Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([I:13])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:14]1([CH3:27])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][C:22](OCC)=[O:23].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[Cl:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4]([OH:6])=[C:21]([O:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:27])[C:22](=[O:23])[NH:1]2)=[CH:8][C:9]=1[I:13]
Reactant: CCOC(=O)COc1ccccc1C
Reactant: COC(=O)c1cc(I)c(Cl)cc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1Oc1c(O)c2cc(I)c(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Methyl 2-amino-4-chloro-5-iodobenzoate (Intermediate 2) (1 g, 3.21 mmol) and ethyl 2-(o-tolyloxy)acetate (Aldrich, 0.655 g, 3.37 mmol) were dissolved in THF (10 mL) and KHMDS 1M/THF (9.63 mL, 9.63 mmol) was added in one portion at room temperature under N2. The reaction mixture was stirred at room temperature for 1 h before quenched with MeOH and concentrated under reduced pressure. The residue was dissolved in 1N NaOH then extracted with Et2O. The aqueous extracts were acidified with 1N HCl and the resulting precipitate was collected by filtration then washed successively with water and diethyl ether to give 7-chloro-4-hydroxy-6-iodo-3-(o-tolyloxy)quinolin-2(1H)-one (1.03 g, 2.409 mmol, 75% yield) as white solid. LCMS: (M+H)+=428; Rt=2.46 min.
Reaction SMILES: [N:1]1([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[N:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:26])=O.CN(C=O)C.CO>ClCCCl>[N:1]1([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[N:16]=[CH:17][C:18]([C:20]([Cl:26])=[O:22])=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cnc2c(c1)N(S(=O)(=O)N1CCCCC1)CCO2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CO
Product: O=C(Cl)c1cnc2c(c1)N(S(=O)(=O)N1CCCCC1)CCO2
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a suspension of 1-(piperidin-1-ylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic acid (110 mg, 0.336 mmol) in DCE (5 mL) was added oxalyl chloride (293 μL, 3.36 mmol) and DMF (5 μL, 0.065 mmol). The reaction was heated to 50° C. and stirred at that temperature for 16 h. The reaction was concentrated in vacuo and used without further purification. The reaction yield was assumed to be 100% for calculation purposes only. LCMS (methanol adduct, i.e. the methyl ester; +ESI) m/z=342.1 [M+H]+.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([NH:10][CH:11]([CH2:14][O:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])=[N:6][C:5]=2[N:27]=1.[ClH:28].N([O-])=O.[Na+]>O>[Cl:28][C:2]1[S:3][C:4]2[C:9]([NH:10][CH:11]([CH2:14][O:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])=[N:6][C:5]=2[N:27]=1
Reactant: COCC(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COCC(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(Cl)sc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the product from example 40 step b) (1.0 g) in a mixture of concentrated hydrochloric acid (40 ml) and water (32 ml) cooled in ice water was added a solution of sodium nitrite (0.4 g) in water (5 mL), stirred at this temp for 2 hours. The mixture was then extracted into ethyl acetate, dried and evaporated to give the subtitle compound, (0.6 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:15])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18][O:19][C:20](=[O:23])[CH2:21]Br>CN(C=O)C>[CH3:1][C:2]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:15])[N:7]([CH2:21][C:20]([O:19][CH3:18])=[O:23])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: Cc1ccnc2[nH]c(=O)c3cccn3c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)c2cccn2c2c(C)ccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-methylpyrido[2,3-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (50 mg, 0.25 mmol) in 2 mL of DMF, was added NaH (60%, 11 mg, 0.28 mmol). The mixture was stirred at room temperature for 1 hour. Methylbromoacetate (26 mL, 0.28 mmol) was added. The mixture was stirred for 16 hours. Solvents were removed under vacuum and the residue was purified by silica gel flash chromatography. (DCM/MeOH=1:10, Rf=0.5) to afford 37 mg (54%) light yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=4.9 Hz, 1H), 7.95 (dd, J=1.5, 2.9 Hz, 1H) 7.36 (dd, J=1.5, 4.0 Hz, 1H), 7.00 (d, J=4.9 Hz, 1H), 6.71 (dd, J=2.9, 4.0 Hz, 1H), 5.25 (s, 2H), 3.77 (s, 3H), 2.83 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.3, 155.5, 143.1, 142.1, 134.8, 124.2, 122.7, 122.6, 120.4, 113.5, 113.4, 52.3, 41.9, 22.9. HRMS (m/z): calcd for C14H34N3O3 (M+H) 272.1035. found 272.1042.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>ClCCl>[C:19]([O:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([Cl:8])[O:10][C:11]=2[CH:17]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc2nc(Cl)oc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc2nc(Cl)oc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (1.48 ml) was added to a suspension of 2-chloro-1,3-benzoxazol-6-ol (1.63 g) [see Preparation 34] in dichloromethane (20 ml), and after 5 minutes acetic anhydride (1.01 ml) was added. The reaction mixture was stirred at room temperature for 18 hours, after which time the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0, changing to 40:10, changing to 0:100, by volume, hexane:ethyl acetate to afford 2-chloro-1,3-benzoxazol-6-yl acetate (1.63 g) as an oil.
