Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[C:13]3[C:18]([NH:19][C:4]=2[C:3]1=[O:20])=[CH:17][CH:16]=[CH:15][CH:14]=3.[H-].[Na+].C1COCC1.[Cl:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>Cl>[ClH:28].[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[C:13]3[C:18]([N:19]([CH2:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:4]=2[C:3]1=[O:20])=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CN1C(=O)c2[nH]c3ccccc3c2Oc2ccccc21
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)c2c(c3ccccc3n2CCCN2CCCCC2)Oc2ccccc21

Procedure:
A mixture of 1.8g of 7-methyl-7H-indolo [3,2-b][1,5]benzoxazepin-6(5H)-one, 0.42g of 57% sodium hydride-mineral oil dispersion and 10ml of THF was refluxed for 15 min. and then treated with 4.0g of 3-chloropropylpiperidine. The mixture was refluxed for 24 hrs., diluted with 2N HCl and extracted with ether. The aqueous layer was made basic with 5% NaOH and the oil extracted with ether. The ether phase was dried and treated with dry HCl to give a white solid. The solid was recrystallized from methanol-ether to give analytical material, mp. 205°-6°.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1)([OH:3])=O.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43](=[N:45]O)[NH2:44])[CH:38]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[CH2:26][O:25][CH:13]1[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:1]3[O:3][N:45]=[C:43]([C:39]4[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=4)[N:44]=3)=[CH:7][CH:8]=2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: NC(=NO)c1cccnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3nc(-c4cccnc4)no3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
(nn) In an analogous manner to that described in Example 38, by condensing tert-butyl (3RS,4RS)-4-(4-carboxymethoxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 86 (mm)] with 3-pyridinamidoxime in the presence of HBTU and subsequent cyclization there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(3-pyridin-3-yl-[1,2,4]oxadiazol-5-ylmethoxy)-phenyl]-piperidine-1-carboxylate as a yellowish solid; MS: 593 (M+H)+.
Reaction SMILES: CN(C=O)C.[NH2:6][C@H:7]([C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:28]([NH:30][C@H:31]([C:39]([NH:41][C@H:42]([C:49]([NH:51][C@H:52]([C:59]([NH:61][C@H:62]([C:72]([O:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)=[O:73])[CH2:63][CH2:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:60])[CH2:53][O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:50])[CH2:43][O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:40])[C@@H:32]([CH3:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:29])[CH2:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[CH3:8].[NH:81]([C:116]([CH3:118])=[O:117])[C@H:82]([C:89]([NH:91][C@H:92]([C:101]([NH:103][C@H:104]([C:106](ON1C(=O)CCC1=O)=[O:107])[CH3:105])=[O:102])[CH2:93][C:94](=[O:100])[O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:90])[CH2:83][O:84][C:85]([CH3:88])([CH3:87])[CH3:86].CCN(CC)CC>O>[NH:81]([C:116]([CH3:118])=[O:117])[C@H:82]([C:89]([NH:91][C@H:92]([C:101]([NH:103][C@H:104]([C:106]([NH:6][C@H:7]([C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:28]([NH:30][C@H:31]([C:39]([NH:41][C@H:42]([C:49]([NH:51][C@H:52]([C:59]([NH:61][C@H:62]([C:72]([O:74][C:75]1[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=1)=[O:73])[CH2:63][CH2:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:60])[CH2:53][O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:50])[CH2:43][O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:40])[C@@H:32]([CH3:38])[O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:29])[CH2:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:17])[CH:13]([CH3:14])[CH3:15])=[O:10])[CH3:8])=[O:107])[CH3:105])=[O:102])[CH2:93][C:94](=[O:100])[O:95][C:96]([CH3:97])([CH3:98])[CH3:99])=[O:90])[CH2:83][O:84][C:85]([CH3:87])([CH3:88])[CH3:86]
Reactant: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C)C(C)C
Reaction time: 17 h

