Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:19](O)=[O:20])=[CH:4][CH:3]=1.[NH2:22][C:23]1[S:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:19]([NH:22][C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:27]=2)=[O:20])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2[nH]c(-c3ccccc3)nc2C(=O)O)cc1
Reactant: Nc1nc(-c2ccccc2)cs1
Product: Cc1ccc(-c2[nH]c(-c3ccccc3)nc2C(=O)Nc2nc(-c3ccccc3)cs2)cc1
Yield: 7.7 %

Procedure:
5-(4-Methylphenyl)-2-phenylimidazole-4-carboxylic acid (0.5 g) and 2-amino-4-phenylthiazole (0.55 g) were reacted and treated in the same manner as in Example 1 to give 5-(4-methylphenyl)-2-phenyl-N-(4-phenylthiazol-2-yl)imidazole-4-carboxamide (0.06 g), melting point 274-276° C.
Reaction SMILES: [Cl:1][C:2]([Cl:23])([Cl:22])[C:3]1[N:8]=[C:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:6]=[C:5]([C:13]2[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=2)[N:4]=1.[O:24]1CCCC1.O>C(N(CC)CC)C>[Cl:1][C:2]([Cl:22])([Cl:23])[C:3]1[N:8]=[C:7]([C:9]([Cl:11])([Cl:10])[Cl:12])[N:6]=[C:5]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:18])=[O:24])=[CH:15][CH:14]=2)[N:4]=1
Reactant: C1CCOC1
Reactant: O=C(Cl)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Reaction time: 0.17 h

Procedure:
4-(4,6-Bis(trichloromethyl)-s-triazin-2-yl)-benzoyl chloride pw) is added to a mixture of tetrahydrofuran (10 pw) and water (5 pw). To complete the reaction, 1 pw of triethylamine is added after 6 minutes, and the mixture is stirred for another 10 minutes. The solvent is removed by distillation, and the residue is recrystallized from toluene/benzine. The product is identical with the compounds described in Examples 12 and 16.
Reaction SMILES: [C:1]([OH:7])(=O)/[C:2](=[CH:4]/[CH3:5])/[CH3:3].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Cl-].[Li+].[CH:24]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1)([CH3:26])[CH3:25]>O1CCCC1>[CH:24]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[N:28]1[C:1](=[O:7])/[C:2](/[CH3:3])=[CH:4]/[CH3:5])([CH3:26])[CH3:25]
Reactant: C/C=C(\C)C(=O)O
Reactant: CC(C)[C@@H]1COC(=O)N1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C/C=C(\C)C(=O)N1C(=O)OC[C@H]1C(C)C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A cooled (−20° C.) solution of tiglic acid (2.005 g, 20.031 mmol) in anhydrous tetrahydrofuran (50 mL) was sequentially treated with triethylamine (6.1 mL, 44.068 mmol) and dropwise pivaloyl chloride (2.7 mL, 22.034 mmol). After stirring at −20° C. for 30 min, lithium chloride (1.019 g, 24.037 mmol) and (R)-(+)-4-isopropyl-2-oxazolidinone (2.587 g, 20.031 mmol) were added. The reaction mixture was allowed to slowly warm to room temperature, stirred for 3 days and was then quenched with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (3.307 g, 78%) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ 0.92 (d, J=6.9 Hz, 3H), 0.94 (d, J=7.1 Hz, 3H), 1.83 (d, J=6.9 Hz, 3H), 1.93 (s, 3H), 2.38 (d of heptet, J=6.9, 4.2 Hz, 1H), 4.19 (dd, J=8.9, 4.6 Hz, 1H), 4.33 (app t, J=8.9 Hz, 1H), 4.49-4.58 (m, 1H), 6.23 (q, J=7.1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]([N:5]([CH2:4][C:3]1[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=1[NH:1][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:15])=[O:14])=[CH2:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC)N(Cc1ccccc1NC(=O)c1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 101.8 %

