Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]([CH3:31])([C:27]([F:30])([F:29])[F:28])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:11][C:10]=1[C:24](O)=[O:25])=O)(=O)C.C([NH2:34])=O>O>[F:29][C:27]([F:28])([F:30])[C:5]([C:6]1[NH:34][C:24](=[O:25])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:16])=[O:17])[CH:11]=2)[N:8]=1)([OH:4])[CH3:31]
Reactant: CC(=O)OC(C)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1C(=O)O)C(F)(F)F
Reactant: NC=O
Solvent: O
Product: CC(O)(c1nc2ccc(S(=O)(=O)c3ccccc3)cc2c(=O)[nH]1)C(F)(F)F

Procedure:
2-Acetoxy-N-(2-carboxy-4-phenylsulfonylphenyl)-3,3,3-trifluoro-2-methylpropionamide (100 mg) and formamide (2 mL) were mixed and heated at reflux for 1 hour. The reaction mixture was then cooled, poured into water and extracted with ethyl acetate. The ethyl acetate was washed (water, brine) dried (Na2SO4) and evaporated. The crude solid was treated with charcoal in ethyl acetate, and then crystallized from warm ethyl acetate by addition of hexanes to the cloud point, to give the title compound (69 mg) as white needles; mp 202°-204° C.; NMR: 1.73 (s,3), 7.62-7.73 (m,4), 7.86 (d,1), 8.01 (d,2), 8.27 (d,1), 8.59 (s,1); MS: m/z=399(M+1). Analysis for C17H13F3N2O4S.0.1 C4H8O2 : Calculated: C, 51.33; H, 3.42; N, 6.88; Found: C, 51.70; H, 3.58; N, 6.98.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.Cl.[CH3:40][NH:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46]>C(Cl)Cl>[C:2]([O:4][CH:5]1[C:14]2[C:15]3([CH3:30])[C:16]([C:17](=[CH:18][N:41]([CH3:40])[CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])[C:23](=[O:24])[O:25][CH:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CNCCCC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC1OC(=O)C(=CN(C)CCCC(=O)O)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added 4-(methylamino)butyric acid hydrochloride (71 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 549 (M+H).
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(O)=O.S(=O)(=O)(O)O.[NH:24]=[N+]=[N-]>C(Cl)CCl>[NH2:24][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(C2CCCc3cncn32)cc1
Reactant: [N-]=[N+]=N
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: Nc1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 2.42 g of 5-(p-carboxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in 100 ml of ethylene dichloride is treated with 6 ml of concentrated sulfuric acid. The reaction mixture is heated to 40° and 6 ml of hydrazoic acid (2M is ethylene dichloride) is added dropwise. When gas evolution has ceased, the reaction mixture is evaporated. The residue is redissolved in water and adjusted to pH 10. The aqueous phase is extracted with methylene chloride (3×30 ml). The organic extracts are dried over potassium carbonate and evaporated to yield the title compound.
Reaction SMILES: FC(F)(F)C(N1CCC([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:23]=4)=[N:20][CH:21]=3)[CH:13]=[N:12]2)CC1)=O.IC1C=NN([C@H:42]2[CH2:47][CH2:46][C@H:45]([N:48]3[CH2:52][CH2:51][O:50][C:49]3=[O:53])[CH2:44][CH2:43]2)C=1>>[CH3:33][N:31]1[CH:32]=[C:28]([C:24]2[CH:23]=[C:22]([C:19]3[N:20]=[CH:21][C:16]([C:14]4[CH:13]=[N:12][N:11]([CH:42]5[CH2:43][CH2:44][CH:45]([N:48]6[CH2:52][CH2:51][O:50][C:49]6=[O:53])[CH2:46][CH2:47]5)[CH:15]=4)=[CH:17][N:18]=3)[CH:27]=[CH:26][CH:25]=2)[CH:29]=[N:30]1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCN(C(=O)C(F)(F)F)CC5)c4)cn3)c2)cn1
Reactant: O=C1OCCN1[C@H]1CC[C@H](n2cc(I)cn2)CC1
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCC(N6CCOC6=O)CC5)c4)cn3)c2)cn1
Yield: 51 %

