCCO>[CH2:19]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][NH:29][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=1)=[O:13])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CN1CCCC1CN
Reactant: COC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Solvent: OCCOCCO
Solvent: O
Product: CC(C)CN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
A suspension of 5.2 g of methyl 2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylate and 4.5 g of 1-isobutyl-2-aminomethylpyrrolidine in 20 ml of diethylene glycol is heated at 130°-140° C. and stirred for 18-19 hours. The reaction solution is cooled to room temperature and poured into 150-200 ml of water while stirring. Under ice-cooling crystals are deposited thoroughly and collected by suction filtration. The crude crystals are washed with cold water, dissolved in chloroform and separated on a column of silica gel (developing solvent: methanol/chloroform=1/9). Crystals obtained are recrystallized from about 35 ml of methanol to give crystals of N-(1-isobutyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 182°-184° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:44][C:45]3[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=3)=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Reactant: Nc1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)Nc1ccncc1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), 4-aminopyridine (25 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C16H17ClN6O2, 361.12. found 361.2.
Reaction SMILES: [NH:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[N:3]1[CH2:13][CH:14]=[CH2:15].[Br:16]N1C(=O)CCC1=O>CS(C)=O.O>[Br:16][CH2:15][CH:14]1[CH2:13][N:3]2[C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]2=[N:1]1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCn1c(=O)[nH]c2ccccc2c1=N
Solvent: O
Solvent: CS(C)=O
Product: O=C1Nc2ccccc2C2=NC(CBr)CN12
Temperature: 25 °C
Yield: 64.3 %

Procedure:
To a solution of 3,4-dihydro-4-imino-3-allyl-2(1H)-quinazolinone (0.5 g, 2.5 mmol) in dimethylsulfoxide (2.5 mL) and water (1 mL) was added N-bromosuccinimide (0.87 g, 5.0 mmol). The mixture was allowed to stir at room temperature and then was quenched with water (100 mL) to get solid. The solid was collected by filtration and washed with water to give 2-bromomethyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one (450 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.C1COCC1.O.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(C2CCC(c3ccc([N+](=O)[O-])cc3)N2c2ccc(F)cc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(C2CCC(c3ccc(N)cc3)N2c2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
To a solution of the product from Example 1D (0.501 g, 1.23 mmol) in ethanol (5 ml) and THF (5.00 ml) was added iron powder (0.412 g, 7.38 mmol) and a solution of ammonium chloride (0.197 g, 3.69 mmol) in water (1.0 ml). The resulting mixture was stirred at 80° C. for 45 min. The mixture was cooled, filtered through celite, washed with ethanol, and concentrated in vacuo. The crude product was purified by chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in hexanes to give the title compound as a mixture of cis and trans isomers (0.135 gm, 32%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:14]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:2]([CH3:1])[CH:3]=1)[CH3:15])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(=O)c1ccc(OCC(F)(F)F)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)ccc1OCC(F)(F)F
Yield: 64 %

Procedure:
The title compound is prepared in 64% yield (6.05 g, colorless oil) from 1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethanone (6.55 g, 28.2 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (5.13 g, 42.3 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C@H:11]([C:32]([O:34][CH3:35])=[O:33])[CH2:12][N:13]1[C:17](=[O:18])[C:16]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[NH:15][C:14]1=[O:31].[CH2:36]([O:43][C:44](ON1C(=O)CCC1=O)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH2:36]([O:43][C:44]([NH:10][C@H:11]([C:32]([O:34][CH3:35])=[O:33])[CH2:12][N:13]1[C:17](=[O:18])[C:16]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[NH:15][C:14]1=[O:31])=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@@H](N)CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.08 g (16.1 mmol) of diisopropylethylamine in 25 ml of absolute DMF are added to a solution of 3.14 g (8.48 mmol) of (34.5) and 2.11 g (8.48 mmol) of N-benzyloxycarbonyloxysuccinimide in 80 ml of absolute DMF and the mixture is left to stir at room temperature for 3 h. The solvent is removed in vacuo and the residue is chromatographed through silica gel using heptane/ethyl acetate=6/4. (34.6) is obtained after concentrating the product fractions.