Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH3:18])[CH:8]=1)=O.Cl.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=1>>[CH2:16]([N:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([C:5]2[CH:4]=[CH:3][N:31]=[C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=3)[N:30]=2)=[CH:8]1)[CH2:17][CH3:18]
Reactant: CCCn1cc(C(=O)/C=C/N(C)C)c2cccnc21
Reactant: N=C(N)Nc1ccc(O)cc1
Agent: Cl
Product: CCCn1cc(-c2ccnc(Nc3ccc(O)cc3)n2)c2cccnc21

Procedure:
Prepared by treatment of (E)-3-(dimethylamino)-1-(1-propyl-1H-pyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one with 1-(4-hydroxyphenyl)guanidine hydrochloride. 1H-NMR (DMSO-d6) δ: 0.88 (t, 3H, J=7.2 Hz, CH3), 1.90 (t, 2H, J=7.6 Hz, CH2), 4.30 (t, 2H, J=6.8 Hz, CH2), 6.74 (m, 2H, Ph-H), 7.16 (d, 1H, J=5.6 Hz, Pyrimidin-H), 7.20 (t, 1H, J=4.8 Hz, Ar—H), 7.51 (m, 2H, Ph-H), 8.30 (d, 1H, J=5.6 Hz, Pyrimidin-H), 8.35 (m, 1H, Ar—H), 8.52 (s, 1H, Ar—H), 8.88 (d, 1H, J=7.6 Hz, Ar—H), 9.05 (s, 1H, NH), 9.11 (s, 1H, OH). MS (ESI+) m/z 346.1659 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: COc1ccnc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2cc(OC)ccn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-methoxypyridine hydrobromide (Preparation is described in Example 105).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:24])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:26][S:27](O)(=[O:29])=[O:28]>C(Cl)Cl>[C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:24])[CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([S:27]([Cl:26])(=[O:29])=[O:28])[CH:19]=[CH:18][C:17]=2[O:22][CH3:23])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: COc1ccccc1CCC(=O)OCCS(=O)(=O)c1ccc(C)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1CCC(=O)OCCS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a mixture of 3-(2-methoxyphenyl)propionic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 59, 5.0 g, 13.8 mmol) and 5 mL of CH2Cl2 was added dropwise chlorosulfonic acid (8.0 g, 69.0 mmol, 5.0 eq) with ice-bath cooling. The mixture was stirred at 0° C. for 30 min. The resulting thick oil was poured onto crushed ice with vigorous stirring. The mixture was extracted with EtOAc. The organic layer was dried over MgSO4, and concentrated by evaporation to give a thick oil, which was purified by column chromatography (CH2Cl2) to yield 3-(5-chlorosulfonyl-2-methoxyphenyl)propionic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 60, 4.7 g, 74%) as a light brown oil.
Reaction SMILES: N#N.[F:3][C:4]([F:18])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14](O)=[O:15])[N:13]=1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>C1(C)C=CC=CC=1>[F:3][C:4]([F:18])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14]([Cl:27])=[O:15])[N:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(F)(F)CCCCc1nc(C(=O)O)co1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(F)(F)CCCCc1nc(C(=O)Cl)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-(5,5-difluoro-hexyl)-oxazole-4-carboxylic acid (280 mg, 1.20 mmol) in toluene (12 mL) was treated at 0° C. with a drop of DMF followed by oxalyl chloride (0.13 mL, 1.44 mmol) and the resulting yellow solution was stirred at rt for 1 h. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-(5,5-difluoro-hexyl)-oxazole-4-carbonyl chloride as a brown oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:37]=[CH:36][C:15]2[N:16]([CH2:28][C:29]3[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=3)[C:17]([C@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[C:25]([OH:27])=[O:26])=[N:18][C:14]=2[CH:13]=1.[N:38]1[CH:43]=[C:42](B(O)O)[CH:41]=[N:40][CH:39]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:37]=[CH:36][C:15]2[N:16]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:42]4[CH:43]=[N:38][CH:39]=[N:40][CH:41]=4)=[CH:31][CH:30]=3)[C:17]([C@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[C:25]([OH:27])=[O:26])=[N:18][C:14]=2[CH:13]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Br)cc1
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(-c2cncnc2)cc1