Procedure:
The title compound was obtained following procedure described for example 182 but starting from 5-Bromo-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2; 200 mg; 0.63 mmol; 1.0 eq.) and trans-3-[4-(4-Iodo-pyrazol-1-yl)-cyclohexyl]-oxazolidin-2-one (intermediate 27; 231 mg; 0.63 mmol; 1.0 eq.). The crude was triturated in acetonitrile and the suspension filtered and dried under vacuum to afford the title compound as a brown solid (151 mg, 51%). 1H NMR (300 MHz, DMSO) δ 9.21 (s, 2H), 8.58 (d, J=3.6 Hz, 2H), 8.38-8.10 (m, 3H), 7.98 (s, 1H), 7.86-7.44 (m, 2H), 4.32 (dd, J=14.8, 6.5 Hz, 3H), 3.95 (s, 3H), 3.78-3.46 (m, 4H), 2.23 (s, 2H), 2.08-1.57 (m, 7H). HPLC (Condition A): Rt 3.39 min (purity 97.9%). MS (ESI+): 470.4.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:33][CH3:34])[N:6]2[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1.[CH3:35][NH:36][CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1>[CH3:35][N:36]([CH2:29][C:28]1[CH:31]=[CH:32][C:25]([CH2:24][N:21]2[CH2:20][CH2:19][CH:18]([CH2:17][CH2:16][N:6]3[C:5]([O:33][CH3:34])=[N:4][C:3]4[C:7]3=[N:8][C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:10][C:2]=4[NH2:1])[CH2:23][CH2:22]2)=[CH:26][CH:27]=1)[CH3:37]
Reactant: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(Cc4ccc(C=O)cc4)CC3)c2n1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(Cc4ccc(CN(C)C)cc4)CC3)c2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34.3 %

Procedure:
The compound (0.31 g, 1.66 mmol) obtained in Step (ii) was dissolved in THF (10 ml), and thereto were added at 0° C. dimethylamine (2M THF solution, 2.62 ml, 5.24 mmol) and sodium triacetoxy borohydride (0.56 g, 2.62 mmol), and the mixture was stirred at room temperature for 20 hours. The mixture was cooled to 0° C., and thereto was added a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted three times with chloroform/ethanol=3/1. The extract was dried over magnesium sulfate, concentrated, and purified by silica gel column (chloroform/methanol/28% aqueous ammonia=100/5/0 to 100/5/1) to give the title compound (0.28 g, 0.57 mmol) as a white solid. Yield: 87%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: CN(CCCCl)C(=O)OC(C)(C)C
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C(=O)OC(C)(C)C)C=C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 137.9 %

