Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O/[N:12]=[C:13]2\[CH2:14][CH2:15][CH2:16][C:17]3[O:21][CH:20]=[C:19]([C:22]([OH:24])=[O:23])[C:18]\2=3)(=O)=O)=CC=1.C([O-])(=[O:27])C.[K+].C(O)C>O>[O:27]=[C:13]1[NH:12][C:18]2[C:19]([C:22]([OH:24])=[O:23])=[CH:20][O:21][C:17]=2[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)O/N=C2\CCCc3occ(C(=O)O)c32)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCCc2occ(C(=O)O)c2N1
Yield: 35.8 %

Procedure:
A mixture of 1.0 g of (E)-4,5,6,7-tetrahydro-4-[[[(4-methylphenyl)sulfonyl]oxy]imino]-3-benzofurancarboxylic acid, 5.9 g of potassium acetate, 23 ml of ethanol and 39 ml of water is heated at reflux for 48 hours. The reaction mixture is concentrated in vacuo, 80 ml of methylene chloride added and the separated organic layer washed with water, brine and dried with Na2SO4. The organic layer is concen-trated in vacuo to a solid which is purified by chroma-tography on a preparative silica gel plate by elution with 0.5% acetic acid in ethyl acetate. The eluted band is washed with 1% acetic acid in ethyl acetate. The organic layer is dried with Na2SO4 and concentrated in vacuo to give 200 mg of off-white solid which is crystallized from ethyl acetate-hexane to give 165 mg of the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CO[CH:23]1[CH2:27][CH2:26][CH:25](OC)O1>ClCCCl>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][C:2]([N:1]2[CH:23]=[CH:27][CH:26]=[CH:25]2)=[CH:7][CH:6]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: c1ccc(-c2ccc(-n3cccc3)cc2)cc1
Temperature: 75 °C
Yield: 61.8 %

Procedure:
To a solution of 4-aminobiphenyl (1.0 g, 5.9 mmol) in 1,2-dichloroethane (20 mL) was added TFA (0.46 ml, 5.9 mmol). To the resultant suspension of the TFA salt was added 2,5-dimethoxy-tetrahydrofuran (0.92 mL, 7.1 mmol). The suspension was heated at 75° C. for 17 hours. The mixture was allowed to cool, partitioned between EtOAc and 1 M pH 7 phosphate buffer, and the aqueousueous layer was extracted again with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to a crude residue, which was purified via flash column chromatography with 10-25% CH2Cl2/hex gradient eluent. The purified material was triturated with MTBE/hex to give 800 mg(62%) of N-biphenyl-4-yl-1H-pyrrole as an off-white solid, mp190-2° C. 1H NMR: δ 7.65 (d, 2H, J=8.5 Hz), 7.61 (d, 2H, J=7.0 Hz), 7.48-7.43 (m, 4H), 7.36 (t, 1H, J=7.0 Hz), 7.14 (t, 2H, J=2.0 Hz), 6.37 (t, 2H, J=2.0 Hz). Anal. Calculated for C16H13N: C, 87.63; H, 5.98; N, 6.39. Found: C, 87.48; H, 6.01; N, 6.30.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][NH:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7].N1C=CC=CC=1.BrN1C(=O)CCC1=O>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]=[N:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7]
Reactant: COCCOC(=O)NNC(=O)OCCOC
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COCCOC(=O)N=NC(=O)OCCOC
Reaction time: 2 h
Yield: 87.8 %

Procedure:
1,2-hydrazinedicarboxylic acid bis(2-methoxyethyl) ester (45 g, 191 mmol), pyridine (15.09 g, 191 mmol), and toluene (450 ml) were added to a 1000 ml flask, and N-bromosuccinimide (37.31 g, 210 mmol) was slowly added thereto at 20° C., followed by allowing the reaction to proceed for two hours. After the reaction, the solution was washed with water (180 mL, ×2), and dehumidified with anhydrous magnesium sulfate, followed by concentration to dryness. The resulting solid was recrystallized with toluene (67.5 ml) and hexane (337.5 ml), to give azodicarboxylic acid bis(2-methoxyethyl) ester as a pale yellow crystal (39.26 g, yield: 88.0%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[C:22]([Br:28])[CH:21]=2)=[O:19])=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(S)C>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Br:28])[CH:21]=2)=[O:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OC)c(Br)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: O=C(c1ccc(O)c(Br)c1)c1c(-c2ccc(O)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.2 %

