Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:32]3[CH2:33][CH2:34][N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:30][CH2:31]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)nn2-c2ccccc2)cc1

Procedure:
121 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (100 mg, 0.307 mmol), 1-phenylpiperazine (0.046 mL, 0.307 mmol), DIPEA (0.080 mL, 0.461 mmol) and NaBH(OAc)3 (195 mg, 0.921 mmol).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Cl>O>[C:1]1([CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cnc3ccccc3c2)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Product: c1ccc(C2CNc3ccccc3C2)cc1

Procedure:
3-phenylquinoline (0.5 g) was dissolved in refluxing absolute alcohol (25 ml) and sodium metal (0.28 g) was added portionwise over 30 min. The reaction mixture was then refluxed for 3 hr. The cooled reaction mixture was diluted with water and acidified with conc. hydrochloric acid, the ethanol was removed in vacuo. The reaction mixture was basified with 10M sodium hydroxide solution and extracted with chloroform (2×100 ml). The chloroform extract was dried (magnesium sulphate), decolorised with activated charcoal and evaporated in vacuo to give 1,2,3,4-tetrahydro-3-phenylquinoline as a semi-solid which was crystallised from petroleum-ether (40°-60°), as an off-white solid, m.pt. 84°-86°, characterised by its nmr spectrum.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:18]([CH3:19])=[C:17]([CH:20]=[N:21][N:22]=[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([F:32])[CH:30]=3)[NH:25][C:24]2=[O:33])[NH:16][C:15]=1[CH3:34])=[O:13].CO.[Li+].[OH-].Cl>O>[F:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:33])[C:23]2=[N:22][N:21]=[CH:20][C:17]1[NH:16][C:15]([CH3:34])=[C:14]([C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[O:13])[C:18]=1[CH3:19]
Reactant: COC(=O)CCCCCCCNC(=O)c1c(C)[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.9 %

Procedure:
8-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-octanoic acid methyl ester (483 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (159 mg, 34% yield) as a red solid. LC-MS (m/z) 470 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[N:18][C:17]([C:20](=O)[CH3:21])=[C:16](Cl)[N:15]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:25][NH2:26]>CC(O)C.O>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]3[NH:25][N:26]=[C:20]([CH3:21])[C:17]3=[N:18][CH:19]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(=O)c1ncc(-c2ccc(NC(=O)OC(C)(C)C)cc2)nc1Cl
Solvent: CC(C)O
Solvent: O
Product: Cc1n[nH]c2nc(-c3ccc(NC(=O)OC(C)(C)C)cc3)cnc12
Temperature: 120 °C

Procedure:
[4-(5-Acetyl-6-chloro-pyrazin-2-yl)-phenyl]-carbamic acid tert-butyl ester (2.18 g) was suspended in a mixture of 21 ml iPrOH and 21 ml 35% hydrazine in water at RT and heated to 120° C. by microwave irradiation for 20 min under stirring in a sealed vessel. The reaction mixture was left to cool to RT, quenched with a saturated aqueous sodium bicarbonate solution (10 ml) and extracted with EtOAc (3×30 ml). The combined organic phases were dried over sodium sulfate, filtered and evaporated to afford the crude product. Purification by trituration in boiling EtOAc and subsequent filtration afforded [4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-carbamic acid tert-butyl ester as a yellow solid. Yield: 1.42 g (70%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:41][CH3:42])=[C:7]([CH:40]=1)[CH2:8][C@H:9]1[C:15](=[O:16])[N:14]([C:17]([NH:19][C@@H:20]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([N+:33]([O-])=O)[CH:25]=2)[CH2:21][CH2:22][CH3:23])=[O:18])[CH2:13][C:12](=[N:36][O:37][CH2:38][CH3:39])[NH:11][CH2:10]1.C(OCC)(=O)C>[Zn].C(O)(=O)C>[NH2:33][C:26]1[CH:25]=[C:24]([C@H:20]([NH:19][C:17]([N:14]2[C:15](=[O:16])[C@H:9]([CH2:8][C:7]3[CH:40]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]=3[O:41][CH3:42])[CH2:10][NH:11][C:12](=[N:36][O:37][CH2:38][CH3:39])[CH2:13]2)=[O:18])[CH2:21][CH2:22][CH3:23])[CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=[O:29]
Reactant: CCC[C@@H](NC(=O)N1CC(=NOCC)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCC[C@@H](NC(=O)N1CC(=NOCC)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c(N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.3 %