Procedure:
Suspend 1.7 g (7.8 mmol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one in 35 ml of DMF and then add 374 mg (9.35 mmol, 1.2 equivalents) of sodium hydride (60% suspension in oil). A clear pale yellow solution is obtained, which is stirred for one hour at 25° C. 1.94 g (9.35 mmol, 1.2 equivalent) of tert-butyl (3-chloropropyl)methylcarbamate dissolved in 10 ml of DMF are then added dropwise. The whole is heated at 50° C. overnight and then the solvent is evaporated to dryness. The residue is taken up in water and extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. 4.2 g of an oil is obtained which is purified by flash chromatography on 200 g of silica (eluant=dichloromethane/ethyl acetate:80/20). 2.3 g of the expected product are obtained in the form of a colourless oil.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH:8]1[O:12][C:11]2[C:13]3[CH2:14][CH2:15][CH2:16][C:17]=3[CH:18]=[CH:19][C:10]=2[CH2:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[O:12]1[CH:8]([CH2:7][OH:6])[CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[CH2:16][CH2:15][CH2:14][C:13]=3[C:11]1=2
Reactant: CC(C)(C)[Si](C)(C)OCC1Cc2ccc3c(c2O1)CCC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OCC1Cc2ccc3c(c2O1)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of (±)-tert-butyl(dimethyl)(3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-ylmethoxy)silane (2.93 g; 9.62 mmol) in tetrahydrofuran (100 mL) cooled to 0° C. was added tetrabutylammonium fluoride (10.6 mL, 1.0 M solution in tetrahydrofuran) and the reaction mixture was allowed to stir at room temperature for 8 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:3) afforded 1.67 g (91%) of (±)-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-ylmethanol as a colorless oil. Rf=0.63 (silica, ethyl acetate:hexanes 1:2); Anal. calcd. for C12H14O2: C, 75.76; H, 7.42. Found: C, 74.46; H, 7.44.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:7]=2[N:8]=1.I[CH3:16].O>CN(C=O)C>[CH3:16][S:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CI
Reactant: N#Cc1ccc2nc(S)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(C#N)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
Sodium hydride (60% in mineral oil, 1.92 g, 48 mmol) was suspended in DMF (60 mL) at 0° C. and 2-mercaptobenzo[d]thiazole-6-carbonitrile (5.76 g, 30 mmol) from Step 2 of this Example was added slowly. After gas evolution ceased, iodomethane (8.4 mL, 135 mmol) was added and the reaction mixture was stirred at rt overnight. To the reaction mixture was added 300 mL of water and the precipitate was collected by filtration to give 2-(methylthio)benzo[d]thiazole-6-carbonitrile as a light yellow solid (5.47 g, 89%). 1H NMR (300 MHz, CDCl3) δ 8.08 (d, J=1.1 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.67 (dd, J=1.5, 8.5 Hz, 1H), 2.83 (s, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8](C(OC(C)(C)C)=O)[C@H:9]([C:19]([NH:21][C@H:22]([C:39]([NH:41][C@H:42]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])=[O:40])[CH2:23][C:24]1[N:28]=[CH:27][N:26]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:25]=1)=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[NH2:8][C@H:9]([C:19]([NH:21][C@H:22]([C:39]([NH:41][C@H:42]([C:58]([O:60][CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)=[O:59])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:49])=[O:40])[CH2:23][C:24]1[N:28]=[CH:27][N:26]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:30])=[O:31])[CH:25]=1)=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)[C@H](COCc3ccccc3)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)[C@@H](N)COCc3ccccc3)C(=O)N[C@@H](CCCCNC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)c2)cc1
Yield: 96.4 %

Procedure:
150 ml of TFA was added to 87.7 g of Boc-Ser(Bzl)-His(Tos)-Lys(Z)-OBzl dissolved in 130 ml of methylene chloride under cooling with ice, and the mixture was stirred at the same temperature for an hour and then at room temperature for an hour. Thereafter, procedures similar to those in (iv) in Example 1 were conducted to obtain 75.5 g of Compound 1.
Reaction SMILES: [H-].[Na+:2].NC1C=CC=CC=1.[CH3:10][C:11]1[CH2:15][C:14]([CH3:16])=[C:13]([CH3:17])[C:12]=1[CH3:18]>O1CCCC1>[CH3:10][C:11]1[CH:15]([Na:2])[C:14]([CH3:16])=[C:13]([CH3:17])[C:12]=1[CH3:18]
Reactant: [Na+]
Reactant: CC1=C(C)C(C)=C(C)C1
Agent: [H-]
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: CC1=C(C)C([Na])C(C)=C1C
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (containing mineral oil; the content of sodium hydride: 60 wt. %) (0.60 g) was suspended in tetrahydrofuran (6.91 g), and then aniline (0.047 g) was dropwise added to the suspension at 25° C. After heating to 50° C., the suspension was stirred for 10 minutes. Thereafter, tetramethylcyclopentadiene (1.22 g) was dropwise added to the suspension while maintaining the suspension at 50° C., followed by stirring for one hour. Thus, tetramethylcyclopentadienylsodium was obtained. After cooling the above solution to 20° C., the solution of (2-allyloxy-3-tert.-butyl-5-methylphenyl)chlorodimethylsilane (3.86 g; purity: 73%; pure compound: 2.82 g) in toluene was dropwise added to the above solution, followed by stirring for 2 hours.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O1CCCC1>[C].[Pd].CO>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:28]=[CH:29][CH:30]=[C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:20][CH:21]=1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc([N+](=O)[O-])cc4)c3)c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc(N)cc4)c3)c2)CC1
Yield: 111.9 %