Procedure:
A 0° C. solution of 6.5 g (14.3 mmol) of 3-bromo-4-methoxyphenyl 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl ketone in 300 mL of dichloromethane was treated with 15.3 g (115 mmol) of AlCl3, followed by 17 mL (230 mmol) of ethanethiol. The cold bath was removed and the reaction was stirred at ambient temperature for 3.5 h. The reaction mixture was cooled to 0° C. and poured into cold water. The layers were separated and the aqueous layer was extracted with EtOAc (2×150 mL). The combined organic layers were dried over Na2SO4 and evaporated to give 5.9 g (13.9 mmol, 97%) of an oil which crystallized out when mixed with CH2Cl2.
Reaction SMILES: C1C2C(COC(=O)N[C@H](C([N:25]3[C:29]4=[N:30][CH:31]=[C:32]([Br:34])[CH:33]=[C:28]4[C:27]([C@@H:35]([C:37]4[C:42]([Cl:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=4[Cl:45])[CH3:36])=[CH:26]3)=O)CC(C)C)C3C(=CC=CC=3)C=2C=CC=1.[OH-].[Na+]>C1COCC1>[Br:34][C:32]1[CH:33]=[C:28]2[C:27]([C@@H:35]([C:37]3[C:42]([Cl:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=3[Cl:45])[CH3:36])=[CH:26][NH:25][C:29]2=[N:30][CH:31]=1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)n1cc([C@H](C)c2c(Cl)ccc(F)c2Cl)c2cc(Br)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12

Procedure:
To a solution of ((S)-1-{5-Bromo-3-[(S)-1-(2,6-dichloro-3-fluorophenyl)ethyl]pyrrolo[2,3-b]pyridine-1-carbonyl}-3-methylbutyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (722 mg, 1.00 mmol) in THF (20 mL) was added NaOH (5N in H2O, 1 mL) at 0° C. with stirring. After stirring for 1 h at that temperature, solvents were removed under reduced pressure to give a residue which was then purified by flash chromatography (eluent: Hexane/ethyl acetate: 75/25, v/v) to give the title compound. 1H NMR and LCMS data match with the data for the racemic compound. Optical rotation: [α]25D=−112.8° (c=1.0, MeOH); α] [25D=−152.6° (c=1.0, CH2Cl2). HPLC (Chiralcel OD-RH, solvent 60:40 acetonitrile/water isocratic, flow rate 0.5 mL/min, column temperature 30° C., UV detection at 220 nm): tR=28.0 min. C15H10BrCl2FN2 (388.07): Calculated: C, 46.43; H, 2.60; Br, 20.59; Cl, 18.27; F, 4.90; N, 7.22. found C, 46.36; H, 2.49; Br, 20.38; Cl, 18.31; F, 4.79; N, 7.09. A crystal structure of Example 85 from application Intl Appl. PCT/US09/65058 prepared using this material, bound to cMet confirmed the absolute configuration as shown.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][N:15]=2)=[N:6]1.[F:26][CH:27]([F:36])[CH2:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>>[F:26][CH:27]([F:36])[CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([NH:21][C:17]2[C:18]([NH2:20])=[N:19][C:14]([C:7]3[C:8]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]([CH2:4][C:3]4[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=4[F:1])[N:6]=3)=[N:15][CH:16]=2)[CH2:31][CH2:30]1
Reactant: Nc1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: O=C1CCN(CC(F)F)CC1
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1NC1CCN(CC(F)F)CC1

