Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].Br[Zn][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C1COCC1>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Br[Zn]c1ccccn1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1-c1ccccn1
Temperature: 63 °C

Procedure:
A solution of 1-bromo-2-methoxy-4-nitrobenzene (7 g, 30.17 mmol), bromo(pyridin-2-yl)zinc (80 mL of 0.5M in THF, 40 mmol), tetrakis(triphenlyphosphine)palladium(0) (1.7 g, 1.47 mmol) in 70 mL THF was degassed with nitrogen for 10 minutes, then heated at 63° C. for 6 hr. The reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica (EtOAc/Hexane 3/7) to give 2-(2-methoxy-4-nitrophenyl)pyridine. MS (ESI) 231 (M++H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)[N:6]=[C:5]2[NH:18][CH3:19].[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:6]=[C:5]3[NH:18][CH3:19])[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CNc1nc(-c2cnccn2)nc2ccc(I)cc12
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(-c2cnccn2)nc2ccc(-c3cccc(OC)c3)cc12
Temperature: 80 °C
Yield: 26.5 %

Procedure:
In a 50 ml, round-bottomed flask was added 6-iodo-N-methyl-2-(pyrazin-2-yl)quinazolin-4-amine (0.100 g, 0.275 mmol), 3-methoxyphenylboronic acid (0.063 g, 0.413 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II) (0.016 g, 0.022 mmol), and potassium phosphate tribasic monohydrate (0.190 g, 0.826 mmol) in dioxane (5 mL) and water (0.5 mL) to give a brown suspension. The reaction mixture was heated at 80° C. overnight under argon. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and then a precipitate formed. The resulting solid was collected by filtration and washed with ethyl acetate and dried to give 25 mg of 6-(3-methoxyphenyl)-N-methyl-2-(pyrazin-2-yl)quinazolin-4-amine as a pale yellow solid in a 26% yield. LCMS m/z=344 (M+1) (Method D) (retention time=1.43 ruin). 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.85-8.78 (m, 1H), 8.77-8.71 (m, 1H), 8.70-8.63 (m, 1H), 8.63-8.55 (m, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.9 Hz, 1H), 7.53-7.31 (m, 3H), 7.09-6.92 (m, 1H), 3.86 (5, 3H), 3.17 (d, J=3.6 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[Cl:9][C:10]([Cl:14])([Cl:13])[CH:11]=O>C(#N)C>[Cl:9][C:10]([Cl:14])([Cl:13])[C@H:11]1[N:1]2[CH2:8][CH2:7][CH2:6][C@@H:2]2[C:3](=[O:5])[O:4]1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: O=C(O)[C@H]1CCCN1
Solvent: CC#N
Product: O=C1O[C@@H](C(Cl)(Cl)Cl)N2CCC[C@H]12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To reactant (D)-Proline (4.6 g, 40 mmol) suspended in anhydrous acetonitrile (100 mL), was added 2,2,2-trichloroacetaldehyde (11.78 g, 80 mmol) slowly. The mixture was stirred at RT for 20 hour and was clear solution. After concentrated in vacuum, the residue was purified by CombiFlash on a 80 g silica gel column using EtOAC/Hexane as eluents to give (3S,7aR)-3-(trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one 155a: 3.63 g, 37%. 1H NMR (400 MHz, Chloroform-d) δ 5.14 (s, 1H), 4.10 (dd, J=8.9, 4.7 Hz, 1H), 3.40 (ddd, J=10.9, 7.8, 6.0 Hz, 1H), 3.11 (dt, J=11.4, 6.0 Hz, 1H), 2.21 (dtd, J=13.0, 8.5, 6.8 Hz, 1H), 2.09 (ddt, J=12.7, 7.0, 5.2 Hz, 1H), 1.91 (ddq, J=12.4, 6.7, 5.7 Hz, 1H), 1.81-1.64 (m, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[N:11]=[C:10]([CH:12]=O)[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.NC1C2C=C(C=O)SC=2N=CN=1.NC1CCNC1.[CH:32]1([CH2:38][N:39]2C(C3C=CC=CC=3)=[C:42]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:41]=[CH:40]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:50]1([CH2:42][N:41]2[C:12]([C:10]3[S:9][C:5]4[N:6]=[CH:7][N:8]=[C:3]([S:2][CH3:1])[C:4]=4[N:11]=3)=[C:38]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:39]=[CH:40]2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: CSc1ncnc2sc(C=O)nc12
Reactant: c1ccc(-c2ncn(CC3CCCCC3)c2-c2ccccc2)cc1
Agent: NC1CCNC1
Agent: Nc1ncnc2sc(C=O)cc12
Product: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC3CCCCC3)nc12

