Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH2:11]([O:18][C:19]1[C:20]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)=[CH:21][C:22]([CH2:40][CH3:41])=[C:23]([CH:39]=1)[O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30]([CH2:36][CH2:37][CH3:38])=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:49][C:50]1([CH3:57])[CH2:54][C:53](=[O:55])[O:52][C:51]1=[O:56]>C1COCC1>[CH2:11]([O:18][C:19]1[C:20]([C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)=[CH:21][C:22]([CH2:40][CH3:41])=[C:23]([CH:39]=1)[O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30]([CH2:36][CH2:37][CH3:38])=[C:31]([NH:32][C:53](=[O:55])[CH2:54][C:50]([CH3:57])([CH3:49])[C:51]([OH:56])=[O:52])[CH:33]=[CH:34][CH:35]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCc1c(N)cccc1OCCCOc1cc(OCc2ccccc2)c(-c2ccc(F)cc2)cc1CC
Reactant: CC1(C)CC(=O)OC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1c(NC(=O)CC(C)(C)C(=O)O)cccc1OCCCOc1cc(OCc2ccccc2)c(-c2ccc(F)cc2)cc1CC
Temperature: 35 °C
Yield: 82.4 %

Procedure:
Add diisopropylethylamine (57 mL, 327 mmol) to a suspension of 3-[3-[5-benzyloxy-2-ethyl-4-(4-fluorophenyl)phenoxy]propoxy]-2-propyl-aniline hydrochloride (90 g, 175 mmol) in THF (450 mL). To this mixture, add dihydro-3,3-dimethyl-2,5-furandione (32.1 g, 251 mmol) and stir at 35° C. until LCMS indicates 5% starting material remaining. Concentrate the mixture in vacuo and add methyl tert-butyl ether (100 mL) and water (75 mL). Adjust to pH=2-3 with phosphoric acid and separate the layers. Wash the aqueous layer with additional methyl tert-butyl ether (2×50 mL). Wash the combined organic extracts with brine and concentrate in vacuo. Dissolve the crude residue in methyl tert-butyl ether (180 mL) and add hexane (450 mL) to obtain a suspension and stir for 30 min. Collect the suspension by filtration and dry to yield the title compound (92.5 g, 88%) as a white solid. ES/MS m/z 642 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C@@H:10]2[NH:15][CH2:14][CH2:13][N:12]([C:16]3[C:17]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:18]=4[NH:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C@@H:10]2[N:15]([CH3:34])[CH2:14][CH2:13][N:12]([C:16]3[C:17]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:18]=4[NH:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc2c(c1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2cccc(F)c2)C1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc2c(c1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
Combine 11-{(S)-3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-3-methyl-5H-dibenzo[b,e][1,4]diazepine (385.5 mg, 0.93 mmol), formaldehyde (83.0 μL, 1.02 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (295.6 mg, 1.39 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 366.2 mg (92%) of the title compound as a yellow foam: mp 63°, dec; mass spectrum (ion spray): m/z=429.3 (M+1).
Reaction SMILES: [C:1]([O:4][CH:5]1[C@@H:9]2[CH:10]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:12])[N:8]2[CH:7]([C:24]([O:26]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:25])[CH:6]1[CH3:40])(=[O:3])[CH3:2].C(Cl)(Cl)Cl>[Pd].C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C@@H:9]2[CH:10]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:12])[N:8]2[CH:7]([C:24]([OH:26])=[O:25])[CH:6]1[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@@H]12
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)OC1C(C)C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@@H]12
Reaction time: 1 h