Reaction SMILES: CC1(C)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC=2C(=O)CC1.[CH3:25][C:26]1([CH3:54])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37][C:38]3[CH:48]=[CH:47][C:41]([C:42]([O:44]CC)=[O:43])=[CH:40][CH:39]=3)=[CH:31][C:30]=2[C:29](=[C:49]([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:28][CH2:27]1>>[CH3:54][C:26]1([CH3:25])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37][C:38]3[CH:39]=[CH:40][C:41]([C:42]([OH:44])=[O:43])=[CH:47][CH:48]=3)=[CH:31][C:30]=2[C:29](=[C:49]([CH2:50][CH3:51])[CH2:52][CH3:53])[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=C(CC)CC)CCC3(C)C)cc1
Agent: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CCC(CC)=C1CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7), 90 mg (0.23 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5(6H)-(3-pentylidene)naphth-3-yl)ethynyl]benzoate (Compound 134) was converted to the title compound using 1 ml (1.0 mmol) of LiOH (1M aqueous solution).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[C:10](=O)[CH3:11].[NH2:23]/[C:24](/[CH3:30])=[CH:25]\[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])O.[Na+]>[Cl-].[Zn+2].[Cl-].O1CCOCC1>[CH3:30][C:24]1[NH:23][C:10]([CH3:11])=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COc1ccccc1C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: COC(=O)/C=C(/C)N
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)C1=C(C)NC(C)=C(c2ccccc2OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixuture of 297 mg (1 mmol) of 3-(2-methoxyphenyl)-4-(3-nitrophenyl)-3-butene-2-one, 575 mg (5 mmol) of methyl 3-aminocrotonate, 273 mg (2 mmol) of zinc chloride, and 500 mg of Molecular Shieves 4A was added to 1,4-dioxane. This reaction mixture was refluxed with application of heat in an inert atmoshpere for 5 hours. The reaction mixture was then cooled to room temperature and neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The solvents contained in the extract were distilled off and the residue was chromatographed on a silica gel column, whereby the captioned compound was obtained. The yield was 216 mg (55%).