Procedure:
The DMF-containing solution of H-Ala-Val-Asp(OtBu)-Thr(tBu)-Ser(tBu)-Ser(tBu)-Glu(OtBu)-OC6H5 (~16.8 mmol) from the preceeding step was cooled to 0° and Ac-Ser(tBu)-Asp(OtBu)-Ala-OSu, VII, (10.92 g, 20.16 mm, 1.2 eq.) added. Stirring proceeded at 0° for 30 min and 25° for 17 h while the pH was maintained at ~8 by addition of Et3N. Water (2.4 L) was added with stirring and the product was collected by filtration and dried in vacuo. The solid was crushed and washed with CH3OH (3×200 mL) and dried in vacuo. Yield: 23.0 g (91.7%); mp 255°-256°; Rf 0.48 (CHCl3 :CH3OH:AcOH; 80-5-1); [α]D25 -25.60° (c 1, TFE). Anal. calc. for C73H122N10O22 (1491.86): C, 58.77; H, 8.24; N, 9.39. Found: C, 58.54; H, 8.23; N, 9.43.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[N+:12]([O-:14])=[O:13])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)Cc1cccc(F)c1[N+](=O)[O-]
Solvent: C1CCOC1
Product: O=C(Cc1cccc(F)c1[N+](=O)[O-])NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
2-(3-Fluoro-2-nitrophenyl)acetic acid (1.17 g, 5.88 mmol) was dissolved in tetrahydrofuran (50 ml). N,N′-Carbonyldiimidazole (1.06 g, 6.54 mmol) was added to the mixture in one portion. Reaction stirred at room temperature for 30 minutes. 1-Benzylpiperidin-4-amine (1.15 ml, 6.09 mmol) was added to the mixture in one portion. Reaction stirred at room temperature for 1.25 hours. Reaction was quenched with water. Material was extracted twice with diethyl ether and the aqueous phase was discarded. Material was washed once with water and once with brine and the aqueous phases were discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as amber oil in 99% yield. MS (M+H)+=372.4.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([CH3:30])=[C:23]([CH2:28]O)[C:24]([CH3:27])=[CH:25][CH:26]=2)[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.S([Cl:42])(C)(=O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([CH3:30])=[C:23]([C:24]([CH3:27])=[CH:25][CH:26]=2)[CH2:28][Cl:42])[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(C)c(CO)c2C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(C)c(CCl)c2C)cn1
Reaction time: 1 h

Procedure:
To a solution of 3-[N-[(E)-3-(6-acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-1-hydroxymethyl-2,6-dimethylbenzene (200 mg) in dimethylformamide (2 ml) were added triethylamine (136.1 μl) and mesyl chloride (52.9 μl) at 0° C., and the mixture was stirred for 1 hour at the same temperature and then for 1 hour at ambient temperature. Chloroform and saturated sodium bicarbonate solution were added to the reaction mixture, and the separated organic layer was washed with water, saturated sodium bicarbonate solution and brine, and dried over magnesium sulfate. The solvent was removed in vacuo to give 3-[N-[(E)-3-(6-acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dimethylbenzyl chloride (191.0 mg) as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1.[F:22][C:23]1[C:31]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:35])=[O:34])=[CH:30][CH:29]=[C:28]([F:39])[C:24]=1[C:25](O)=[O:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:22][C:23]1[C:31]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:34])=[O:35])=[CH:30][CH:29]=[C:28]([F:39])[C:24]=1[C:25]([NH:12][C:9]1[CH:10]=[C:11]2[C:3]([O:2][CH3:1])=[N:4][N:5]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]2=[N:7][CH:8]=1)=[O:26]
Reactant: COc1ccc(Cn2nc(OC)c3cc(N)cnc32)cc1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(OC)nn3Cc2ccc(OC)cc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
3-Methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (0.0118 g, 0.0414 mmol), 2,6-difluoro-3-(propylsulfonamido)benzoic acid (0.0127 g, 0.0455 mmol), EDCI (0.00873 g, 0.0455 mmol), and HOBt (0.00615 g, 0.0455 mmol) were dissolved in DMF (1.5 mL) and stirred overnight at room temperature. The solution was partitioned between water and EtOAc. The organic layer was washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil, which was purified by column chromatography (4:1 to 3:2 hexane/EtOAc to give 2,6-difluoro-N-(3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.003 g, 13.3%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13][C:12]=2[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][C:12]=2[CH:24]=1
Reactant: COC(=O)C1=Cc2cc(OCc3cccc(OC)c3)ccc2S(=O)(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cccc(COc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)c1
Temperature: 60 °C
Reaction time: 14.5 h
Yield: 64.5 %