Procedure:
The procedure of Example 33 was followed using the product from Example 32 (500 mg, 1.268 mmol), triethylamine (0.884 ml, 6.34 mmol), and benzoyl chloride (0.324 ml, 2.79 mmol) in methylene chloride (60 ml) to give 620 mg (100%) of the product.
Reaction SMILES: C(N(CC)C(CCCC(NF)C)CC)C.CCN([C:21]1[CH:26]=[CH:25][C:24]2[C:27]3([C:37]4[CH:43]=[C:42](Cl)[CH:41]=[CH:40][C:38]=4[O:39][C:23]=2[CH:22]=1)OC(=O)C1C3=CC=CC=1)CC.CC1C=C2OC3C=C(N4CCCCC4)C=CC=3C3(OC(=O)C4C3=CC=CC=4)C2=CC=1NC1C=CC=CC=1>>[CH:43]1[C:37]2[CH2:27][C:24]3[C:23](=[CH:22][CH:21]=[CH:26][CH:25]=3)[O:39][C:38]=2[CH:40]=[CH:41][CH:42]=1
Reactant: CCN(CC)c1ccc2c(c1)Oc1ccc(Cl)cc1C21OC(=O)c2ccccc21
Agent: CCC(CCCC(C)NF)N(CC)CC
Agent: Cc1cc2c(cc1Nc1ccccc1)C1(OC(=O)c3ccccc31)c1ccc(N3CCCCC3)cc1O2
Product: c1ccc2c(c1)Cc1ccccc1O2

Procedure:
Rhodamine B anilinolactam, Rhodamine B p-chloro-anilinolactam, 3-diethylamino-7-dibenzylaminofluoran, 3-diethylamino-7-octylaminofluoran, 3-diethylamino-7-phenylfluoran, 3-diethylamino-7-chlorofluoran, 3-diethylamino-6-chloro-7-methylfluoran, 3-diethylamino-7-(3,4-dichloroanilino)fluoran, 3-diethylamino-7-(2-chloroanilino)fluoran, 3-diethylamino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-tolyl)amino-6-methyl-7-anilinofluoran, 3-piperidino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-tolyl)amino-6-methyl-7-phenethylfluoran, 3-diethylamino-7-(4-nitroanilino)fluoran, 3-dibutylamino-6-methyl-7-anilinofluoran, 3-(N-methyl-N-propyl)amino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-isoamyl)amino-6-methyl-7-anilinofluoran, 3-(N-methyl-N-cyclohexyl)amino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-tetrahydrofuryl)-amino-6-methyl-7-anilinofluoran, etc.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#N)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(C)C=CC(S(O[CH2:22][C:23]([CH3:29])([CH3:28])[CH2:24][CH2:25][CH2:26]O)(=O)=O)=CC=1.C[N:32]([CH:34]=O)C>CCCCCC>[C:3]1([C:9]2([CH2:10][C:34]#[N:32])[CH2:26][CH2:25][CH2:24][C:23]([CH3:29])([CH3:28])[CH2:22]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)CCCO)cc1
Reactant: N#CCc1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CC1(C)CCCC(CC#N)(c2ccccc2)C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
NaH (60% dispersion in mineral oil, 72.3 mmol) was washed several times with n-hexane and suspended in DMF. A mixture of phenylacetonitrile (24.1 mmol) and de-O-p-toluene-sulfonyl-2,2-dimethyl-1,5-pentanediol (24.1 mmol) in DMF was added dropwise. The reaction mixture was stirred at 70° C. for 3 h and DMF was evaporated under reduced pressure. Excess hydride was then decomposed by the cautious addition of H2O. Extraction with Et2O, drying of the organic layer (MgSO4) and evaporation of the solvent afforded 1-phenyl-3,3-dimethylcyclohexaneacetonitrile that was chromatographed on silica using petroleumether-EtOAc 98:2 as eluent; 1H NMR (CDCl3) δ 0.96 (s, 3H), 1.26 (m, 1H), 1.31 (m, 3H) 1.59 (m, 2H), 1.78 (m, 2H), 1.92 (m, 2H), 2.23 (m, 1H), 7.49 (m, 5H). 7.0 mmol of the nitrile was refluxed with KOH (40%, 15 mL) in ethyleneglycol (40 mL) for two days. It was then allowed to cool to room temperature and was extracted with Et2O. The aqueous layer was acidified and extracted with Et2O. The organic layer was dried (MgSO4) and concentrated to provide 1.5 g (27%) of the desired carboxylic acid.
Reaction SMILES: ClC(Cl)(Cl)COC(=O)C1C=CC=CC=1CSC1C=CC=C(CC(O[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=O)C=1.[Cl:38][C:39]([Cl:63])([Cl:62])[CH2:40][O:41][C:42](=[O:61])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][S:50][C:51]1[CH:56]=[CH:55][C:54]([CH2:57][C:58]([OH:60])=[O:59])=[CH:53][CH:52]=1.FC(F)(F)C1C=CC(CO)=CC=1.C(Cl)Cl>CN(C1C=CN=CC=1)C.CCCCCCC.CCOC(C)=O>[Cl:63][C:39]([Cl:38])([Cl:62])[CH2:40][O:41][C:42](=[O:61])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][S:50][C:51]1[CH:52]=[CH:53][C:54]([CH2:57][C:58]([O:60][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=2)=[O:59])=[CH:55][CH:56]=1
Reactant: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)Cc1ccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: OCc1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=C(Cc1ccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)cc1)OCc1ccc(C(F)(F)F)cc1
Yield: 35 %