Procedure:
The title compound was prepared using analogous conditions described in Step A of Example 97 using racemic cis-2-(5-(benzo[d]thiazol-2-ylmethoxy)-1-(4-bromobenzyl)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid and pyrimidin-5-ylboronic acid. MS (ESI): mass calcd. for C33H29N5O3S, 575.69; m/z found, 576.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 9.20-9.10 (s, 1H), 9.10-9.00 (s, 2H), 8.11-7.94 (m, 2H), 7.77-7.69 (d, J=8.3, 2H), 7.60-7.51 (m, 2H), 7.51-7.42 (m, 2H), 7.38-7.30 (m, 3H), 6.01-5.78 (q, J=17.2, 2H), 5.71-5.65 (s, 2H), 3.74-3.60 (dt, J=12.1, 3.6, 1H), 3.05-2.92 (q, J=4.1, 1H), 2.44-2.26 (m, 1H), 2.24-2.15 (m, 1H), 2.13-2.04 (m, 1H), 2.02-1.93 (m, 1H), 1.88-1.74 (m, 1H), 1.75-1.62 (m, 1H), 1.63-1.40 (m, 2H).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([CH:22](OC)[O:23]C)=[CH:18][C:17]=2[F:27])=[C:10]([N+:29]([O-])=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.CCO>O.CCOC(C)=O.[Cl-].[Na+].O.[Fe]>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][C:17]=3[F:27])=[N:29][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)c1ccc(C(=O)Nc2ccc(Cc3ccccc3)cc2[N+](=O)[O-])c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: OCc1ccc(-c2nc3cc(Cc4ccccc4)ccc3[nH]2)c(F)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a yellow-orange solution of N-(4-benzyl-2-nitrophenyl)-4-(dimethoxymethyl)-2-fluorobenzamide (0.466 g, 1.1 mmol) in 5 mL 3:2 AcOH/EtOH was added iron powder—325 mesh (0.078 mL, 11 mmol). The reaction was fitted with a reflux condensor and was stirred rapidly at 120° C. bath. The reaction became a nearly solid mass after 10 min, and 3 mL 2:1 AcOH/EtOH was added to promote stirring. After 3 h, the mixture was bright yellow. The reaction was diluted with water, EtOAc, and brine, and the layers were separated. The aqueous layer was extracted 2× EtOAc, and the combined organics were washed 2×1N NaOH and 1× brine, dried over sodium sulfate, filtered, and concentrated to an orange oil. The material was purified by silica gel chromatography, ISCO, 40 g, 0-40% 90/10 DCM/MeOH in DCM to give title compound. MS (ESI) m/z: Calculated: 332.1; Observed: 333.1 (M++1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[O:13][CH:12]=[N:11][C:10]=1[C:14]([O:16]C)=[O:15])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[O:13][CH:12]=[N:11][C:10]=1[C:14]([OH:16])=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ncoc1CCC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)CCc1ocnc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.8 %

Procedure:
A mixture of methyl 5-(3-tert-butoxy-3-oxopropyl)-1,3-oxazole-4-carboxylate (Reference Example 21, 6.20 g, 24.3 mmol) and 2 M NaOH (73 mL) in MeOH (290 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between diethyl ether and water. The water layer was acidified with 1 M HCl and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.92 g) as a light brown oil.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[C-:19]#[N:20].[K+].[CH2:22]([N:29]1[CH2:33][CH:32]([C:34]2[S:35][CH:36]=[C:37]([Br:39])[CH:38]=2)[CH:31]([CH2:40]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CS(C)=O.O>[CH2:22]([N:29]1[CH2:33][CH:32]([C:34]2[S:35][CH:36]=[C:37]([Br:39])[CH:38]=2)[CH:31]([CH2:40][C:19]#[N:20])[CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CC2c2cc(Br)cs2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1CN(Cc2ccccc2)CC1c1cc(Br)cs1
Temperature: 80 °C
Yield: 44 %