Procedure:
Benzhydryl 1-acetoxy-2-methyl-6-(2-phenoxyacetamido)carbapenam-3-carboxylate (18 mg.) was dissolved in 3 ml. of ethyl acetate. Hydrogenation catalyst (18 mg. of 10% palladium on carbon) was added and the mixture hydrogenated at atmospheric pressure and room temperature for 1 hour. When tlc (4:1 chloroform:ethyl acetate) indicated no change, a second aliquot of catalyst (18 mg.) was added. According to tlc assay, some conversion occurred during the next hour, at which time a third aliquot of catalyst (18 mg.) was added. At the end of another hour of hydrogenation, tlc assay indicated reduction to be complete. Catalyst was recovered by filtration with ethyl acetate wash. The combined filtrate and washes were evaporated to dryness in vacuo to yield 1-acetoxy-2-methyl-6-(2-phenoxyacetamido)carbapenam-3-carboxylic acid [Rf 0.77 (18:1 acetone:water); ir (CH2Cl2) 1775, 1725, 1675 cm-1 ].
Reaction SMILES: [CH2:1]([C@H:4]1[C:13]2=[C:14]3[C:19](=[CH:20][CH:21]=[C:12]2[C:11]2[C:10]([OH:25])=[CH:9][CH:8]=[CH:7][C:6]=2[O:5]1)[NH:18][C:17]([CH3:23])([CH3:22])[CH:16]=[C:15]3[CH3:24])[CH:2]=[CH2:3].[C:26](O[K])(C)(C)C.IC.[NH4+].[Cl-]>C1COCC1.CC(OC)(C)C>[CH2:1]([C@H:4]1[C:13]2=[C:14]3[C:19](=[CH:20][CH:21]=[C:12]2[C:11]2[C:10]([O:25][CH3:26])=[CH:9][CH:8]=[CH:7][C:6]=2[O:5]1)[NH:18][C:17]([CH3:23])([CH3:22])[CH:16]=[C:15]3[CH3:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1Oc2cccc(O)c2-c2ccc3c(c21)C(C)=CC(C)(C)N3
Reactant: CC(C)(C)O[K]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C=CC[C@@H]1Oc2cccc(OC)c2-c2ccc3c(c21)C(C)=CC(C)(C)N3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 9 (157 mg) in THF (10 ml) was treated with a 1.0 M solution of tBuOK (1.0 ml) at 0° C. and then treated with iodomethane (0.1 ml). After stirring at room temperature for 2 hours, the mixture was poured into a solution of saturated NH4Cl (15 mL) and stirred briefly before MTBE (15 mL) was added. After stirring for 5 minutes, the organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by column chromatography to give the title compound (134 mg). Anal. calcd for C23H25NO2: C, 79.51; H, 7.25 and N, 4.03; Found: C, 79.26; H, 7.12 and N, 3.80; 1H NMR [(CD3)2SO] δ1.16 (3H, s) 1.17 (3H, s), 2.18 (3H, s), 2.22 (1H, m), 2.46 (1H, m), 3.85 (3H, s), 5.01 (2H, m), 5.44 (1H, br s), 5.77 (1H, dd), 5.82 (1H, M), 6.10 (1H, br s), 6.52 (1H, d), 6.60 (1H, d), 6.70 (1H, d), 7.06 (1H, t) and 7.96 (1H, d); 13CNMR [(CD3)2SO] δ23.8, 28.8, 28.9, 36.5, 49.7, 55.6, 73.4, 105.6, 110.5, 113.4, 113.4, 116.1, 116.4, 127.3, 117.3, 127.3, 127.7, 132.2,133.8, 134.5, 145.8, 151.1, 156.4; APCI-MS: m/z 348 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:10]2([CH3:11])[CH:5]([CH:6]([OH:12])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][C:19]([CH2:23][CH3:24])([OH:22])[CH2:20][CH3:21].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:25][C:2]1([CH3:1])[C:10]2([CH3:11])[CH:5]([C:6](=[O:12])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][C:19]([CH2:23][CH3:24])([OH:22])[CH2:20][CH3:21]
Reactant: CCC(O)(CC)CCCOCCC1CC2C(O)CCCC2(C)C1(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(O)(CC)CCCOCCC1CC2C(=O)CCCC2(C)C1(C)C
Yield: 73.1 %

