Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[F:22][C:23]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:24]=1[CH2:25][O:26][NH2:27]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([NH:27][O:26][CH2:25][C:24]4[C:28]([F:35])=[C:29]([F:34])[C:30]([F:33])=[C:31]([F:32])[C:23]=4[F:22])=[O:18])=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1cc2ncn(Cc3ccc(F)cc3)c2cn1
Reactant: NOCc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Product: O=C(NOCc1c(F)c(F)c(F)c(F)c1F)c1cc2ncn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 3-(4-fluorobenzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-[(2,3,4,5,6-pentafluorobenzyl)oxy]amine hydrochloride under the same conditions as those in step (c) of example 1. 1H NMR (300 MHz, MeOH-d4) δ: 8.69 (s, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 7.33-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.56 (s, 2H), 5.09 (s, 2H). LCMS (API-ES, M+H+): 467.0. HRMS calcd for C21H13F6N4O2 (M+H) 467.0943, found 467.0942. HPLC: >80% purity.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[N:19]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[O:26])[CH2:20]2>O1CCCC1>[CH2:17]([O:16][C:13](=[O:15])[CH2:14][C:21]1([OH:26])[CH:22]2[CH2:25][N:19]([CH2:24][CH2:23]2)[CH2:20]1)[CH3:18]
Reactant: CCOC(C)=O
Reactant: O=C1CN2CCC1C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC1(O)CN2CCC1C2
Temperature: 25 °C

Procedure:
To a cooled (-78° C.) solution of diisopropylamine (2.65 ml. 0.0203 moles) in tetrahydrofuran (150 ml) was added 2.5M n-BuLi in hexanes (8.1 ml. 0.0203 moles) dropwise over one minute. After ten minutes, ethyl acetate (1.97 ml. 0.0203 moles) was added dropwise over one minute. After a further ten minutes, 1-azabicyclo[2.2.1]heptan-3-one (1.5 g, 0.0135 moles, prepared by the method of J Chem Soc, Chem Commun, 1618, 1988) in tetrahydrofuran (25 ml) was added dropwise over five minutes. After twenty five minutes, the cold bath was removed and the mixture was allowed to warm to ambient temperature. To this mixture was added water (100 ml) followed by chloroform (250 ml). The organic layer was separated and the aqueous layer was extracted with chloroform (100 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give the subtitle compound (1.12 g).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25]O)[CH2:23][S:24][C@H:19]23)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[SH:39][C:40]1[N:44]([CH3:45])[N:43]=[N:42][N:41]=1.CNC(N1C2C(=CC=CC=2)C(=O)C1=O)=O>C(#N)C>[C:8]1([CH2:14][C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25][S:39][C:40]4[N:44]([CH3:45])[N:43]=[N:42][N:41]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: Cn1nnnc1S
Agent: CNC(=O)N1C(=O)C(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
In acetonitrile (14 ml) is dissolved 7β-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt (900 mg), followed by the addition of triethylamine (200 mg), 5-mercapto-1-methyl-1H-tetrazole (464 mg) and N-(methylcarbamoyl)isatin (916 mg). The mixture is stirred at 30° C. overnight. The solvent is then distilled off and the residue is dissolved by the addition of water and ethyl acetate. After separation, the water layer is taken, rinsed once with ethyl acetate and rendered acidic with hydrochloric acid. Following the addition of ethyl acetate, the mixture is stirred for 30 minutes. After separation , the organic layer is taken and rinsed with an aqueous solution of sodium chloride. It is extracted with an aqueous solution of sodium hdyrogen carbonate. The water layer is purified by column chromatography on Sephadex LH-20 . The fractions rich in the contemplated compound are pooled, concentrated, rendered acidic with phosphoric acid and extracted with ethyl acetate. After drying, the extract is concentrated, followed by addition of ether to the residue. The procedure provides 7β-phenylacetamido-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid. The NMR spectrum of this product is in good agreement with that of the compound obtained in Example 6.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[CH:6][C:7]([N+:29]([O-:31])=[O:30])=[C:8]([NH:10][C:11]2[S:12][C:13]([C:26]([NH2:28])=[O:27])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:15]=2)[CH:9]=1.C(#N)C.Cl>O>[CH:3]([C:4]1[CH:5]=[CH:6][C:7]([N+:29]([O-:31])=[O:30])=[C:8]([NH:10][C:11]2[S:12][C:13]([C:26]([NH2:28])=[O:27])=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)[N:15]=2)[CH:9]=1)=[O:2]
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3ccc(C(F)(F)F)cc3)c(C(N)=O)s2)c1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1ccc(C(F)(F)F)cc1
Yield: 70.7 %