Reaction SMILES: ClC(OCC(C)C)=O.[Cl:9][C:10]1[CH:11]=[C:12]([NH:18][C@@H:19]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20](O)=[O:21])[CH:13]=[CH:14][C:15]=1[C:16]#[N:17].CN1CCOCC1.[BH4-].[Na+]>C1COCC1.O>[Cl:9][C:10]1[CH:11]=[C:12]([NH:18][C@H:19]([CH2:20][OH:21])[CH2:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH:13]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: CC(C)(C)OC(=O)C[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](CO)Nc1ccc(C#N)c(Cl)c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
A solution of isobutyl chloroformate (2.01 g, 14.8 mmol) in THF (5 mL) was added dropwise to a solution of (2S)-2-[(3-chloro-4-cyanophenyl)amino]-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (4.57 g, 14.1 mmol) and NMM (1.56 g, 15.5 mmol) in THF (50 mL) at −10° C. After stirring for 30 min, the reaction was filtered through a pad Celite and the filtrate was cooled to −10° C. To the cold filtrate, a solution of NaBH4 (0.80 g, 21 mmol) in H2O (10 mL) was added slowly and the reaction solution was stirred at −10° C. for 15 min and then at room temperature for 45 min. The reaction was quenched with aqueous NH4Cl and extracted with Et2O (2×). The organic extracts were washed with 5% Na2CO3, cold 0.1N HCl and H2O, dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography with 0% MeOH in CH2Cl2 grading to 3% MeOH in CH2Cl2 to afford the titled product (2.83 g, 64%) as a solid. 1H-NMR (CDCl3) δ: 1.45 (9H, s), 2.61 (2H, m), 3.79 (2H, d, J=4.4 Hz), 3.93 (1H, m), 6.55 (1H, dd, J=8 Hz, 4 Hz), 6.72 (1H, d, J=2 Hz), 7.41 (1H, d, J=8.8 Hz). LC-MS (ES) m/e 311.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](SC)[N:3]=1.[CH3:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[OH:20].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([O:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH3:18])[N:3]=1
Reactant: CSc1nc(N)nc(-c2ccc(C)o2)c1C#N
Reactant: CC(O)c1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(-c2nc(N)nc(OC(C)c3ccccn3)c2C#N)o1

Procedure:
From 2-amino-4-(5-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile, (RS)-alpha-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 344 (M+Na+, 20), 322 (M+H+, 100).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH2:34]([CH2:36][NH2:37])[OH:35]>C1COCC1>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:29](=[O:31])[NH:37][CH2:36][CH2:34][OH:35])=[CH:32][CH:33]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(C(=O)O)cc1
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCc1ccc(C(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
1,1′-Carbonyldiimidazole (0.6 g, 3.71 mmol) was added into the solution of 26 (0.91 g, 3.09 mmol) in THF (50 mL). The reaction mixture was stirred at room temperature overnight under argon atmosphere, then ethanolamine (0.28 mL, 4.64 mmol) was added. The stirring was continued for 24 h at room temperature and argon atmosphere. The solvent was evaporated and the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, 18:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide). 0.74 g (71%) of a white solid 27 was isolated. 1H NMR (300 MHz, CDCl3) δ 1.40 (s, 9H), 1.48 (m, 2H), 1.60 (m, 2H), 2.62 (m, 2H), 3.10 (m, 2H), 3.79 (m, 2H), 4.55 (br s, 1H), 6.74 (m, 1H), 7.18 (d, 2H), 7.66 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(O[CH2:21][C:22]([F:36])=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)(=O)C>O1CCCC1>[CH2:34]([O:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2([CH:23]=[C:22]([F:36])[CH2:21][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:4]=3)[CH2:25][CH2:26]2)=[CH:28][CH:29]=1)[CH3:35]
Reactant: CCOc1ccc(C2(C=C(F)COC(C)=O)CC2)cc1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc(C2(C=C(F)Cc3ccc(F)c(Oc4ccccc4)c3)CC2)cc1