Procedure:
The title compound was prepared by a similar process to that described for Example 65 but using 7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine-2-carbaldehyde (Intermediate 77) in place of 4-aminothieno[2,3-d]pyrimidine-6-carbaldehyde (Intermediate 73) and using cyclohexamethylamine in place of 3-aminopyrrolidine. Yellow solid (542 mg) (the product contained 33% of 1-(cyclohexylmethyl)-4,5-diphenyl-1H-imidazole but was used in subsequent steps without further purification);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[I:15].[CH3:19]C([O-])(C)C.[K+].CI.ClC1C=C(C=CC=1)OC1C=C2C(=CC=1)N(C)N=C2I>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:14]=[CH:13][C:12]2[C:8](=[C:9]([I:15])[N:10]([CH3:19])[N:11]=2)[CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: Clc1cccc(Oc2ccc3[nH]nc(I)c3c2)c1
Agent: Cn1nc(I)c2cc(Oc3cccc(Cl)c3)ccc21
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc2ccc(Oc3cccc(Cl)c3)cc2c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
To a solution of 5-(3-chlorophenoxy)-3-iodo-1H-indazole (194 mg, 524 μmol) in THF (5 mL) at 0° C. was added KOtBu (82.2 mg, 733 μmol) and the mixture stirred at 0° C. for 30 min. MeI (104 mg, 45.8 μL, 733 μmol) was added. The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane. The combined organics were dried over MgSO4 and concentrated to a clear oil, then purified by chromatography (40 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min) to afford the desired less polar 5-(3-chlorophenoxy)-3-iodo-1-methyl-1H-indazole (154 mg, 400 mmol, 77%) as a clear yellow oil. MS (M+H)+=384.8; 1H NMR (CDCl3) δ: 7.38 (d, J=9.1 Hz, 1H), 7.17-7.29 (m, 2H), 7.11 (d, J=2.3 Hz, 1H), 7.06 (dt, J=7.9, 0.9 Hz, 1H), 6.94 (t, J=2.3 Hz, 1H), 6.86 (dd, J=8.3, 2.3 Hz, 1H), 4.12 (s, 3H). The regioisomer, 5-(3-chlorophenoxy)-3-iodo-2-methyl-2H-indazole, (32 mg, 83.2 μmol, 16%) was also obtained as a clear yellow oil.
Reaction SMILES: C(N1CCC(OC2C=CC3N4CCCNC(=O)C4=CC=3C=2)CC1)(C)C.[CH2:26]([O:28][C:29]([C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([O:40][CH:41]1[CH2:46][CH2:45][N:44]([CH:47]([CH3:49])[CH3:48])[CH2:43][CH2:42]1)=[C:35]([Br:50])[CH:34]=2)=[O:30])[CH3:27].[C:51]([O:55][C:56]([N:58]1[CH2:62][C@H:61]([CH3:63])OS1(=O)=O)=[O:57])([CH3:54])([CH3:53])[CH3:52].CC(C)([O-])C.[K+]>>[CH2:26]([O:28][C:29]([C:31]1[N:32]([C@H:61]([CH3:63])[CH2:62][NH:58][C:56]([O:55][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:57])[C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([O:40][CH:41]1[CH2:46][CH2:45][N:44]([CH:47]([CH3:49])[CH3:48])[CH2:43][CH2:42]1)=[C:35]([Br:50])[CH:34]=2)=[O:30])[CH3:27]
Reactant: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Br)cc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: CC(C)(C)[O-]
Agent: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCCNC2=O)CC1
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Br)cc2n1[C@H](C)CNC(=O)OC(C)(C)C
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate b), from 6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid ethyl ester, (S)-5-methyl-2,2-dioxo[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (prepared according to WO 02/010169) and potassium tert-butoxide, to give the desired compound as a light yellow oil (53%). The thus obtained crude product was used without further purification for the next step.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12].[C-:13]#[C-:14].[Na+].[Na+]>CN(C=O)C>[Br:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:13]#[CH:14]
Reactant: [C-]#[C-]
Reactant: BrCCCCCCCCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCCCCCCCCCCBr
Yield: 106 %