Procedure:
The titled compound was prepared according to the method described for 2-[3-(4-trifluoromethyl-benzyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid 2,2,2-trichloro-ethyl ester above from 2-(4-carboxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (155 mg, 0.357 mmol), (4-trifluoromethyl-phenyl)-methanol (157 mg, 0.893 mmol), EDCxHCl (206 mg, 1.072 mmol), DMAP (4.4 mg, 0.036 mmol) and DCM (3 mL). The crude was submitted to flash chromatography using heptane and EtOAc (90/10) as eluent to yield the titled compound (74 mg, 35%) as an oil; 1H NMR (400 MHz, CDCl3): δ 3.64 (dd, 2H), 4.54 (s, 2H), 4.96 (s, 2H), 5.17 (s, 2H), 7.16 (d, 2H), 7.18-7.28 (m, 3H), 7.31-7.44 (m, 4H), 7.60 (d, 2H), 8.08 (d, 1H)); Mass spectrum: M−H− 590.
Reaction SMILES: O1CCCC1.[Br-].[O:7]1[CH2:12][CH2:11][CH2:10][O:9][CH:8]1[CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][CH:51]([CH2:54][CH:55]=O)[CH2:50][CH2:49]2)=[CH:44][CH:43]=1)#[N:41]>CCOCC>[O:9]1[CH2:10][CH2:11][CH2:12][O:7][CH:8]1[CH2:13][CH:14]=[CH:55][CH2:54][CH:51]1[CH2:50][CH2:49][CH:48]([C:45]2[CH:44]=[CH:43][C:42]([C:40]#[N:41])=[CH:47][CH:46]=2)[CH2:53][CH2:52]1
Reactant: N#Cc1ccc(C2CCC(CC=O)CC2)cc1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1ccc(C2CCC(CC=CCC3OCCCO3)CC2)cc1
Reaction time: 1 h
Yield: 50 %

Procedure:
Tetrahydrofuran (100 ml) was added to 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (19.2 g, 42 mmols), followed by suspending, stirring under ice cooling till the liquid temperature reached 10° C. The reaction mixture was added potassium t-butoxide (4.7 g, 42 mmols), followed by elevating the temperature up to room temperature under ice cooling for one hour, stirring for one hour, dropwise adding a tetrahydrofuran (20 ml) solution of 2-(4-(4-cyanophenyl)cyclohexyl)acetaldehyde (9.0 g, 40 mmols) over 30 minutes from the dropping funnel, further stirring the reaction mixture for 5 hours after completion of the dropwise addition, adding ether (100 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain white solids (6.8 g, 20 mmols) of 1-(4-(1,3-dioxan-2-yl)-2-butenyl)-4-(4-cyanophenyl)cyclohexane.
Reaction SMILES: C([O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[Cl:24])C1C=CC=CC=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[C:11]([Cl:24])[CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-Benzyloxy-2 chloro-benzoic acid benzyl ester from Step A with DIBAL-H 1M in toluene (2.2 eq) in THF were stirred at room temperature for 3 hours. The quenched with tartrate saturated solution and extracted with ethyl acetate. Concentrated to dryness and purified by chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: COc1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNC(=O)c2ccc(Cl)nc2)cc1
Yield: 97.6 %

Procedure:
A solution of 6-chloronicotinic acid (473 mg, 3 mmol), 4-methoxybenzylamine (412 mg, 3 mmol), 1-(3-dimethlaminopropyl)-3-ethylcarbodiimide hydrochloride (700 mg, 3.6 mmol) and HOBt (200 mg)) in DMF (15 ml) was stirred at room temperature for 3 h. Water (100 ml) was added. The solution was extracted with ethyl acetate (150 ml×2), washed with saturated K2CO3 solution (100 ml) and water (200 ml). Organic layer was dried over Na2SO4 and evaporated under reduced pressure to give the desired product (810 mg, 97%). HPLC (6 minute gradient) tR=3.12 min; MS m/z 275.00, 276.95 (M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1O.[C:10]1([CH2:16][C:17]([OH:19])=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.P(Cl)(Cl)(Cl)(Cl)Cl.CN([CH:29]=[O:30])C>>[Cl:1][C:2]1[CH:3]=[C:5]2[C:6](=[CH:7][C:8]=1[OH:9])[O:19][CH:17]=[C:16]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:29]2=[O:30]
Reactant: O=C(O)Cc1ccccc1
Reactant: Oc1cccc(O)c1Cl
Reactant: CN(C)C=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=c1c(-c2ccccc2)coc2cc(O)c(Cl)cc12
Yield: 85 %