Procedure:
To methyl 7-(3-methoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (436 mg) dissolved in THF-methanol (10-5 ml) was added a 2 M aqueous solution of potassium carbonate (1.2 ml), and the resulting mixture was stirred at 60° C. for 14.5 hours. The reaction mixture was treated with 1 N hydrochloric acid to bring the pH to 2. The resulting mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the precipitated crystals were washed with hexane-ethyl acetate to obtain 7-(3-methoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (271 mg) as white crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH3:21])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-:35].[K+].[K+].[I-].[Na+]>CN(C=O)C.O>[OH2:35].[CH2:20]([N:7]1[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[CH2:29][CH2:30]2)=[C:18]2[C:9]([C:10]([NH2:19])=[N:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=32)=[N:8]1)[CH3:21]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc2c(N)nc3ccccc3c2c1CCCCN1CCN(c2ccccn2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A mixture of 1-(4-chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinoline-4-amine (prepared as described in Example 19, 1.0 g, 3.3 mmol), 1-(2-pyridyl)piperazine (0.752 mL, 4.95 mmol), potassium carbonate (1.8 g, 13.2 mmol), and sodium iodide (123 mg, 0.825 mmol) in DMF (6 mL) was heated at 60° C. for 1 hour, then at 90° C. for 2 hours. The reaction was allowed to cool to ambient temperature and white solid formed. Water (100 mL) was added to the mixture. The mixture was stirred for 30 min and the solid was isolated by filtration and dried to yield 1.4 g of 2-ethyl-1-[4-(4-pyridin-2-ylpiperazin-1-yl)butyl]-2H-pyrazolo[3,4-c]quinolin-4-amine monohydrate as a white solid, mp 183-184° C.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][C:8]=1[C:14]([O-:16])=O)[C:4](=[O:6])[CH3:5])[CH3:2].C[O-].[Na+]>O1CCOCC1>[CH2:1]([N:3]1[C:7]2[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][C:8]=2[C:14]([OH:16])=[CH:5][C:4]1=[O:6])[CH3:2]
Reactant: CCN(C(C)=O)C1=C(C(=O)[O-])CCC(C)C1
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1c2c(c(O)cc1=O)CCC(C)C2

Procedure:
The reaction of a 1:9 mixture of the methyl and ethyl esters of 2-(N-ethyl-acetamido)-4-methyl-cyclohex-1-ene-1-carboxylate (36.3 g; 0.144 mole) with dry sodium methoxide in dioxan as described in Example 8 gave the title product as a white crystalline solid; m.p. (EtOH) 335° - 338° C
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].[H-].[Na+].[H][H].[C:16]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](I)[CH:21]=1)(=[O:18])[CH3:17]>C1COCC1.C1(C)C=CC=CC=1.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>[C:16]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:8])[CH3:7])[CH:9]([CH3:11])[CH3:10])[CH:21]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Oc1cccc(I)c1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: [H][H]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc(S[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
Triisopropylsilanethiol (2.91 ml, 13.5 mmol) was added dropwise to a suspension of sodium hydride (325 mg, 13.5 mmol) in THF (10 ml). After the evolution of hydrogen ceased, a solution of 3-iodophenyl acetate (2.37 g, 9.0 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.04 g, 0.9 mmol) in toluene (90 ml) was added. After refluxing for 16 h under argon, the reaction was cooled to room temperature and the solvent was evaporated under vacuum. The resulting residue was dissolved in ethyl acetate, washed with 1N NaOH and brine, dried with sodium sulfate, filtered, and evaporated under vacuum. The crude product was chomatrographed over silica gel to yield 1.53 g (52%) of 3-[1,1-bis (Methylethyl)-2-methyl-1-silapropylthio]phenyl acetate. NMR 1H Cl3CD δ: 7.34 (m, 2H), 7.23 (t, 1H, J=2.4 Hz), 6.94 (dd, 1H, J=1.2, 8.4 Hz), 2.28 (s, 3H), 1.25 (m, 3H), 1.08 (d, 18 H, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]3[N:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:13](C(O)=O)[N:7]3[C:6]=2[CH:21]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3=[N:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][N:7]3[C:6]=2[CH:21]=1
Reactant: COC(=O)C1=NC2=COc3ccc(Cl)cc3N2C1C(=O)O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cn2c(n1)COc1ccc(Cl)cc1-2
Yield: 95 %

Procedure:
5.4 g (17.5 mmol) of the 4H-8-chloro-2-methoxycarbonyl-imidazo-[2,1-c][1,4]-benzoxazine-1-carboxylic acid prepared in Step E were stirred in 50 ml of Dowtherm A on an oil bath. The solution obtained bubbled vigorously when the oil bath reached 185°-195° C. When the effervescence had ceased, the solution was cooled and diluted with ether. The product crystallized out and was filtered off, washed well with ether and dried under vacuum over P2O5 to obtain 4.4 g (95% yield) of methyl 8-chloro-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate with a melting point of 239°-40° C. in the form of off-white needles.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[F:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:7]=4[C:8]=3[CH:9]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(OC)c(F)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.1 g, 2.3 mmol), 2-(3-Fluoro-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.59 g, 3.4 mmol), Na2CO3 (2 M, 5.4 mL), and Pd(PPh3)2Cl2 (260 mg, 0.23 mmol) in toluene/ethanol (1:1, 15 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give 2-(3-Fluoro-4-methoxy-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 60% yield.
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[NH2:7][C:8]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>>[NH2:7][C:8]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([O:12][CH3:1])=[O:11]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(Cl)c1N
Temperature: -5 °C
Yield: 61 %