Procedure:
200 mg (0.596 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5-diamine (synthesis described in US2004/67937; Example V) were reacted in analogy to the method in example 88A with 1-(2,2-difluoroethyl)piperidin-4-one. After purification by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient), this gave 219 mg of the title compound (76% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)=[O:13].[C:24](Cl)(=[O:26])[CH3:25]>C(O)C.C1(C)C=CC=CC=1>[C:24]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:21])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:13])(=[O:26])[CH3:25]
Reactant: Nc1c(C(=O)c2cccc(S(N)(=O)=O)c2)[nH]c2cc(Cl)ccc12
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)Nc1c(C(=O)c2cccc(S(N)(=O)=O)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-(3-amino-6-chloroindole-2-carbonyl)benzenesulfonamide (Example 142) and acetyl chloride. m.p.: 250-251° C. (ethanol/toluene)
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]3)[C:12]2=[NH:15])=[CH:8][CH:7]=1.O=[C:23]([CH3:27])[C:24](=[S:26])[NH2:25]>CO>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([C:12]42[NH:25][C:24](=[S:26])[C:23]([CH3:27])=[N:15]4)[CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH2:20]3)=[CH:8][CH:7]=1
Reactant: N=C1c2cc(OCCCF)ccc2CC12CCC(O)CC2
Reactant: CC(=O)C(N)=S
Solvent: CO
Product: CC1=NC2(NC1=S)c1cc(OCCCF)ccc1CC21CCC(O)CC1
Temperature: 60 °C
Yield: 36 %

Procedure:
To N-(5′-(3-fluoropropoxy)-4-hydroxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Intermediate 32, 275 mg, 0.70 mmol) in dioxane (1 mL) under an atmosphere of nitrogen was added HCl (4 M in 1,4-dioxane, 1.74 mL, 6.95 mmol). The mixture was stirred at r.t. for 2 h and was then concentrated. DCM (1-2 mL) and Et2O was added and a solid was formed. The solid was filtered off and washed with diethylether. The solid was dissolved in DCM. Sat. aq. NaHCO3 was added and mixture was poured in to a phase separator. The organic phase was collected and concentrated to give 6′-(3-fluoropropoxy)-1′-imino-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-4-ol (227 mg). The obtained imine was mixed with 2-oxopropanethioamide (Intermediate 1, 239 mg, 2.32 mmol) in dry MeOH (4 mL) and the resulting orange solution was heated at 60° C. under an atmosphere of nitrogen overnight. The mixture was allowed to cool to r.t., and concentrated. The residue was purified by flash column chromatography using a gradient of 0-100% EtOAc in heptane, providing 104 mg (36% yield) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.04-1.21 (m, 4 H) 1.41-1.48 (m, 2 H) 1.66-1.73 (m, 2 H) 2.02 (t, 1 H) 2.07 (quin, 1 H) 2.26 (s, 3 H) 2.93 (d, 1 H) 3.01 (d, 1 H) 3.22-3.29 (m, 1 H) 3.97 (tq, 2 H) 4.52 (t, 1 H) 4.55 (d, 1 H) 4.62 (t, 1 H) 6.32 (d, 1 H) 6.89 (dd, 1 H) 7.26 (d, 1 H) 12.28 (s, 1 H); MS (ES+) m/z 377.07 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.N#N.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.O>[CH3:14][O:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[C:30]([C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:34][CH:33]=1)=[O:31]
Reactant: COc1ccc2cc(OC)ccc2c1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Agent: N#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OC)ccc2c1
Temperature: 0 °C

Procedure:
Dissolve 2,6-dimethoxynaphthalene (1.0 eq.) in CH2Cl2 (5 volume eq.) at ambient temperature in a dry round bottom flask equipped with stir bar, temperature probe and N2 line. Cool the solution to 0° C. with an ice bath, and add 4-(2-piperidin-1-yl-ethoxy)-benzoyl chloride (1.1 eq.). Add aluminum chloride (2.0 eq.). Once the reaction is determined to be complete, quench the reaction slowly with 1 N NaOH and dilute with additional water and CH2Cl2. Wash the aqueous layer with CH2Cl2 (20 mL). Combine the organic extracts and wash with brine and dry (Na2SO4). Recrystallize the crude product from methanol to give (2,6-dimethoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([CH2:22][C:23]2([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[CH2:22][C:23]1([C:26]([F:27])([F:28])[F:29])[CH2:25][CH2:24]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)CC2(C(F)(F)F)CC2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)CC2(C(F)(F)F)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methyl-pyrimidin-5-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine. LCMS (MH+): m/z=377.1, tR (minutes, Method F)=1.68
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:29])[CH:6]=[C:7]([S:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[O:8]2.C(OC([N:37](C(OC(C)(C)C)=O)[CH2:38][C:39](O)=[O:40])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:64]>ClCCl.C(OCC)(=O)C>[ClH:64].[CH2:19]([CH:16]([O:15][C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:29])[CH:6]=[C:7]([S:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:39](=[O:40])[CH2:38][NH2:37])=[CH:24][CH:23]=3)[O:8]2)=[C:3]([O:2][CH3:1])[C:12]=1[O:13][CH3:14])[CH2:17][CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCC(CC)Oc1cc2oc(Sc3ccc(O)cc3)cc(=O)c2c(OC)c1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(CC)Oc1cc2oc(Sc3ccc(OC(=O)CN)cc3)cc(=O)c2c(OC)c1OC
Reaction time: 3 h