Procedure:
A mixture of 0.9023 g (1.87 mmole) of 2-(5-dimethoxymethyl-2-nitro-phenylamino)-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide, 34 mL of acetonitrile and 17 mL of 1M hydrochloric acid was heated at 60 degrees for 2 hours. The cooled mixture was diluted with 50 mL of water. The resulting precipitate was collected by filtration, washed with water and dried to give 0.5766 g of 2-(5-formyl-2-nitro-phenylamino)-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.47b) as an orange-red solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:32].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:32])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)C(=O)O1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(F)cc1F)C(=O)O

Procedure:
Analogously to Example 1i), 3.1 g (7.18 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(2,4-difluorophenyl)methyl]-dihydrofuran-2-(3H)-one in 77 ml of dimethoxyethane and 19 ml of water are hydrolysed with 28.7 ml of 1M lithium hydroxide solution (19 h RT): tRet (I)=14.7 min.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:47][C:48](=[O:55])[C@H:49]([C@H:51]([CH2:53][CH3:54])[CH3:52])[NH2:50])(C)(C)C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:50][C@H:49]([C:48]([OH:55])=[O:47])[C@H:51]([CH2:53][CH3:54])[CH3:52])=[O:37])=[CH:29][CH:28]=2)=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC[C@H](C)[C@H](NC(=O)CCCOc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)cc1)C(=O)O

Procedure:
The product from Example 233 and L-isoleucine tert-butyl ester hydrochloride were processed as described in Example 251A and 258B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.06-12.82 (br.s, 1 H), 8.94 (s, 1 H), 7.99 (d, 1 H), 7.23 (m, 7 H), 6.87-7.09 (m, 7 H), 6.82 (d, 2 H), 4.19 (dd, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.93 (m, 2 H), 2.91 (s, 3 H), 2.38 (s, 3 H), 2.33 (m, 2 H), 1.92 (m, 2 H), 1.76 (m, 1 H), 1.40 (m, 1 H), 1.18 (m, 1 H), 0.83 (m, 6 H); MS (ESI+) m/z 688 (M+H)+.
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([F:35])=[CH:29][C:28]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.CS(OCCCC1CCCC1)(=O)=O>>[CH:25]1([CH2:20][CH2:19][CH2:18][N:39]2[CH2:40][CH2:41][N:36]([C:28]3[CH:29]=[C:30]([F:35])[C:31]([O:33][CH3:34])=[CH:32][C:27]=3[F:26])[CH2:37][CH2:38]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Reactant: BrCCc1ccccc1
Agent: COc1ccc(N2CCNCC2)cc1
Agent: CS(=O)(=O)OCCCC1CCCC1
Agent: Cl
Product: COc1cc(F)c(N2CCN(CCCC3CCCC3)CC2)cc1F

Procedure:
Production Example 1 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and (2-bromoethyl)-benzene were replaced with 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (342 mg) and 3-cyclopentylpropyl methylsulfonate (309 mg), respectively, to provide crude 1-(3-cyclopentylpropyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (486 mg).
Reaction SMILES: Br[CH:2]([CH3:13])[CH2:3][NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH2:17]>[I-].[K+].Cl>[CH3:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=1[NH:4][CH2:3][CH:2]([NH:17][C:16]1[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:15]=1[CH3:14])[CH3:13]
Reactant: Cc1cccc(C)c1NCC(C)Br
Reactant: Cc1cccc(C)c1N
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: Cc1cccc(C)c1NCC(C)Nc1c(C)cccc1C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A mixture of 106.8 g (0.441 moles) of N-(β-bromopropyl)-2,6-dimethyl-aniline, obtained as described in point (a) above, 110 ml (107.4 g, 0.88 moles) of 2,6-dimethylaniline and 1.6 g (10 mmoles) of potassium iodide is stirred at 100° to 105° C. for 3 hours under nitrogen atmosphere. The mixture is allowed to cool, 600 ml of 10% aqueous hydrochloric acid are added, and the resulting mixture is allowed to stand at room temperature overnight. The separated precipitate, which is a mixture of the hydrochloride and the hydrobromide of the expected product, is filtered off, washed with water, dried, and then treated as described in point (b) of Method (b) above in order to liberate the base. In this way 93.8 g (75.3%) of 1,2-bis(2',6'-dimethylphenyl-amino)-propane are obtained; m.p.: 54°-56° C.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][C:14]=3[N:15]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:16]([O:21][C@@H:22]([C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1)[CH3:23])(=[O:20])[CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>C(O)(C)C>[C:16]([O:21][C@@H:22]([C:24]1[N:25]=[C:26]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[O:8][C:9]4[CH:10]=[N:11][CH:12]=[CH:13][C:14]=4[N:15]=3)[CH2:2][CH2:3]2)[CH:27]=[CH:28][N:29]=1)[CH3:23])(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: c1cc2nc(N3CCNCC3)oc2cn1
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCN(c3nc4ccncc4o3)CC2)n1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 2-(1-piperazinyl)oxazolo[5,4-c]pyridine (775 mg, 3.8 mmol; J. Org. Chem. 1995, 60, 5721) in isopropanol (38 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 868 mg, 3.8 mmol) followed by triethylamine (1.6 mL, 11.4 mmol). This mixture was stirred at reflux overnight, cooled to room temperature, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2×; 3% methanol/chloroform then 6→8% methanol/ethyl acetate, where used herein, the arrow symbol, →, indicates a gradient) to give 1.2 g (79%) of the title compound of Example 2, Step A as a pale yellow oil which solidified upon standing. 1H NMR (CDCl3, 250 MHz) δ 8.57 (s, 1H), 8.39 (d, 1H), 8.28 (d, 1H), 7.30 (d, 1H), 6.44 (d, 1H), 5.70 (q, 1H), 3.85 (s, 8H), 2.42 (t, 2H), 1.78-1.61 (c, 2H), 1.60 (d, 3H), 0.98 (t, 3H); MS (APCI) 397 (MH+).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17](N3CCCC3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].[F:24][C:25]1([F:30])[CH2:29][CH2:28][NH:27][CH2:26]1.Cl>CO>[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:27]3[CH2:28][CH2:29][C:25]([F:30])([F:24])[CH2:26]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10]
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CO
Product: Nc1ccc(N2CCC[C@@H](C(=O)N3CCC(F)(F)C3)C2)nc1N