Procedure:
A 100 mL round-bottom dry flask was purged with Argon gas. Anhydrous DMF (20 mL) and 1,10-dibromdecane (7.5 g, 25 mmol) were mixed and stirred with a stir bar. Sodium acetylide (7.4 g, 18% wt in xylene) was added slowly. The mixture was stirred at 70° C. overnight. The reaction was quenched with DI water (40 ml). The solution was extracted with CH2Cl2 (3×50 mL), re-extracted with DI water (2×50 mL), dried with sodium sulfate overnight, and filtered. After the removal of the solvent by rotoevaporation, 12-bromo-dodec-1-yne (6.5 g) was obtained. The resultant product was added to triethyl phosphate (10.9 ml, 62.5 mmol) and stirred for 24 h at 150° C. After cooling to room temperature, the excess amount of triethyl phosphate was removed under vacuum. A light yellow liquid was obtained (1 g, 20%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:19](S(C2C=CC=CC=2)(=O)=O)[C:18]2[C:13](=[N:14][C:15]([N:29](C(OC(C)(C)C)=O)[NH:30][C:31](OC(C)(C)C)=O)=[CH:16][CH:17]=2)[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].[NH4+].[Cl-].[CH3:49]C(O)=O>>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[NH:19][C:18]2[CH:17]=[CH:16][C:15]3[N:14]([C:31]([CH3:49])=[N:30][N:29]=3)[C:13]=2[CH:12]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(CCO[Si](C)(C)C(C)(C)C)n2S(=O)(=O)c2ccccc2)n1
Reactant: CC(=O)O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1nnc2ccc3[nH]c(CCO[Si](C)(C)C(C)(C)C)cc3n12
Temperature: 180 °C
Reaction time: 0.25 h