Procedure:
To the compound 101 (2.76 g) in an ethyl acetate (32 ml) and acetic acid (16 ml) suspension, zinc powder (2.88 g) was added under ice cooling, and the mixture was stirred at that temperature for 20 minutes and at room temperature for 4 hours. The reaction mixture was filtered by a glass filter spread with Celite®, then the residue was washed with ethyl acetate (50 ml). The filtrate and the washings were combined, then the mixture was successively washed with saturated aqueous ammonium chloride solution and brine, dried over sodium sulfate, then concentrated. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate/methanol=6/6/1) to obtain the title compound (2.5 g).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[ClH:7].Cl.[NH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([N:17]2[C:21](=[O:22])[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][NH:18]2)[CH:12]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:7].[CH:1]([NH:4][C:5]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([N:17]2[C:21](=[O:22])[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][NH:18]2)[CH:12]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)NC(=O)NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.0 mg (470 μmol) isopropyl isocyanate are dissolved in 5 ml DMF under argon, 80.0 mg (235 μmol) of the compound from Example 35 and 71.4 mg (705 μmol) triethylamine are added and the mixture is stirred overnight at RT. The mixture is then concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]1[C:11]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:10][C:9]([N+:17]([O-:19])=[O:18])=[CH:8][N:7]=1>CN(C=O)C>[Cl:3][C:6]1[C:11]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:10][C:9]([N+:17]([O-:19])=[O:18])=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1cnc(O)c(-n2cccn2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(Cl)c(-n2cccn2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Thionyl chloride (6 ml) and DMF (0.1 ml) were added to 2-hydroxy-5-nitro-3-(1H-pyrazol-1-yl)pyridine (1.37 g), followed by stirring at 80° C. for 2.5 hours. The reaction solution was adjusted to room temperature and slowly added to ice water, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1 to 3:1), and a yellow solid of 2-chloro-5-nitro-3-(1H-pyrazol-1-yl)pyridine (0.12 g) was thus obtained.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[C:26]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=[C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:36])=[O:3])[N:19]=2)[CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1cccc(OC(C)(C)C(=O)O)c1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-{3-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the desired product. mp 67-71° C.; Rf=0.09 in 60% ethyl acetate/hexanes; 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.65-7.63 (m, 3H), 7.51-7.41 (m, 3H), 7.35 (t, J=7.2 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.72 (s, 1H), 6.38 (d, J=8.0 Hz, 1H), 6.53 (d, J=8.0 Hz), 4.19 (t, J=7.4 Hz, 2H), 2.92 (t, J=7.4 Hz, 2H), 2.36 (s, 3H), 1.58 (s, 6H); MS (EI) 479.9 (M+Na)+, 457.9 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:14])=[CH:5][N:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH3:2].[H-].[Na+].[CH2:17](I)[CH:18]=[CH2:19].O>CN(C=O)C>[CH2:1]([C:3]1[C:4]([F:14])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH2:19][CH:18]=[CH2:17])[CH:9]=[CH:8]2)[CH3:2]
Reactant: C=CCI
Reactant: CCc1c(F)cnc2ccc(=O)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc2ncc(F)c(CC)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
8-Ethyl-7-fluoro-1,5-naphthyridin-2(1H)-one (0.810 g, 4.22 mmol) was suspended in dry DMF (12.5 mL) under argon at 0° C., this was then treated with sodium hydride (0.371 g of a 60% w:w dispersion in oil, 2.2 eq.) added in portions. The suspension was allowed to warm to rt; after stirring for 30 mins at rt, the mixture was treated with allyl iodide (0.858 ml, 2.2 eq). It was then stirred for a further 30 mins before addition of water (10 ml). The mixture was then extracted with 10% MeOH/DCM (3×20 ml). The organic extracts were combined, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give a brown oil. This residue was then purified by column chromatography on silica gel (50 g) eluting with 0-100% EtOAc in hexane gradient to give title compound as a brown oil (0.9588 g, 98%).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.[CH2:13]([C@@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH2:8][CH2:9][C:10]([N:25]1[CH2:24][CH2:23][N:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[CH2:21][C@@H:20]1[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)CN)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 91 using tert-butoxycarbonylamino acetic acid and (S)3-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (Example 7, Compound 95) as staring materials to afford product as an oil. LC/MS (Method B) 3.55 min, [M+1]+ 410. Potency class C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].CN(C=O)C.[H-].[Na+].Cl[CH2:20][O:21][CH2:22][CH3:23]>O>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:11][CH2:20][O:21][CH2:22][CH3:23])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: CCOCCl
Reactant: Nc1cc(S)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCSc1ccc([N+](=O)[O-])c(N)c1
Reaction time: 0.5 h