Procedure:
18-Crown-6 (5.3 g, 0.020 mol) and potassium cyanide (1.3 g, 0.020 mol) were added, respectively, to a solution of the product from step c) (6.7 g, 0.013 mol) in 50 mL of DMSO. The reaction mixture was heated at 80° C. overnight, cooled to room temperature, diluted with water (150 mL) and extracted with ethylacetate (3×150 mL). The combined organic extracts were washed with brine (200 mL), dried with MgSO4, and evaporated in vacuo to give the crude product that was purified by column chromatography (SiO2) using 1-100% ethylacetate-hexane gradient to give the subtitle compound (2.1 g, yield: 44%). MS calculated for C17H17BrN2S+H: 361, observed: 361 and 363.
Reaction SMILES: C(OC[N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18](=[O:19])[C:13]=2[C:12]([CH:28]([CH3:30])[CH3:29])=[C:11]1[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH:42]2[CH2:44][CH2:43]2)[CH:32]=1)C1C=CC=CC=1.N.[H][H]>[Pd].C(O)C>[CH:42]1([O:41][C:33]2[CH:32]=[C:31]([C:11]3[NH:10][C:14]4[CH:15]=[N:16][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:18](=[O:19])[C:13]=4[C:12]=3[CH:28]([CH3:30])[CH3:29])[CH:36]=[CH:35][C:34]=2[O:37][CH:38]([F:40])[F:39])[CH2:44][CH2:43]1
Reactant: CC(C)c1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCc2ccccc2)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CCO
Product: CC(C)c1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 60.1 %

Procedure:
To 313 mg (0.500 mmol) of 1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-isopropyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 7-(a) were added 15 ml of ethanol, 1.6 ml of 28% aqueous ammonia and 39 mg of 5% palladium-active carbon, and the mixture was stirred under 1 atm hydrogen atmosphere at 30° C. for 7 days. After completion of the reaction, the reaction suspension was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; toluene:ethyl acetate=9:1→4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 152 mg of the title compound as a white foam. (Yield: 60%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:22][C:23](=[O:25])[CH3:24])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2CCC(C)C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nc(C#N)c2c(ccn2CCC(C)C)c1OC(C)=O
Yield: 96.3 %

Procedure:
To a solution of 7-cyano-4-hydroxy-1-(3-methyl-butyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (0.4 g, 1.33 mmol), example 97(a), and acetic anhydride (0.25 mL, 2.65 mmol) in methylene chloride (8 mL) at ambient temperature was added triethylamine (0.37 mL, 2.65 mmol). The reaction mixture was stirred at ambient temperature for 2.5 h before 100 mL of methylene chloride was added. The organic solution was washed with 80 mL of water, dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-50% ethyl acetate in hexanes to produce 0.44 g of a colorless oil. MS: (+) m/z 344.3 (M+1).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)(C)(C)C.O1CCOCC1.[ClH:38]>>[ClH:38].[NH2:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](N)Cc1ccc(-c2cc(F)ccc2OC)cc1
Reaction time: 1 h

Procedure:
A solution of (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(5′-fluoro-2′-methoxybiphenyl-4-yl)butanoate, (2.86 g, 6.62 mmol) in 4M HCl in 1,4-dioxane (33.1 ml, 132 mmol) is stirred at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure to give (R)-ethyl 3-amino-4-(5′-fluoro-2′-methoxybiphenyl-4-yl)butanoate hydrochloride salt (2.44 g). HPLC retention time=1.46 minutes (condition A); MS (m+1)=332.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15 (t, J=6.4 Hz, 3 H) 2.66-2.77 (m, 1 H) 2.78-2.91 (m, 1 H) 2.94-3.10 (m, 1 H) 3.42-3.53 (m, 1 H) 3.67 (s, 3 H) 3.83-3.96 (m, 1 H) 4.07 (q, J=6.8 Hz, 2 H) 6.77-6.84 (m, 1 H) 6.87-6.96 (m, 2 H) 7.23 (d, J=7.1 Hz, 2 H) 7.38 (d, J=7.1 Hz, 2 H) 8.64 (br. s., 2 H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1COCC1>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of aniline (9.31 g, 100 mmol) and triethylamine (15.2 g, 150 mmol) in THF (150 mL) is cooled to −40° C. before chloroacetic acid chloride (11.3 g, 100 mmol) is slowly added in portions such that the temperature does not rise above 0° C. After completion of the addition, the brown suspension is stirred at rt for 1 h. The dark purple mixture is poured onto water (300 mL) and extracted twice with EA (300 mL). The organic extracts are washed with sat. aq. NaHCO3, 0.5 N aq. HCl, followed by water, and evaporated. The brown residue is suspended in diethyl ether, filtered off, washed with additional diethyl ether and dried under high vacuum to give 2-chloro-N-phenyl-acetamide. LC-MS: tR=0.75 min, [M+1]+=170, 1H NMR (CDCl3): δ 8.22 (s br, 1H), 7.56-7.51 (m, 2H), 7.40-7.24 (m, 2H), 7.20-7.14 (m, 1H), 4.20 (s, 2H).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Cl-].[Cl-].[Al+3].O>C1(C)C=CC=CC=1>[CH:1]1([C:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:7])=[CH:2][CH:3]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)C2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 199.9 %