Procedure:
Using 3-(1-cyanocyclopropyl)-N-[3-(4-nitrophenoxy)phenyl]benzamide (5.1 g, 12.7 mmol), tetrahydrofuran (50 mL), methanol (50 mL) and 10% palladium-carbon (455.9 mg) as starting materials, and in the same manner as in Example A12(iii), the title compound (5.25 g) was obtained as a colorless amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:35][CH2:36][CH3:37])=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:35][CH2:36][CH3:37])=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc2ncnc(Cl)c2cc1OCC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: CCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCC
Temperature: 90 °C

Procedure:
A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (0.137 g, 0.5 mmol), 4-chloro-6,7-diethoxyquinazoline from the previous step (0.126 g, 0.5 mmol), and Cs2CO3 (0.326 g, 1 mmol) in isopropanol (6 mL) was heated at 90° C. for 4 hours. The reaction was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc/hexane as eluant to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(6,7-diethoxyquinazolin-4-yloxy)phenyl]urea as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.03 (s, 1H), 8.56 (s, 1H), 7.57 (m, 1H), 7.55 (s, 1H), 7.40 (t, 1H), 7.37 (s, 1H), 7.25 (d, 1H), 6.96 (dd, 1H), 6.47 (s, 1H), 4.26 (m 4H), 1.43 (m, 6H), 1.27 (s, 9H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[F:16][C:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH:18]=1>CCO>[F:16][C:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:19][CH:18]=1
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CC=C(F)CC1
Agent: Cl
Solvent: CCO
Product: CC(=O)Nc1ccc(NCC2CC=C(F)CC2)c([N+](=O)[O-])c1

Procedure:
N-(4-Fluoro-3-nitrophenyl)acetamide (460 mg, 2.32 mmol) and [(4-fluorocyclohex-3-en-1-yl)methyl]amine hydrochloride (350 mg, 2.11 mmol) were stirred in 20 mL of EtOH containing TEA (0.735 mL, 5.28 mmol) at 75° C. for 48 h. The solvent was concentrated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 2:1/hexanes:acetone as eluent. Yield: 553 mg (85%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.51-1.61 (m, 1 H), 1.84-1.93 (m, 1 H), 1.96-2.03 (m, 2 H), 2.16-2.18 (m, 3 H), 2.22-2.32 (m, 3 H), 3.26 (m, 2 H), 5.19 (m, 1 H), 6.84 (d, J=9.37 Hz, 1 H), 7.21 (s, 1 H), 7.79 (dd, J=9.18, 2.54 Hz, 1 H), 8.09 (d, J=2.54 Hz, 2 H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:23])[NH:6][C:7]1[CH:8]=[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[NH:13][C:10]2=[N:11][CH:12]=1)([CH3:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26].N1C=CC=CC=1.Cl>CN1C(=O)CCC1>[CH:1]([O:4][C:5](=[O:23])[NH:6][C:7]1[CH:8]=[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:25]([CH3:24])(=[O:27])=[O:26])[CH:17]=3)[NH:13][C:10]2=[N:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)Nc1cnc2[nH]c(-c3cccc(N)c3)nc2c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1cnc2[nH]c(-c3cccc(NS(C)(=O)=O)c3)nc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
45 mg of the product from example 5-1 were dissolved in 1 ml dry NMP and cooled to 0° C. 18.3 mg methylsulfonylchloride were added and the mixture was stirred for 1 hr at 0° C. and another hr at room temperature. 12 μl (1 equivalent) pyridine were added and stirring was continued for another 60 min. After addition of 0.1 ml conc. HCl, the solvent was removed under vacuum and the residue purified by chromatography on C-18 RP silica in methanol water mixtures.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[OH-].[Na+].O1CCCC1>O>[CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: NCCCCC(=O)O
Reactant: CN(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1ccc(S(=O)(=O)NCCCCC(=O)O)cc1
Reaction time: 4 h
Yield: 61.7 %