Procedure:
di-tert-Butyl 1-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (4.9 g, 7.6 mmol, from Step 2) in AcOH (60 mL) was divided into portions and each was heated in the microwave to a temperature of 180° C. for 4 minutes. The portions were combined and AcOH was removed in vacuo and the residue was dissolved in tetrahydrofuran (61 mL) and methanol (61 mL) and cooled to 0° C. 2.8 M NaOH (70 mL, 200 mmol) was added. After stirring for 15 minutes, sat′d NH4Cl was added and the product was extracted with DCM. The combined extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-10% MeOH in DCM afforded product as an off-white solid (1.2 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH:17]([OH:19])[CH3:18])=[CH:12]2)=[O:5]>ClCCl.[O-2].[Mn+4].[O-2]>[C:17]([C:13]1[CH:14]=[N:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:4](=[O:5])[C:3]1[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:2]=1[Cl:1])(=[O:19])[CH3:18]
Reactant: CC(O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-3-(1-hydroxyethyl)quinoline (562 mg) in dichloromethane (20 ml) was added manganese (IV) oxide (2.71 g), and the mixture was stirred at ambient temperature overnight. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. The residue was crystallized from ethanol to give 3-acetyl-8-(2,6-dichlorobenzoylamino)quinoline (101 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=O)#[N:2].O=S(Cl)[Cl:17]>ClCCl>[Cl:17][C:1]1[C:3]2[C:4](=[CH:5][C:6]([O:9][CH3:10])=[CH:7][CH:8]=2)[CH:11]=[C:12]([OH:14])[N:2]=1
Reactant: COc1ccc(C#N)c(CC(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(Cl)nc(O)cc2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
2-(2-cyano-5-methoxyphenyl)acetic acid (3.8 g, 19.88 mmol), and SOCl2 (20 mL, 274 mmol) were stirred in dichloromethane (25 mL) at RT. The suspension became a solution over 8 h. The reaction was stirred overnight. The volitile organics were removed under vacuum and the residue was taken up in DCM and filtered. The filtrate was concentrated and then dissolved in 4 N HCl dioxane (30 mL) and transferred to a sealed vessel and heated to 60° C. for 3 h. The reaction was cooled and the solid was collected, washed with dioxane, and dried under vacuum to give the product 1-chloro-6-methoxyisoquinolin-3-ol (3.3 g, 70% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (d, J=9.6 Hz, 1H), 7.12 (dd, J=9.3, 2.5 Hz, 1H), 6.95 (s, 2H), 3.98 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:37][CH2:38][C:39]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)=[O:40].C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([NH:37][CH2:38][C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[O:40])=[O:9])[CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: COc1ccc(C(=O)CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(C(=O)NCC(=O)c2ccc(OC)cc2)c1
Reaction time: 8 h
Yield: 194.4 %

Procedure:
1.8 g (5.5 mmol) of isophthalic acid monomethyl ester from Preparation 1, 3.5 g (18.5 mmol) of EDAC.HCl, 2.5 g (18.5 mmol) of HOBt, and 3.1 g (15.4 mmol) of 2-amino-1-(4-methoxy-phenyl)-ethanone hydrochloride were dissolved in 20 mL of dimethylformamide. 1.9 g (15.4 mmol) of di-isopropyl ethylamine was then added. Stirring was continued overnight at room temperature. Water (60 ml) was added, and the product was filtered, washed with water. The resulting solid was triturated in hot methanol, filtered and dried in a vacuum oven overnight at 70° C. to provide 3.5 g (69%) desired product. MS: m/z (APCI, AP+) 328 [M−]+ NMR: DMSO 1H δ (ppm) 3.84 (3H, s); 3.88 (3H, s); 4.73 (2H, d, J=5.6 Hz); 7.04–7.08 (2H m); 7.63–7.66 (1H, t, J=7.8 Hz); 7.99–8.027 (2H, m); 8.097–8.16 (2H, m); 8.47–8.48 (1H, m); 9.00–9.03 (1H, t, J=5.8 Hz).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccccc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
7-Chloro-3-[(benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was prepared starting from intermediate I and benzoyl chloride. MS calcd. for C25H20ClN2O4 [(M+H)+] 447.1, obsd. 446.9.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:7]=2[N:6]=[N:5]1.[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:16][C:12]1[C:7]2[N:6]=[N:5][N:4]([CH2:3][C:2]([CH3:15])([CH3:14])[CH3:1])[C:8]=2[CH:9]=[CH:10][C:11]=1[NH2:13]
Reactant: [Br-]
Reactant: CC(C)(C)Cn1nnc2cc(N)ccc21
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)Cn1nnc2c(Br)c(N)ccc21
Temperature: 25 °C