Procedure:
300 ml in dichloromethane of 5.66 g of 5,6-dimethoxy-7-(1-ethylpropoxy)-2-(4-hydroxyphenylthio)chromone obtained in Example 25, 2.62 g of N-t-butoxycarbonyl(Boc)glycine, and 3.08 g of 1,3-dicyclohexylcarbodiimide (DCC) was stirred over 5.5 hours at room temperature. The solution thus reacted was gravitationally filtered. The solvent was distilled out from the filtrate, so that N-t-butoxycarbonyl(Boc)glycine ester was obtained. This product was dissolved in 100 ml of ethyl acetate. Then, hydrochloric acid gas was introduced and bubbled in the solution for 10 min., followed by stirring for 3 hours. Subsequently, 200 ml ether was added and the resulting crystals were collected by filtration and dried, whereby 6.44 g of 7-(1-ethylpropoxy)-5,6-dimethoxy-2-(4-glycyloxyphenylthio)chromone hydrochloride with the following physicochemical properties was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([O:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]1)[CH:7]=[CH:6]2)=O.[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C([BH3-])#N.[Na+]>>[C:20]([C@H:17]1[CH2:18][CH2:19][C@H:14]([O:13][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([CH2:1][NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:4]=3)[N:9]=2)[CH2:15][CH2:16]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: NCCC(=O)O
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3n2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCC(=O)O)ccc3n2)CC1

Procedure:
6-bromo-2-hydroxyquinoline was treated with cis-4-tert-butylcyclohexanol under Mitsunobu conditions, affording 6-bromo-2-((trans)-4-tert-butylcyclohexyloxy)quinoline. 6-bromo-2-((trans)-4-tert-butylcyclohexyloxy)quinoline was then exposed to n-butyllithium and DMF, providing 6-formyl-2-((trans)-4-tert-butylcyclohexyloxy)quinoline. This aldehyde was then treated with 3-aminopropionic acid and sodium cyanoborohydride to afford the title compound, 3-((2-((trans)-4-tert-butylcyclohexyloxy)quinolin-6-yl)methylamino)propanoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(Cl)cc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(Cl)cc(Cl)c1Cl
Reaction time: 3.5 h

Procedure:
To a solution of 2,3,5-trichlorobenzaldehyde (Aldrich, 50 gms) in ethanol (1.0 L) at room temperature was added NaBH4 (7.00 gms) and the resulting mixture stirred for 3.5 hours. The reaction was quenched with water, and the solvent evaporated in vacuo before partitioning the residue between CHCl3 and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and the solvent evaporated in vacuo to leave a white solid. 43.00 gms, mp. 90°-93° C.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[NH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>C(O)C>[O:19]=[C:20]1[N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:10][CH:27]=[C:21]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: N=C(NCc1ccccc1)c1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2)n(Cc2ccccc2)c1=O
Temperature: 25 °C

Procedure:
To a stirred solution of N-(phenylmethyl)-benzenecarboximidamide (i.e. the product from Step A) (2.54 g, 12.1 mmol) in ethanol (15 mL) was added diethyl ethoxymethylenemalonate (2.61 g, 12.1 mmol), and the reaction mixture was heated to reflux for 24 h. The reaction mixture was then allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 30% ethyl acetate in hexanes to afford the title product as a white solid (2.9 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:3]=1.C[Sn](C)(C)[C:30]1[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH:35]=1>>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:4]1[N:3]=[C:2]([C:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=2)[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: CC(C)(C)OC(=O)N1CC=C([Sn](C)(C)C)CC1
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1