Procedure:
This compounds was synthesised in the same manner as described above. Chlororesorcinol (0.87 g, 6 mmol), phenylacetic acid (0.82 g, 6 mmol), BF3Et2O (4 ml), PCl5 (1.9 g, 9.1 mmol), DMF (5 ml and 10 ml). The pink precipitate formed was filtered and re-crystallized from methanol to give 6-Chloro-7-hydroxy-3-phenyl-chromen-4-one as fine light pink crystals (1.4 g, 85%); Rf 0.6 ethyl acetate/hexane (75/25).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@@H:11]([CH2:21][O:22][C:23]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]3[C:24]=2[C:25]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([Cl:43])[CH:37]=2)=[N:26][CH:27]=[N:28]3)[CH2:10]1)(C(C)(C)C)(C)C.C(#N)C>FC(F)(F)C(O)=O>[Cl:43][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][C:39]=1[F:42])[NH:35][C:25]1[C:24]2[C:29](=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:23]=2[O:22][CH2:21][C@@H:11]2[NH:12][CH2:13][C@H:9]([OH:8])[CH2:10]2)[N:28]=[CH:27][N:26]=1
Reactant: COc1cc(OC[C@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC[C@H]2C[C@@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.3 %

Procedure:
tert-Butyl (2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[({4-[3-chloro-4-fluoro-anilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate (839 mg) was dissolved in trifluoroacetic acid (50 ml) and stirred at room temperature for 72 hours. The reaction mixture was then concentrated in vacuo, and excess water was added, followed by the careful addition of saturated aqueous sodium hydrogen carbonate. The mixture was extracted with 3% methanol in DCM and the organic layer was separated, dried (Na2SO4) and concentrated in vacuo to leave a green solid. Trituration with cold acetonitrile gave (3R,5R)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxy-quinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol as grey solid (540 mg, 98%); NMR spectrum (DMSO-d6) 10.54-10.02 (br s, 1H), 8.48 (s, 1H), 8.32 (dd, 1H), 7.93-7.88 (m, 1H), 7.38 (t, 1H), 6.79 (d, 1H), 6.69 (d, 1H), 5.05-4.74 (br s, 1H), 4.40-4.32 (m, 2H), 4.16 (t, 1H), 3.91 (s, 3H), 3.80-3.40 (br m, 21), 2.98 (dd, 1H), 2.86 (dd, 1H), 2.22-2.14 (m, 1H), 1.52-1.44 (m, 1H); Mass spectrum MH+ 419.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:14](Cl)(=O)C(Cl)=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(Cl)cccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a suspension containing 3.0 g (15 mmol) of 2-chloro-6-nitrobenzoic acid in 150 ml of dichloromethane was added 2.8 g (22 mmol) of oxalyl chloride followed by 0.055 ml (0.75 mmol) of N,N-dimethylformamide. The reaction was allowed to stir at room temperature for 2 h, quenched with 50 ml of methanol and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 10% ethyl acetate/hexanes gave 3.1 g (9-7%) of product.
Reaction SMILES: Br[C:2]([CH3:17])([CH3:16])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4].[P:18]([O:23]C)([O:21][CH3:22])[O:19][CH3:20]>>[P:18]([O:21][CH3:22])([O:19][CH3:20])([O:4][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[C:2]([CH3:17])[CH3:16])=[O:23]
Reactant: COc1ccc2c(C(=O)C(C)(C)Br)n[nH]c2c1
Reactant: COP(OC)OC
Product: COc1ccc2c(C(OP(=O)(OC)OC)=C(C)C)n[nH]c2c1