Procedure:
1-(2,2-Dimethylpropyl)-1H-1,2,3-benzotriazol-5-amine (3.52 g, 17.23 mmol, 1.0 equiv.) was dissolved in chloroform (172 ml) and treated with pyridinium tribromide (5.51 g, 17.23 mmol, 1.0 equiv.). The mixture was stirred at room temperature until LCMS indicated the reaction was complete. The mixture was filtered, the solid was collected and washed with hexanes. The solid was dissolved in diethyl ether/ethyl acetate and treated with saturated aqueous sodium bicarbonate. The organic layers was separated, dried with magnesium sulfate, filtered and concentrated in vacuo, providing the titled compound as pale white solid: 1H NMR (500 MHz, CD3OD) 7.30 (d, 1H, J=8.8 Hz), 7.07 (br s, 3H), 7.02 (d, 1H, J=8.8 Hz), 4.34 (s, 2H), 1.03 (s, 9H) ppm. LRMS m/z (M+H) 283.0 and 285.0 (intensity ratio ˜1:1) found, 283.1 and 285.1 required.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:32]=[CH:31][C:18]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])[N:21]=2)=[CH:17][CH:16]=1>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])[N:21]=3)=[CH:31][CH:32]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(NC(=O)Nc2ccc(Oc3ccnc(NCCCO)n3)cc2)cc1
Reaction time: 8 h

Procedure:
A solution of 154 mg (0.880 mmol) 4-t-butyl-phenyl isocyanate in 3 ml THF was given at 0° C. to a solution of 229 mg (0.880 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 5 ml THF within 10 min. After stirring overnight the reaction mixture was evaporated and the residue purified by chromatography on silica gel (dichloromethane/methanol 97:3). The obtained material was washed with dichloromethane and the precipitate was isolated by filtration and dried. Yield: 80 mg (21%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]([N:16]=[N+]=[N-])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]([NH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1C(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1C(=O)O
Yield: 91.1 %

Procedure:
Azido acid 5b (1.10 g, 4.29 mmol) was dissolved in 100 ml 10% water/ethanol containing 150 mg Pd/C and hydrogenated at 100 psi for 16 h. The mixture was filtered through a pad of celite, washed with 50 mL of 1:1 water/ethanol and the filtrate concentrated to dryness. This material was recrystallized from water/ethanol to give 900 mg of 6 (84% yield), m.p.=225°-227° C. (decomp.) 1H NMR (D2O) δ 1.40/1.44 (m, 9H), 2.11 (m, 1H), 2.68 (m, 1H), 3.69 (m, 2H), 3.99 (m, 2H), 4.20 (dd, J=9.0/3.9 Hz, 1H). Anal. (C10H18N2O4.H2O) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[C:12]#[C:13][C@@:14]1([CH3:29])[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].BrC(Br)C>C(O)C.[Zn]>[CH2:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][CH2:18][C@@:14]1([C:13]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[C:3]=2[CH:12]=1)[CH3:29])=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cccc(N)c1C#C[C@@]1(C)CCCN1C(=O)OCc1ccccc1
Agent: CC(Br)Br
Agent: [Zn]
Solvent: CCO
Product: COC(=O)c1cccc2[nH]c([C@@]3(C)CCCN3C(=O)OCc3ccccc3)cc12