Procedure:
3 ml (0.074 mol) of methanol was added to a 50 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer, and a dropping funnel, and 1.43 g (0.012 mol) of thionyl chloride was added dropwise with stirring at −5° C. Then, a mixture of 1.71 g (0.010 mol) of 2-amino-3-chlorobenzoic acid in 2.0 ml (0.049 mol) of methanol was added dropwise with stirring at −5° C. Then, the mixture was stirred at room temperature for 15 hours and at 65° C. for 17 hours. The reaction solution was analyzed by HPLC by the absolute calibration method, and as a result, the yield was 61%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
Compound 1 was prepared from 4,5-dichlorophenylenediamine (Compound J18) (172 mg, 0.97 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (K1) (289 mg, 0.97 mmol) by refluxing in xylene according to the general procedure M. Obtained as an off-white solid (310 mg). MS (ISP) 382.2 [(M+H)+], 384 [(M+2+H)+] and 386 [(M+4+H)+]; mp 241° C.
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[C:19](=[O:25])[CH2:18][CH2:17]3)[CH:11]=[N:12][CH:13]=1.S(Cl)([Cl:28])=O>>[Cl:28][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[C:19](=[O:25])[CH2:18][CH2:17]3)[CH:11]=[N:12][CH:13]=1
Reactant: CN1C(=O)CCc2cc(-c3cncc(N4CCC[C@H]4CO)c3)ccc21
Reactant: O=S(Cl)Cl
Product: CN1C(=O)CCc2cc(-c3cncc(N4CCC[C@H]4CCl)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate A-5 [B], 6-[5-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one (example 5) has been reacted with thionyl chloride to give the title compound as an orange oil. MS: 356.1 (M+H+).
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]([CH:17](N(C)C)[CH3:18])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11].Cl[C:29]1[C:30]2[C:37]([CH3:39])([CH3:38])[C:36](=[O:40])[NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.[CH3:41][N:42](C=O)[CH3:43]>>[F:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:22]3[CH2:27][CH2:26][N:25]([C:29]4[C:30]5[C:37]([CH3:39])([CH3:38])[C:36](=[O:40])[NH:35][C:31]=5[N:32]=[CH:33][N:34]=4)[CH2:24][CH2:23]3)[N:15]([CH2:17][CH2:18][N:42]([CH3:43])[CH3:41])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: CC(N(C)C)n1cc(-c2ccc(F)c(F)c2)nc1C1CCNCC1
Reactant: CN(C)C=O
Reactant: CC1(C)C(=O)Nc2ncnc(Cl)c21
Agent: Cl
Product: CN(C)CCn1cc(-c2ccc(F)c(F)c2)nc1C1CCN(c2ncnc3c2C(C)(C)C(=O)N3)CC1
Temperature: 25 °C
Yield: 15.92 %

Procedure:
Combine 2-(4-(3,4-difluorophenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl-N,N-dimethyl ethanamine tris hydrochloride (0.28 g; 0.00064 mol), 4-chloro-5,5-dimethyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.15 g; 0.00076 mol), TEA (0.74 mL; 0.0053 mol) in DMF (8.43 mL) and heat in microwave at 150° C. for 3 h; cool to RT and evaporate under vacuum. Quench the reaction with saturated sodium bicarbonate solution and extract with EA. Evaporate the EA layer and purify on silica column (60-120 mesh) packed in DCM, first with two volumes of 10% Acetone/DCM followed by 1-5% MeOH/DCM as eluent to give the title compound (0.05 g; 15.92%). MS (ES+): m/z=496 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8]1[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=1.C[N:18](C)C=O.COC(OC)N(C)C.C1C[CH2:39][N:38]2[C:33](=[N:34]CCC2)CC1>CC(O)C>[NH2:18][C:33]1[N:34]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:7]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)=[CH:39][N:38]=1
Reactant: CN(C)C=O
Reactant: Cn1cc(CC(=O)c2ccco2)ccc1=O
Reactant: C1CCC2=NCCCN2CC1
Agent: COC(OC)N(C)C
Solvent: CC(C)O
Product: Cn1cc(-c2cnc(N)nc2-c2ccco2)ccc1=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
To 5-(2-furan-2-yl-2-oxo-ethyl)-1-methyl-1H-pyridin-2-one (8) (10.0 g, 46.04 mmol) obtained in Example 2 were added dimethylformamide (20 mL), N,N-dimethylformamide dimethyl acetal (9.21 mL, 69.06 mmol) and DBU (10.3 mL, 69.06 mmol), and the reaction mixture was stirred at 80° C. for about 5 hours and then allowed to cool. Next, to the reaction mixture was added 2-propanol (100 mL), and the reaction mixture was stirred at 8° C. for about 16 hours. The precipitated crystals were collected by filtration, washed with 2-propanol (45 mL), and then air-dried at 50° C. for 20 minutes to give 10.2 g of a crude product of the title compound (10) as pale yellow crystals (content 10.2 g, yield 82.3%).