Yield: 12.4 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.246 g), tetrahydrofuran (2 ml) and magnesium (21 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-ethoxyphenyl)cyclopropane (Example 18) (0.176 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C18; solvent: methanol; flow rate: 8 ml/min) to afford 1-(4-ethoxyphenyl)-1-(2-fluoro-3-(4-fluoro-3-phenoxyphenyl)-prop-1-enyl)cyclopropane (32 mg, 12%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:14][N:13](C(OC(C)(C)C)=O)[C:12]([CH3:23])([CH3:22])[C:4]=2[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[ClH:24]>C(O)C>[ClH:24].[ClH:24].[NH2:1][C:2]1[C:3]2[CH2:14][NH:13][C:12]([CH3:22])([CH3:23])[C:4]=2[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)n1nc(N)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)n1nc(N)c2c1C(C)(C)NC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.5 %

Procedure:
To a stirred slurry of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (I(H), 30.0 g, 92.5 mmol) in ethanol (200 mL) was drop wise added HCl 4 M solution in hexanes (116 mL) drop wise. The resulting clear solution was stirred at room temperature for 12 h. The reaction mixture was concentrated under vacuum to a residue and stirred with hexane (250 mL) for 10 min. The solid product was collected by filtration, washed with hexane (100 mL) and dried under vacuum at 40° C. for 15 h to get ethyl 3-amino-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate dihydrochloride (54a, 27.0 g, 98.5%) as white solid. 1H NMR (300 MHz, dmso-d6): δ 1.31 (td, J=7, 1.3 Hz, 3H), 1.59 (s, 6H), 4.09 (t, J=3.7 Hz, 2H), 4.36 (qd, J=7.2, 1.2 Hz, 2H), 10.12 (br s, 2H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:21][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][CH:24]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CC(=O)OCC)c(Cc2ccc(C(=O)OC(C)(C)C)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(CC(=O)OCC)c(Cc2ccc(C(=O)O)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
160 mg of the product of Example 3 were introduced into 4 ml of methylene chloride and 1 ml of trifluoroacetic acid and after the mixture was stirred at ambient temperature for 2 hours 30 minutes, it was diluted with 20 ml of methylene chloride, washed twice with 10 ml of water, extracted again with 20 ml of methylene chloride and evaporated to dryness under reduced pressure to obtain 140 mg of product which was crystallized from 1 ml of methylene chloride with 3 ml of isopropyl ether added to it. After standing at rest for approximately 16 hours, separation took place to obtain 77 mg of the expected product melting at 130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])(O)[CH3:13])[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])\[CH3:13])[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccc(Cl)cc2Cl)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(Cl)cc1Cl
Temperature: 0 °C

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(2,4-dichlorophenyl)propan-2-ol (1 g, 2.36 mmol, 1 equiv) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. in ice-water bath. KOH (15% aqueous solution) was added dropwise to the reaction mixture until pH 9-10. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of isomers, which were separated by HPLC. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.50 (d, 1H), 7.40 (d, 1H), 7.36-7.20 (m, 4H), 6.55 (d, 1H), 4.78 (m, 1H), 4.10 (m, 1H), 3.90 (m, 1H), 3.40 (m, 3H), 3.0 (s, 3H), 1.80 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[CH:21]1([N:27]=[C:28]=[N:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:30]1([NH:29][C:28]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[N:27][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: NCCCCCCCCOc1cccc2ccccc12
Product: c1ccc2c(OCCCCCCCCNC(=NC3CCCCC3)NC3CCCCC3)cccc2c1
Temperature: 120 °C

Procedure:
700 Milligrams (mg) of 1-amino-8-(1-naphthyloxy)octane and 505 mg of dicyclohexylcarbodiimide were mixed well and heated to 120° C. for 1 hour. The crude product was chromatographically separated on a silica gel column eluting with a mobile phase of 25 parts 2-propanol to 1 part water to 1 part acetic acid affording 1,2-dicyclohexyl-3-[8-(1-naphthyloxy)octyl]guanidine as a gum.