Procedure:
To a refluxing solution of (R)-benzyl 2-((2-amino-6-(methoxycarbonyl)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate (1.1 g, 2.8 mmol) and dibromoethane (5.21 g, 2.8 mmol) in ethanol (20 mL) was added zinc powder (1.43 g, 22 mmol) in one portion. After refluxing for 8 h, the reaction mixture was filtered and the the filtrate was concentrated to 3 mL, which was poured into water (15 mL). The reaction mixture was extracted with EA (20 mL×3). The combined extracts were dried over sodium sulfate, filtered, and evaporated to give pale brown oil, which was chromatographed over silica gelelution with hexane:ethyl acetate (5:1) to give the (R)-methyl 2-(1-(benzyloxycarbonyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate and (307 mg, 0.78 mmol). 1H NMR (CDCl3-d) δ 10.3 (s, 1H), 7.83 (d, 1H, J=7.8 Hz), 7.53 (d, 1H, J=7.8 Hz), 7.29-7.35 (m, 5H), 7.16 (t, 1H, J=7.8 Hz), 6.96 (s, 1H), 5.15 (s, 2H), 3.95 (s, 3H), 3.56-3.59 (m, 2H), 2.83-2.85 (m, 1H), 2.03-2.07 (m, 2H), and 1.84-1.93 (m, 4H). MS (ESI) m/e [M+1]+ 393.0.
Reaction SMILES: C(C1C=CC=CC=1S(O)(=O)=O)CCCCCCCCCCC.[C:23]([OH:26])(=[O:25])[CH3:24].[OH-].[Mg+2:28].[OH-].CCCCCCCC/C=C\CCCCCC[CH2:46][C:47]([O:49]CC(O)[C@H]1OC[C@H](O)[C@H]1O)=[O:48]>>[C:23]([O-:26])(=[O:25])[CH3:24].[Mg+2:28].[C:47]([O-:49])(=[O:48])[CH3:46]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Reactant: CC(=O)O
Agent: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O
Agent: [Mg+2]
Agent: [OH-]
Product: CC(=O)[O-]

Procedure:
To a 4-liter beaker are charged 1890 g kerosene, 94 g (about 0.3 equiv.) dodecylbenzenesulfonic acid and 64 g (about 1.067 mole) glacial acetic acid. The contents are stirred until homogeneous. With stirrer on, 1250 g (about 21.44 moles) magnesium hydroxide is added followed by 218 g kerosene and 154 g sorbitan mono-oleate. A magnesium sulfonate and magnesium acetate are formed in situ. The mass is stirred for three hours. The viscosity of the mass is about 5000 cps. The magnesium content is calculated at about 14.2% for 3670 g total suspension. There was no separation of layers after 4 months of standing.
Reaction SMILES: [C:1]([N:4]1[CH2:20][CH2:19][CH2:18][C:7]2=[N+:8]([O-])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]([CH3:16])=[C:6]2[CH2:5]1)(=[O:3])[CH3:2].[C:21]([O:24]C(=O)C)(=[O:23])[CH3:22]>C1C=CC=CC=1>[C:1]([N:4]1[CH2:20][CH2:19][CH:18]([O:24][C:21](=[O:23])[CH3:22])[C:7]2=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]([CH3:16])=[C:6]2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCc2c(c(C)c3ccccc3[n+]2[O-])C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)OC1CCN(C(C)=O)Cc2c1nc1ccccc1c2C

Procedure:
A mixture of 3 gm (11 millimols) of 2-acetyl-2,3,4,5-tetrahydro-11-methyl-1H-azepino[4,3-b]quinoline 6-oxide, 80 ml of benzene and 23 ml of acetic acid anhydride was heated at its boiling point for 3 hours. Thereafter, the benzene was distilled off and the residue ws recrystallized from ether.
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13]3[C:17](Br)=[C:16]([O:19][CH3:20])[N:15]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([Li])CCC.[CH2:32]([O:34][C:35]([C:37]1[CH:38]=[C:39]([N:43]=[C:44]=[O:45])[CH:40]=[CH:41][CH:42]=1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35](=[O:36])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:44]([C:17]2[C:13]([CH2:12][O:11][C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[N:14][N:15]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:16]=2[O:19][CH3:20])=[O:45])[CH:38]=1)[CH3:33]
Reactant: COc1c(Br)c(COC23CC4CC(CC(C4)C2)C3)nn1C1CCCCC1
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Agent: [Li]CCCC
Product: CCOC(=O)c1cccc(NC(=O)c2c(COC34CC5CC(CC(C5)C3)C4)nn(C3CCCCC3)c2OC)c1

Procedure:
The compound was prepared by treating 3-(adamantan-1-yloxymethyl)-4-bromo-1-cyclohexyl-5-methoxy-1H-pyrazole with n-butyl lithium and 3-ethoxycarbonylphenyl isocyanate as outlined in Reaction Scheme 4.