Procedure:
The title compound was prepared from 2-bromo-1-(6-methoxy-1H-indazol-3-yl)-2-methylpropan-1-one from the above by heating in excess trimethyl phosphite at 62° C. for 21 hours. Excess trimethyl phosphite was removed by vacuum distillation. The residue was purified on RP-HPLC using 10-90% MeCN gradient in water without TFA. Fractions containing the title compound were pooled, evaporated to dry, and recrystallized from ethyl acetate to give the title compound as colorless crystals. 1H NMR (CDCl3, 500 MHz) δ 11.41 (br s, 1NH), 7.63 (d, 9.0 Hz, 1H), 6.815 (dd, 2.2 & 8.8 Hz, 1H), 6.77 (d, 1.8 Hz, 1H), 3.83 (s, 3H), 3.65 (d, JP-H=11.2 Hz, 6H), 2.04 (d, JP-H=2.5 Hz, 3H), 1.81 (d, JP-H=3.5 Hz, 3H). LC-MS: 2.79 min. (m/Z=201.1, 327.0, 349.2).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([N:15]=[C:16]=[N:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[C:18]1([NH:17][C:16]([NH:8][NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NNc1ccccc1
Reactant: C(=Nc1ccccc1)=Nc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(N=C(NNc2ccccc2)Nc2ccccc2)cc1
Yield: 60.5 %

Procedure:
To 300 ml of benzene was added 10 g of phenylhydrazine and the mixture was stirred under ice-cooling. To the solution thus formed was added dropwise 17 g of diphenylcarbodiimide and the mixture was stirred for 5 hours as it was to precipitate crystals, which were recovered by suction filtration to provide 16 g of 1,2-diphenyl-3-anilinoguanidine. Then, 5.8 g of the compound thus obtained and 3.4 g of benzoyl chloride were heat refluxed in 100 ml of toluene for 6 hours; after the reaction was over, toluene was distilled off under reduced pressure, and the oily material thus obtained was dissolved in 80 ml of ethanol. After adding 10 ml of aqueous ammonia to the solution, water was gradually added to the mixture, whereby Compound (1) was obtained as light yellow crystals. The yield for the product was 62.1% and the melting point was 226° to 227.5° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]([CH:17]([CH3:19])[CH3:18])[CH3:16])[CH2:11][C@H:10]1[CH2:20][CH:21]([OH:25])[CH:22]([CH3:24])[CH3:23])C1C=CC=CC=1.[ClH:33]>C(O)C.C(O)(=O)C.CO.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]([CH:17]([CH3:19])[CH3:18])[CH3:16])[CH2:11][C@H:10]1[CH2:20][CH:21]([OH:25])[CH:22]([CH3:24])[CH3:23].[ClH:33]
Reactant: CC(C)C(O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)C(O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N
Reaction time: 24 h

Procedure:
Examples 11p and 11q, Step 9: To a solution of the isomeric mixture of 1-((1S,2S,5R)-2-(dibenzylamino)-5-(isopropyl(methyl)amino)cyclohexyl)-3-methylbutan-2-ol (166 mg, 0.38 mmoles) in 5 ml of ethanol and 1 ml of acetic acid was added about 150 mg of Pd(OH)2 on carbon (20%, wet, Aldrich), and the mixture was stirred under hydrogen (52 psi) for 24 hours. After removal of the catalyst by filtration. The solvents were evaporated off to give an oily residue. The residue was dissolved in methanol and 1 ml of 1N—HCl was added. It was evaporated and azeotroped with toluene twice to remove the excess acid and water, and dried under vacuum to give 1-((1S,2S,5R)-2-amino-5-(isopropyl(methyl)amino)cyclohexyl)-3-methylbutan-2-ol as a bis-HCl salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([NH:14][CH3:15])=[O:13])[CH:6]=O.[N:16]1([C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][N:19]2[CH2:18][CH2:17][N:16]([C:22]3[CH:23]=[CH:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=3)[CH2:21][CH2:20]2)[CH:8]=[CH:9][C:10]=1[O:11][C:12]([NH:14][CH3:15])=[O:13]
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CNC(=O)Oc1ccc(C=O)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CNC(=O)Oc1ccc(CN2CCN(c3ccc(C(C)=O)cc3)CC2)cc1OC

Procedure:
To a solution of 3-methoxy-4-(methylaminocarbonyloxy)benzaldehyde (1.0 g) in 1,2-dichloroethane (20 ml) was added 4′-piperazinoacetophenone (0.98 g), followed by sodium triacetoxyborohydride (1.53 g), with stirring. The reaction mixture was stirred overnight at ambient temperature, poured into saturated sodium carbonate solution (75 ml) and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatographed (silica gel and dichloromethane), eluting with the same solvent system, followed by 1% methanol:dichloromethane. The appropriate fractions were combined and concentrated. The residue was recrystallized from ethyl acetate to give product, mp 120-123° C.