Procedure:
A solution of 3.4 g. of 2-nitro-5-mercaptoaniline in 20 ml. of DMF is treated with 0.5 g. of 100% sodium hydride, and 2.2 g. of chloromethyl-ethyl ether is added to the solution. After 30 minutes at 20°-25° C, the solution is diluted with water and extracted with chloroform. Removal of the chloroform leaves 2-nitro-5-(ethoxymethylthio) aniline as an oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:14]([O:16][C:17](=[O:27])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH3:15].CCO>C1COCC1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:27])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)C=Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC(c1cccc(F)c1)C(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (1.59 g, 63.1 mmol) in 200 mL THF was added diethyl malonate (10.0 g, 62.4 mmol) gradually. The reaction mixture was stirred for 1 hr at room temperature. 3-(3-Fluorophenyl)acrylic acid ethyl ester (2-1) (11.1 g, 57.2 mmol; prepared via standard procedures from 3-fluorocinnamic acid) and EtOH (5 mL) are added. The mixture was then stirred at 90° C. for 12 hr, concentrated under diminished pressure and treated with 50 mL 10% sodium hydrogencarbonate solution. The aqueous mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried (Na2SO4). After solvent removal, the residue was purified using silica gel flash chromatography (6:1 hexane/EtOAc) to give 2-2 as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:16]([CH3:24])[C:17](=O)OC(C)(C)C.[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:43]=[CH:42][C:36]([O:37][CH2:38]C(O)=O)=[CH:35][CH:34]=2)[S:27]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:24]([CH2:38][O:37][C:36]4[CH:35]=[CH:34][C:33]([CH2:32][CH:28]5[S:27][C:26](=[O:25])[NH:30][C:29]5=[O:31])=[CH:43][CH:42]=4)[N:16]([CH3:17])[C:3]=3[CH:4]=2)=[CH:14][CH:13]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccc(O)cc2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Sc3ccc(O)cc3)cc21
Yield: 21.5 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-hydroxyphenylthio)phenyl]-N-methylcarbamate (2.36 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (2.87 g), diethyl cyanophosphonate (1.67 g), triethylamine (1.03 g) and anhydrous tetrahydrofuran (60 ml) and the reaction mixture was purified. Then, in a similar manner to that described in Example (2-2a) a reaction was carried out using the above product and 4N hydrogen chloride/dioxane (20 ml) and the reaction mixture was purified to give the desired compound (0.72 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].C[O:17][P:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]2[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=2[O:19]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([P:18]1(=[O:17])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]2[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=2[O:19]1)=[O:7]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COP1Oc2ccccc2-c2ccccc21
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)P2(=O)Oc3ccccc3-c3ccccc32)cc(OC)c1OC
Temperature: 115 °C

Procedure:
35.6 g (0.154 mol) of 3,4,5-trimethoxybenzoyl chloride were warmed to 100° C. under a nitrogen atmosphere. 35.5 g (0.154 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were then added dropwise while stirring, and the temperature was increased to 115° C. When the reaction was complete, 70 ml of toluene were added at 90° C., and the mixture was then cooled further. After crystallization, 44 g (70% of theory) of the abovementioned compound of melting point 147° to 149° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[O:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[O:26][CH2:25][CH2:24][NH:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ncc(-c2nc(-c3cccc4c3OCCN(C(=O)OC(C)(C)C)C4)no2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 206 %

Procedure:
A mixture of 1,1-dimethylethyl 9-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 89) (190 mg, 0.390 mmol), 4M hydrogen chloride in dioxane (1 ml, 4.00 mmol) and 1,4-dioxane (10 ml) was stirred at 60° C. overnight. The reaction mixture was cooled and a white precipitate formed. The solid was filtered off to give the product as a white solid (170 mg). MS (ES) C19H1935ClN4O3 requires 386 Found 387 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([OH:10])[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.O[C@@H:19]1[CH:24]2C[CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1>C1(C)C=CC=CC=1>[N:21]12[CH2:22][CH2:23][CH:24]([CH2:19][CH2:20]1)[C@@H:1]([O:2][C:3](=[O:17])[C:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([OH:10])[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH2:26]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COC(=O)C(O)(c1cccs1)C1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1cccs1)C1CCCCC1
Yield: 40.1 %