Procedure:
4.4 g of 4-dimethylaminobenzenesulphonyl chloride (Chem. Ber. 43, 3038, (1910)) are added to a solution comprising 2.34 g of 5-aminovaleric acid and 2.4 g of sodium hydroxide dissolved in 24 cm3 of water, followed by the addition of 24 cm3 of tetrahydrofuran in order to obtain a solution. The temperature rises to 36° C. The mixture is kept stirring for 4 hours, the tetrahydrofuran is evaporated off, the reaction medium is acidified using acetic acid and extracted with chloroform, the organic phase is dried and the solvents are removed under reduced pressure. 3.7 g of expected product are obtained. M.p. 105°-110° C. After crystallization in an isopropanol/water mixture (1:1), the product, melting point 118°-120° C., is obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][NH:9]C(=O)OC(C)(C)C)[CH:5]=[CH:4][N:3]1[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=2)[C:2](=[O:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccn(-c2ccnc(C(F)(F)F)c2)c(=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccn(-c2ccnc(C(F)(F)F)c2)c(=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of tert-butyl (2-oxo-1-(2-(trifluoromethyl)pyridin-4-yl)-1,2-dihydropyridin-4-yl)methylcarbamate 56-6 (95 mg, 0.26 mmol) in DCM (2 mL) was added TFA (2 mL) at room temperature. The reaction was stirred at room temperature for 30 minutes. The solvent and TFA was removed by rotary evaporation to give crude 4-(aminomethyl)-1-(2-(trifluoromethyl)pyridin-4-yl)pyridin-2(1H)-one 56-7. MS m/z 270.2 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:13]=2)=[C:8]([CH:10]=1)[NH2:9])(=[O:3])[CH3:2].[OH-].[Na+].[CH:26](O)=O>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:13]=3)[CH:26]=[N:9][C:8]=2[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Nc2cccc(-c3cccnc3)c2)c(N)c1
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1

Procedure:
5-acetyl-2-(3-(3-pyridyl)phenylamino)aniline (5 g, 16.5 mmol) in formic acid (50 ml) is stirred at 90° C. for 1.5 hours. The cooled reaction mixture is made alkaline by addition of 12 M NaOH. 5-acetyl-1-(3-(3-pyridyl)phenyl)benzimidazole is filtered off washed with water and dried. Quantitative yield. m.p. 195-97° C.
Reaction SMILES: [Br-].[CH:2]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[N+:33]([C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH:38]=O)([O-:35])=[O:34]>C1COCC1>[C:2]1(=[CH:38][C:37]2[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=2[N+:33]([O-:35])=[O:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1C=C1CCCCC1
Reaction time: 0.5 h

Procedure:
To a slurry of cyclohexyl triphenylphosphonium bromide (16.6 g) in THF (100 mL) at 24° C. was added potassium t-butoxide (4.38 g). The mixture was stirred for 30 min. o-Nitrobenzaldehyde (3.93 g) in THF (50 mL) was added dropwise below 30° C. and stirred for 30 min. The mixture was then partitioned between EtOAc and ice water. The EtOAc layer was washed well with water, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica gel with 5% EtOAc/hexanes to give 1-(cyclohexylidenemethyl)-2-nitrobenzene.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]([N:18]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=2)[CH3:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]([N:18]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=2)[CH3:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: COCO[C@H]1CCN(C[C@H](c2ccccc2)N(C)c2ccc(C(=O)OC)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCO[C@H]1CCN(C[C@H](c2ccccc2)N(C)c2ccc(C(=O)O)cc2)C1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate (1.99 g, 5.00 mmol) and 4N-NaOH (12.5 ml, 50.0 mmol) in MeOH (35 ml) was stirred at 75° C. for 3 h. The mixture was neutrallized with 5N-HCl at 0° C. The solvent was removed in vacuo. CH2Cl2 was added o the residue and insoluble solid was removed by filtration. The filtrate was concentrated to give 2.04 g (quant) of pale brown amorphous.