Procedure:
251 mg (0.71 mmol) of 49 is reacted with 212 mg (0.99 mmol) of pyridinium chlorochromate in 16 ml of methylene chloride analogously to 30., and 183 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:23](=[O:24])[C:11]3([CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=4)[CH2:12]3)[NH:10][C:9]2=[O:25])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[CH2:30]([N:10]1[C:11]2([CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=3)[CH2:12]2)[C:23](=[O:24])[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=2)[C:9]1=[O:25])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(CN2C(=O)NC3(Cc4ccc([N+](=O)[O-])cc4C3)C2=O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)N(Cc3ccccc3)C3(Cc4ccc([N+](=O)[O-])cc4C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (±)-1-(4-methoxybenzyl)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione from Step A (165 mg, 0.45 mmol) in DMF (1 mL) was added sodium hydride (18 mg of a 60% dispersion in mineral oil, 0.45 mmol). The mixture was stirred for 5 min at ambient temperature and benzyl bromide (230 mg, 1.35 mmol) was added. After 30 min, the mixture was partitioned between saturated aqueous NaHCO3 (3 mL) and CHCl3 (5 mL). The aqueous phase was extracted further with CHCl3 (5 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc—75:25, to give the title compound. MS: m/z=458 (M+1).
Reaction SMILES: [F:1][C:2]1([F:37])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24](C(C)(C)C)=[C:25]([CH:29]=[CH:30][CH:31]=5)[C:26]([O-:28])=[O:27])[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O.Cl>CC#N>[F:37][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=5)[C:26]([OH:28])=[O:27])[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)[O-])c1C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CC#N
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)O)c1
Temperature: 45 °C
Reaction time: 36 h

Procedure:
To a slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in MeCN (3.0 vol) is added water (0.83 vol) followed by concentrated aqueous HCl (0.83 vol). The mixture is heated to 45±5° C. After stirring for 24 to 48 hours the reaction is complete and the mixture is allowed to cool to ambient. Water (1.33 vol) is added and the mixture stirred. The solid is collected by filtration, washed with water (2×0.3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60° C. with a slight N2 bleed to afford 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.HCl as an off-white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:19]2[CH:23]=[C:22]([C:24]3[C:25]4[CH:32]=[CH:31][N:30]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH:21]=[N:20]2)[CH2:7][N:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([F:18])[CH:9]=2)[CH2:5]1)#[N:2].[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([CH2:3][C:4]1([N:19]2[CH:23]=[C:22]([C:24]3[C:25]4[CH:32]=[CH:31][N:30]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:40])[CH3:39])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH:21]=[N:20]2)[CH2:5][N:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:18])[CH:9]=2)[CH2:7]1)#[N:2]
Reactant: COC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)c(F)c5)C4)c3)ncnc21
Temperature: 35 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
To a solution of methyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-fluorobenzoate (1.22 g, 2.17 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium hydroxide (0.21 g, 8.8 mmol) in water (9.8 mL). The reaction mixture was then stirred at 35° C. for 24 hours. The reaction mixture was diluted with water (5 mL) and pH was adjusted to ˜4 with 1 N HCl, extracted with ethyl acetate. The organic fraction was washed with water (1×), brine (1×), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The solid was then triturated with methylene chloride-methanol (95:5), filtrated to afford the desired product (0.917 g, 77.1%). LCMS (M+H)+: m/z=562.2.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[N:16]=[C:10]2[C:11](=O)[NH:12][NH:13][CH:14]=[C:9]2[C:8]=1[CH3:17].[OH-].[Na+]>>[Cl:3][C:11]1[N:12]=[N:13][CH:14]=[C:9]2[C:8]([CH3:17])=[C:7]([CH3:6])[NH:16][C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(=O)[nH][nH]cc-2c1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1[nH]c2c(Cl)nncc2c1C
Temperature: 0 °C