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[CH:46]=[C:45]([OH:47])[C:38]3[CH2:39][CH:40]([CH2:42][O:43][CH3:44])[O:41][C:37]=3[CH:36]=2)=[O:34])=[N:28]1.[N:48]1([C:52]([C:54]2[CH:59]=[CH:58][C:57](F)=[CH:56][C:55]=2[F:61])=[O:53])[CH2:51][CH2:50][CH2:49]1>>[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[CH:46]=[C:45]([O:47][C:57]3[CH:58]=[CH:59][C:54]([C:52]([N:48]4[CH2:51][CH2:50][CH2:49]4)=[O:53])=[C:55]([F:61])[CH:56]=3)[C:38]3[CH2:39][CH:40]([CH2:42][O:43][CH3:44])[O:41][C:37]=3[CH:36]=2)=[O:34])=[N:28]1
Reactant: O=C(c1ccc(F)cc1F)N1CCC1
Reactant: COCC1Cc2c(O)cc(C(=O)Nc3ccn(C)n3)cc2O1
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: COCC1Cc2c(Oc3ccc(C(=O)N4CCC4)c(F)c3)cc(C(=O)Nc3ccn(C)n3)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (204d) and azetidin-1-yl-(2,4-difluoro-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1 H) 7.54 (t, J=8.08 Hz, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.13 (s, 1 H) 7.08 (s, 1 H) 6.81 (dd, J=8.59, 2.27 Hz, 1 H) 6.78 (d, J=2.02 Hz, 1 H) 6.68 (dd, J=11.12, 2.27 Hz, 1 H) 5.00-5.08 (m, 1 H) 4.22 (t, J=7.71 Hz, 2 H) 4.16 (t, J=7.71 Hz, 2 H) 3.81 (s, 3 H) 3.60 (d, J=5.05 Hz, 2 H) 3.43 (s, 3 H) 3.15 (dd, J=16.42, 9.60 Hz, 1 H) 2.92 (dd, J=16.42, 7.33 Hz, 1 H) 2.27-2.38 (m, 2 H); LCMS for C25H25FN4O5 m/z 481.00 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1.Br[CH2:14][CH2:15][CH2:16]Br.C(O)(C)C>CS(C)=O.CCOCC.O>[F:3][C:4]1[CH:5]=[C:6]([C:10]2([C:11]#[N:12])[CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1
Reactant: BrCCCBr
Reactant: N#CCc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2cccc(F)c2)CCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
CHART B, Preparation of the amine used in Chart B, Step B-2. A stirred suspension of freshly washed and dried sodium hydride (50% by wt, 9.59 g, 200 mmol) in dry dimethyl sulfoxide (75 mL) under N2 is cooled to 0° C. A mixture of 3-fluorophenylacetonitrile (8.6 mL, 74.0 mmol) and 1,3-dibromopropane (8.3 mL, 81.4 mmol) in ether (40 mL) is then added dropwise over 35 minutes, via cannula. The resulting orange-red mixture is allowed to stir at 20°-25° C. overnight. The thick reaction mixture is cooled to 0° C. and treated with isopropanol (4 mL). After stirring for 15 minutes, water (64 mL) is added in 10 mL increments and the phases are separated. The aqueous layer is extracted with ether (4×100 mL). The combined organics are washed with water (3×100mL), brine (1×100 mL), dried (MgSO4), filtered and concentrated. The product is distilled at 95° C. (1.0 torr) to afford 7.41 g of 1-(3-fluorophenyl)cyclobutanecarbonitrile. 1H NMR (CDCl3) δ7.39 (m, 1 H), 7.19 (m, 1 H), 7.13 (m, 1 H), 7.05 (m, 1 H), 2.81 (m, 2 H), 2.60 (m, 4 H), 2.50 (m, 1 H), 2.12 (m, 1 H); 13C NMR (CDCl3) δ164.6, 161.3, 142.2, 130.6, 130.5, 123.8, 121.37, 121.32, 115.0, 114.7, 113.0, 112.7, 77.2, 40.9, 39.9, 34.6, 17.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)#[N:13].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.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:12]([C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH:17]=[CH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1cc([N+](=O)[O-])ccc1-c1cccc(C#N)c1
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
A solution of 2-bromo-5-nitrotoluene (8.82 gm, 40.83 mmol) in 1,2-dimethoxyethane (150 mL) was added to a solution of tetrakis(triphenylphosphine)palladium(0) (2.35 gm, 2.04 mmol) in 1,2-dimethoxyethane (100 mL) under nitrogen at room temperature. A solution of 3-cyanophenylboronic acid (J. Med.Chem., 1997, 40, 4208)(9.0 gm, 61.25 mmol) in ethanol (45 mL) was added and stirred for 10 mins. Finally, 2M aqueous sodium carbonate (234 mL) was added and the mixture was heated under reflux for 18 h. After being cooled, the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with water, dried (Na2SO4), concentrated under reduced pressure and triturated with diethyl ether to give 1-(3-cyanophenyl)-2-methyl-4-nitrobenzene (8.48 gm, 87%) as a brown solid.