Procedure:
Dissolve cyclohexanecarbonyl chloride (2 g, 13.6 mmol) in anhydrous toluene (30 mL). Cool the solution to 0° C., add aluminum trichloride (2.72 g, 20.46 mmol) in three portions and stir the reaction mixture at ambient temperature overnight. Cool to 0° C., add slowly water and extract the mixture with EtOAc. Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate (2.75 g, 100%).
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:17][CH:18]=[CH2:19])[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:20]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:17][CH2:18][CH3:19])[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: C=CCC(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCC(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1

Procedure:
0.50 Parts of 2-(2,2-diphenyl-4-pentenyl)-1-azabicyclo[2.2.2]octane is dissolved in 50 parts by volume of ethanol. This solution is then added to a Parr hydrogenation bottle which contains 0.05 parts of 5% palladium-on-carbon. The mixture is hydrogenated at room temperature and atmosphere pressure using a 50 ml buret to measure hydrogen uptake. After the hydrogenation is completed the catalyst is removed by filtration. The solution is then stripped in vacuo to afford a gum. Crystallization of this gum from methanol/water affords a white solid which is dried in vacuo at 60° C. for 4 hours to give 2-(2,2-diphenylpentyl)-1-azabicyclo[2.2.2]octane. This compound melts at about 115°-117.5° C. and is represented by the following structural formula ##STR8##
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]1>CN(C=O)C>[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH:21][C:2]2[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:15][CH2:14]1
Reactant: COC(=O)c1cccc(F)c1F
Reactant: NCCN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(F)c1NCCN1CCOCC1
Temperature: 100 °C
Yield: 70.4 %

Procedure:
Methyl 2,3-difluorobenzoate (817 mg, 4.746 mmol) and 2-morpholinoethanamine (2.5 mL, 19.20 mmol) were dissolved in DMF (15 mL) and heated in a microwave for 30 mins at 100° C. The crude material was purified by silica gel column chromatography with EtOAc/Hexanes to yield 943 mg (70%) of desired methyl 2-(2-morpholinoethylamino)-3-fluorobenzoate. LC/MS: 283.15 (M+1) Rt=1.48 min (10-90% 3/5 min (grad/run) with formic acid).
Reaction SMILES: [CH3:1][C:2]1C=CC(C(C)C)=C[CH:7]=1.C([C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[C:16](C(C)C)[CH:15]=1)(C)C>>[CH:2]([C:15]1[CH:14]=[CH:19][C:18]([CH:20]([CH3:21])[CH3:22])=[CH:17][CH:16]=1)([CH3:7])[CH3:1]
Reactant: CC(C)c1cc(C(C)C)cc(C(C)C)c1
Reactant: Cc1ccc(C(C)C)cc1
Product: CC(C)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
[RuCl2 (1,3,5-triisopropylbenzene)]2 was prepared by stirring a suspension of [RuCl2 (p-cymene)]2 (3 g) in 120 mL 1,3,5-triisopropylbenzene (Aldrich, 97%) for a total of 8 hours at 190° C. under N2. The solution was cooled to room temperature and then placed in a refrigerator for 2-3 days. Solids were collected by cold filtration, washed with heptane, and dried in a vacuum oven at 70° C. A red-brown solid product was obtained (3.25 grams). 1H NMR analysis of this product was consistent with the material being 90+% pure [RuCl2 (1,3,5-triisopropylbenzene)]2 with a small amount of unreacted [RuCl2 (p-cymene)]2. 1H NMR data for [RuCl2 (1,3,5-triisopropylbenzene)]2 (CDCl3 solvent): δ1.3 (d, 18H), 3.1 (m, 3H), 5.2 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)CC>[CH2:19]([NH:26][CH2:15][CH:14]([OH:16])[CH2:13][O:12][C:11]1[CH:17]=[CH:18][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:9][CH:10]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Solvent: CCCO
Product: OC(CNCc1ccccc1)COc1ccc(CCOCC2CC2)cc1
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
1-[4-(2-Cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane (10 g) and benzylamine (13 g) were stirred under reflux, in n-propanol (100 ml) for 20 hours. The mixture was cooled and evaporated under reduced pressure to give a residue. This was stirred under petroleum ether (60°-80°) for 30 minutes; the solvent was decanted and the residue triturated with further petroleum ether. A white solid was obtained, collected by filtration and recrystallised from acetonitrile to afford N-benzyl-3-[4-(2-(cyclopropylmethoxy)ethyl)phenoxy]-2-hydroxypropylamine (8.8 g), m.p. 75°-6° C.
Reaction SMILES: C(NC(=O)[O-])C.C[O:8][C:9]1[C:10]([Cl:22])=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1>Cl>[OH:8][C:9]1[C:10]([Cl:22])=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1
Reactant: COc1cc2c(cc1Cl)C(C)C1CNCC21
Agent: CCNC(=O)[O-]
Agent: Cl
Product: CC1c2cc(Cl)c(O)cc2C2CNCC12
Temperature: 25 °C