Procedure:
45 ml of phosphorus oxychloride were added to 3.35 g (0.021 mole) of 2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]pyridazin-7-one and the mixture was heated under reflux for 2 hours. After completion of the reaction, the reaction mixture was slowly poured into ice-water and the aqueous mixture was neutralized with an aqueous solution of sodium hydroxide. The precipitated yellow solids were collected by filtration and washed well with water. The solids were dissolved in dichloromethane and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 15:1 mixture of chloroform and methanol as an eluent to give 2.39 g of 7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].I[CH2:18][CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:18][CH2:19][CH3:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cccc2oc(C(=O)OCC)c(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (200 mg) was mixed with iodopropane (0.5 mL), K2CO3 (200 mg) and 2 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent gave the crude product, which was purified by column chromatography to give 176 mg of 3-methyl-4-propoxy-benzofuran-2-carboxylic acid ethyl ester as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[O:14][C:13]3[C:15]4[C:20]([C:21]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[C:22]([C:23]([O:25][CH2:26][CH2:27][OH:28])=[O:24])[C:12]=3[CH:11]=[CH:10]2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:5][CH:4]=1.[C:43](Cl)(=[O:46])[CH2:44][CH3:45]>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:35]3[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=3)[O:14][C:13]3[C:15]4[C:20]([C:21]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[C:22]([C:23]([O:25][CH2:26][CH2:27][O:28][C:43](=[O:46])[CH2:44][CH3:45])=[O:24])[C:12]=3[CH:11]=[CH:10]2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:7][CH:8]=1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(C2(c3ccc(OC)cc3)C=Cc3c(C(=O)OCCO)c(-c4ccccc4)c4ccccc4c3O2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)OCCOC(=O)c1c2c(c3ccccc3c1-c1ccccc1)OC(c1ccc(OC)cc1)(c1ccc(OC)cc1)C=C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2,2-Bis(4-methoxyphenyl)-5-(2-hydroxyethoxycarbonyl)-6-phenyl-[2H]-naphtho[1,2-b]pyran (U.S. Pat. No. 6,113,814) (0.50 g, 0.90 mmol) was dissolved in dry dichloromethane (20 ml) together with triethylamine (0.25 ml), under nitrogen. To this solution was added propionyl chloride (0.083 g, 0.90 mmol) and the mixture stirred at RT for 15 minutes. The solvent was evaporated and the crude residue purified by column chromatography (silica gel, EtOAc/hexane, 2:3) giving a pink foamy solid on evaporation of the solvent in vacuo. Analysis of the purified product by 1H NMR gave a spectrum consistent with the structure of 2,2-Bis(4-methoxyphenyl)-5-(2-propionyloxy-ethoxycarbonyl)-6-phenyl-[2H]-naphtho[1,2-b]pyran.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9]([CH3:17])=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:20]=1[CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:20]=1[CH2:21][NH:1][C:2]1[C:3]2[N:4]([C:9]([CH3:17])=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCOC(=O)c1nc2c(N)cc(C)cn2c1C
Reactant: Cc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1nc2c(NCc3c(C)cccc3C)cc(C)cn2c1C
Yield: 45.7 %

Procedure:
Ethyl 8-amino-3,6-dimethylimidazo[1,2-a]pyridin-2-carboxylate (1.3 g, 5.6 mmol), 2,6-dimethylbenzyl chloride (0.9 g, 6.2 mmol), potassium carbonate (1.5 g, 11 mmol) and sodium iodide (0.1 g, 0.6 mmol) were added to acetonitrile (15 ml) and refluxed for 20 h. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride , washed twice with water and the organic layer was separated dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using heptane:ethyl acetate (2:1) as eluent gave 0.9 g (47%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C([Li])CCC.[CH3:14][S:15]SC>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:15][CH3:14]
Reactant: CSSC
Reactant: Fc1cccc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1c(F)cccc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 794.2 %

Procedure:
Dissolve 1,3-difluorobenzene (3.5 g, 30.7 mmol) into THF (100 mL). Cool the mixture to −78° C. and add n-butyl lithium (19 mL, 30.7 mmol). Stir for 20 minutes and add dimethyldisulfide (3 mL, 3.38 mmol). Remove the cooling bath and warm to room temperature. Pour the reaction mixture into ice (10 g) and add diethyl ether (100 mL). Separate the layers and wash the organic layer with brine (20 mL). Dry with MgSO4, filter, and concentrate in vacuo to give 4.3 g of 1,3-difluoro-2-methylsulfanyl-benzene (88%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:39])=[CH:5][C:6]([Cl:38])=[C:7]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[C:17]([O:33][CH2:34][CH:35]([F:37])[F:36])[C:18]([C:20]([NH:22][C@H:23]4[CH2:28][CH2:27][C@H:26]([C:29]([F:32])([F:31])[F:30])[CH2:25][CH2:24]4)=[O:21])=[CH:19][C:12]=3[N:11]=2)[CH:8]=1.[F:40][C:41]([F:49])([F:48])[C:42]1([C:45](O)=[O:46])[CH2:44][CH2:43]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:38][C:6]1[CH:5]=[C:4]([F:39])[C:3]([CH2:2][NH:1][C:45]([C:42]2([C:41]([F:49])([F:48])[F:40])[CH2:44][CH2:43]2)=[O:46])=[CH:8][C:7]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[C:17]([O:33][CH2:34][CH:35]([F:36])[F:37])[C:18]([C:20]([NH:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]([F:31])([F:32])[F:30])[CH2:25][CH2:24]3)=[O:21])=[CH:19][C:12]=2[N:11]=1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: Cn1c(Nc2cc(CN)c(F)cc2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)c(F)cc2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc21