Procedure:
The title compound was prepared from 7-bromo-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND HHH2) and tert-butyl 4-(trimethylstannyl)-3,6-dihydropyridine-1(2H)-carboxylate (INTERMEDIATE 69)by a procedure analogous to that described in EXAMPLE HHH1, Step A. Mass spectrum (ESI) 582 (M+1).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>C(N(CC)CC)C.C(O)C>[Br:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:8]=1
Reactant: O=c1ncc(Br)c[nH]1
Reactant: O=C(CBr)c1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Br)cnc1=O)c1ccccc1

Procedure:
A solution of 5-bromopyrimidin-2-one hydrobromide (512 mg) and α-bromoacetophenone (398 mg) in triethylamine (2 ml) and ethanol (10 ml) was stirred at ambient temperature for three and a half hours. After evaporation of solvents, the residue was triturated with water. The product was filtered off and recrystallised from ethanol to give the title pyrimidinone: yield 253 mg: m.p. 161°-163°, λmaxEtOH 241.5 nm (ε 18810), 285 nm (ε 1690), 334.5 nm (ε 3190).
Reaction SMILES: [CH2:1]([S:9](Cl)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:13][C:14]1[C:19]2[CH:20]=[C:21]([CH2:23][CH:24]([NH:34]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:25]([N:27]3[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]3)=[O:26])[S:22][C:18]=2[CH:17]=[CH:16][N:15]=1>>[NH2:13][C:14]1[C:19]2[CH:20]=[C:21]([CH2:23][CH:24]([NH:34][S:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:11])=[O:10])[C:25]([N:27]3[CH2:28][CH2:29][CH:30]([CH3:33])[CH2:31][CH2:32]3)=[O:26])[S:22][C:18]=2[CH:17]=[CH:16][N:15]=1
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Reactant: CCCCCCCCS(=O)(=O)Cl
Product: CCCCCCCCS(=O)(=O)NC(Cc1cc2c(N)nccc2s1)C(=O)N1CCC(C)CC1

Procedure:
This compound was prepared from 0.15 mL of octane sulfonyl chloride and 210 mg of 30a using the procedure described for 58c. Yield: 150 mg; m.p. 101-112° C., (+)-FAB-MS: 495 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[N:5](S(C2C=CC=CC=2)(=O)=O)[CH:4]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+]>CO.C1COCC1>[CH2:1]([C:3]1[C:11]2[C:6]([NH:7][CH:8]=[N:9][C:10]=2[N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:14][CH2:13]2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCC(NC(=O)c4ccccc4)CC3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cnc2[nH]cnc(N3CCC(NC(=O)c4ccccc4)CC3)c1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-{1-[5-ethyl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide D7 (174 mg) and cesium carbonate (347 mg, 1.066 mmol) in MeOH (1.5 mL) and THF (3 mL) was stirred at room temperature for 3 hours. LCMS showed loss of starting material so the mixture was partitioned between EtOAc (10 mL) and water (10 mL). The organic phase was isolated (phase separator) and then concentrated. The crude material was purified by MDAP to give E18 (6 mg), 1H NMR (d6-DMSO) δ 11.59 (1H, brs), 8.38 (1H, d), 8.24 (1H, s), 8.78 (2H, d), 7.52 (1H, t), 7.46 (2H, t), 7.09 (1H, s), 4.06 (1H, m), 3.95 (2H, d), 3.02 (2H, t), 2.77 (2H, q), 1.94 (2H, d), 1.76 (2H, ddd), 1.26 (3H, t), MS(ES+) 350 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[N+](=[CH2:15])=[N-]>C(OCC)(=O)C.C(OCC)C>[CH3:15][O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[Cl:12]
Reactant: Cc1cc(Br)cc(Cl)c1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1c(C)cc(Br)cc1Cl
Reaction time: 1 h
Yield: 113 %

Procedure:
4-Bromo-2-chloro-6-methylbenzoic acid (1.10 g, 4.41 mmol) was dissolved in ethyl acetate (15 mL). A solution of diazomethane in diethyl ether was added until the yellow colour persisted. After fifteen minutes the reaction was quenched with acetic acid. After one hour, the mixture was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound as a yellow oil (1.31 g, 113%). 1H NMR CDCl3: 7.43 (s, 1H), 7.31 (s, 1H), 3.94 (s, 3H), 2.33 (s, 3H).