Procedure:
A solution of N-ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 3, Step A) (61 mg, 0.2 mmol) in concentrated HCl was stirred overnight at 120° C. The reaction solution was cooled to room temperature and concentrated on a speed vac. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. 1H NMR (d6-DMSO 300 MHz)*7.04 (s, 1H), 6.73 (s, 1H), 3.52 (m, 1H), 3.22 (m, 2H), 2.83 (m, 3H), 2.41 (m, 1H), 1.18 (d, 3H) ppm. MS calculated for C12H14ClNO+H: 224, observed: 224.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][N:3]=1.[CH2:10]1[CH2:12][CH:11]1[CH2:13][NH2:14]>>[CH:11]1([CH2:13][N:14]=[CH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)[CH2:12][CH2:10]1
Reactant: Nc1nccc(C=O)n1
Reactant: NCC1CC1
Product: Nc1nccc(C=NCC2CC2)n1

Procedure:
2-Aminopyrimidine-4-carboxaldehyde and 2-cyclopropylmethyl amine were reacted by the procedure of example 1(c) to afford the title compound as a yellow oil.
Reaction SMILES: C([C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[N:9][CH:8]=[C:7]([Br:17])[CH:6]=2)C.O.[OH-].[Li+]>CO.O>[C:20]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:4]1[C:5]2[C:10](=[N:9][CH:8]=[C:7]([Br:17])[CH:6]=2)[C:11](=[O:16])[C:12]([C:13]([OH:15])=[O:14])=[CH:3]1
Reactant: CCc1c(C(=O)O)c(=O)c2ncc(Br)cc2n1Cc1ccccc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(Cc2ccccc2-c2ccccc2)c2cc(Br)cnc2c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.8 %

Procedure:
To a colorless solution of ethyl 1-(biphenyl-2-ylmethyl)-7-bromo-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (18) (50 mg, 0.11 mmol) in methanol (5 mL) was added solid lithium hydroxide monohydrate (22.6 mg, 0.54 mmol) at room temperature. The resulting colorless solution was stirred for 15 h at room temperature at which time LCMS analysis indicated the absence of starting material. Then, the mixture was diluted with water and the methanol was removed under vacuum. The resulting basic aqueous solution was diluted with water (˜50 mL) and 1.0N NaOH (˜10 mL) and then neutralized with 1.0N HCl. The resulting off-white solids were collected by filtration and washed with water and hexanes. After air drying, 32 mg of 1-(biphenyl-2-ylmethyl)-7-bromo-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (19) (67% yield) was isolated as an off-white solid.