Procedure:
The title compound was prepared in accordance with the procedure in Example 72, step (c) using 2-[5-(aminomethyl)-2-chloro-4-fluoro-phenyl]amino-6-(2,2-difluoroethoxy)-1-methyl-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzo[d]imidazole-5-carboxamide (150 mg; 0.26 mmol), 1-(trifluoromethyl)-cyclopropanecarboxylic acid (40 mg; 0.26 mmol), HBTU (99 mg; 0.26 mmol), TEA (53 mg; 0.52 mmol) and DMF (4 mL). Yield: 39 mg (21%). 400 MHz 1H-NMR (DMSO-d6, ppm) 8.40 (1H, t, J=5.8 Hz) 8.32 (1H, s) 7.90-7.82 (2H, m) 7.78-7.74 (1H, m) 7.44 (1H, d, J=9.6 Hz) 7.23-7.19 (1H, m) 6.63-6.34 (1H, m) 4.51-4.40 (2H, m) 4.29 (2H, d, J=5.8 Hz) 3.78-3.65 (4H, m) 2.28-2.17 (1H, m) 2.03-1.97 (2H, m) 1.91-1.85 (2H, m) 1.39-1.19 (8H, m). MS m/z: 714, 716 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH2:12].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]1[N:12]([CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:15](=[O:14])[CH2:16][CH2:19][CH2:20]1
Reactant: NCc1ccc2ccccc2c1
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2ccccc2c1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available naphthalen-2-ylmethanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions H): tR=1.35 min.; [M+H]+: 375.79 g/mol.
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.[N:28]1([C:33]2[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=2)[CH:32]=[CH:31][N:30]=[CH:29]1>>[N:28]1([C:33]2[CH:38]=[CH:37][C:36]([O:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][CH:16]=3)=[CH:35][CH:34]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(CCOc2ccc(-n3ccnc3)cc2)cc1)c1ccccc1
Yield: 62 %

Procedure:
The title compound was prepared as its TFA salt in 62% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 4-imidazol-1-yl-phenol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:18]1([CH:24]2[CH2:28][NH:27][C:26](=[O:29])[CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([N:27]2[CH2:28][CH:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:25][C:26]2=[O:29])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N(C)S(C)(=O)=O)c1
Reactant: O=C1CC(c2ccccc2)CN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N2CC(c3ccccc3)CC2=O)cc(N(C)S(C)(=O)=O)c1
Temperature: 110 °C
Reaction time: 7 h
Yield: 82 %

Procedure:
A mixture of methyl 3-bromo-5-[methyl(methylsulfonyl)amino]benzoate obtained in Reference Example 15 322 mg (1.0 mmol), 4-phenyl-2-pyrrolidinone 177 mg (1.1 mmol), cesium carbonate 456 mg (1.4 mmol), tris(dibenzylideneacetone)dipalladium(0) 4.6 mg (0.005 mmol), Zandphos 8.7 mg (0.015 mmol) and 1,4-dioxane (2 mL) was stirred at 110° C. under argon atmosphere for 7 hours. The reaction solution was diluted with ethyl acetate and the resulting precipitates were filtered. The solvent was evaporated and the residual solid was purified by a column chromatography on silica gel (eluted with hexane/ethyl acetate=3:1→1:1) to give 329 mg (0.817 mmol) of the title compound (yield: 82%).