Procedure:
Prepared using the same method as for Intermediate I-1, but from 16.2 g (0.064 mol) of 2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic acid methyl ester (Intermediate I-12), dissolved in 400 ml of toluene, 9.5 g (0.074 mol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 1.51 g (0.038 mol) of HNa (60% dispersion In mineral oil). The oil obtained (10.97 g) was purified by chromatography on silica gel, eluting with chloroform/methanol/ammonia 95:5:0.5, to obtain 8.97 g of a pure product as a mixture of diastereomers, structure confirmed by 1H-RMN. Three crystallisations of this mixture from ethyl ether yield 1.68 g (15.2%) of a pure diastereomer (Intermediate I-6a). The mother liquors of the crystallisations were enriched with the other diastereomer (Intermediate I-6b).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH:13]1[CH2:15][CH2:14]1)[CH2:6][C@H:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22].Cl[C:24]([O:26][CH2:27][CH2:28]Cl)=[O:25]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH:13]1[CH2:15][CH2:14]1)[CH2:6][C@H:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:28][CH2:27][O:26][C:24]1=[O:25]
Reactant: O=C(Cl)OCCCl
Reactant: Nc1ccccc1[C@@H]1CN(C2CC2)Cc2c(Cl)cc(Cl)cc21
Solvent: C1CCOC1
Product: O=C1OCCN1c1ccccc1[C@@H]1CN(C2CC2)Cc2c(Cl)cc(Cl)cc21
Reaction time: 8 h
Yield: 132.1 %

Procedure:
2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (400 mg) was dissolved in absolute THF (25 ml), and 2-chloroethyl chloroformate (102 mg) was added with stirring. After stirring at room temperature for 3 h, the mixture was left to stand overnight. The solvent was then removed and the residue purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. 380 mg of the desired product were obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>C(#N)C>[CH2:27]([N:29]([CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][CH:19]=2)[O:14]1)[CH2:30][CH3:31])[CH3:28]
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCN(CC)CC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-ethylethanamine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 297 (M+, 1), 131 (4), 87 (6), 86 (bp), 58 (5), 56 (3).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1.[CH:11](O)=[O:12].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>ClCCl>[CH:11]([NH:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1)=[O:12]
Reactant: NCc1csc2cncn12
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CNCc1csc2cncn12
Yield: 87 %

Procedure:
0.33 g of the above-obtained 3-aminomethylimidazo[5,1-b]-thiazole was dissolved in 10 ml of dichloromethane. To this solution, a mixture which had been prepared in advance by reacting 0.5 ml of formic acid with 0.5 ml of acetic anhydride at 50° C. for 10 minutes was added with stirring, and the resulting mixture was stirred at room temperature for an additional one hour. To the reaction solution was added 20 ml of a saturated aqueous solution of sodium hydrogencarbonate, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 0.338 g (yield 87%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([F:15])[C:10]([N+:12]([O-])=O)=[CH:11][C:6]=2[CH2:5][S:4]1(=[O:17])=[O:16])[CH3:2].[H][H]>O1CCCC1.[Pd]>[CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([F:15])[C:10]([NH2:12])=[CH:11][C:6]=2[CH2:5][S:4]1(=[O:17])=[O:16])[CH3:2]
Reactant: CCN1c2cc(F)c([N+](=O)[O-])cc2CS1(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCN1c2cc(F)c(N)cc2CS1(=O)=O
Yield: 0.1 %

Procedure:
1-Ethyl-6-fluoro-1,3-dihydro-5-nitro-2,1-benzisothiazole 2,2-dioxide (Compound B from Example 1, Step C, 1.0 g), was suspended in tetrahydrofuran (20 mL) with 10% palladium on carbon (100 mg). The suspension was placed in Parr® shaker and treated with 50 psi (3.45×105Pa) of hydrogen overnight. The catalyst was then filtered off through diatomaceous earth (Celite®), and the filtrate was evaporated under reduced pressure to give the title compound of Step A as a brown solid (0.510 mg). 1H NMR (CDCl3): δ 6.92 (dd,1H), 6.04 (dd,1H), 4.08 (s,2H), 3.80 (br s,2H), 3.64 (q,2H), 1.32 (t,3H).