Procedure:
The title compound was prepared by a method analogous to the one used for Intermediate 1, but using 3,3-difluoropyrrolidine instead of pyrrolidine for Step 1 and a solution of hydrogen chloride in methanol (1.25 M) for Step 2. MS (ES+) (M+H) 326.1; LCMS retention time: 0.26 minutes (Method M). 1H NMR (DMSO, 400 MHz): δ 1.45-1.62 (m, 2H), 1.65-1.72 (m, 1H), 1.82-1.90 (m, 1H), 2.30-2.45 (m, 2H), 2.76-2.91 (m, 2H), 3.46-3.54 (m, 1H), 3.64-3.78 (m, 2H), 3.84-3.92 (m, 1H), 3.95-4.04 (m, 2H), 4.06-4.13 (m, 1H), 4.13-4.62 (m, 6H), 6.14 (d, 1H), 7.24 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH2:20]=[O:21]>C(#N)C>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:20]=[O:21]
Reactant: COc1ccc(O)cc1
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(O)c(C=O)c1
Temperature: 45 °C
Yield: 74 %

Procedure:
A mixture of 600 g of acetonitrile, 186.2 g of 4-methoxyphenol (1.5 moles) and 214 g (2.25 moles) of anhydrous magnesium chloride was warmed to 45° C. and 227.4 g (2.25 moles) of triethylamine was added dropwise at that temperature. Paraformaldehyde (150 g, 4.75 moles) was then added and the reaction was heated to reflux. Methanol was removed over 3 hours by distillation, using a 10-inch column packed with Penn-State packing. The weight of the methanol removed (vapor temperature 60-65° C.) was 130 g. The solution was cooled to 60° C. and added to 900 mL of water. The solution was acidified with 240 mL of conc. HCl and extracted with 150 g of ethyl acetate. The ethyl acetate solution was washed once with 300 mL of tap water, clarified through diatomaceous earth, and stripped on a rotary evaporator at 10 mm pressure and 85° C. bath temperature. The weight of the product was 206.5 g, the liquid chromatograph area percent was 86%, and liquid chromatograph weight percent was 82%. The overall assay yield was 74%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O=[C:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:15]2[CH2:16][CH2:17][CH:18]([NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])[CH2:19][CH2:20]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (5 g, 20.57 mmol) and tert-butyl (4-oxocyclohexyl)carbamate (5.67 g, 26.74 mmol) in methanol (50 mL), acetic acid (1.2 g, 20.57 mmol) was added and reaction stirred at room temperature for 4 h. Then sodium cyanoborohydride (1.68 g, 26.74 mmol) was added and reaction stirred 18 h. On completion, solvent was removed under reduced pressure; water was added and extracted with DCM. Combined organic were dried, concentrated and purified by column chromatography using silica (100-200 mesh size) to afford the desired compound (3 g, 33%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CN4CCOCC4)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (200 mg) in 1,2-dichloroethane (5 mL) was added morpholine (240 μL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (280 mg), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (192 mg, yield 83%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 536 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1(C)C(C)(C)OB([C:30]2[CH:42]=[CH:41][C:33]([CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:32][CH:31]=2)O1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[CH2:20]([N:13]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:4]1[C:5]([CH3:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[C:2]([C:30]2[CH:31]=[CH:32][C:33]([CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:41][CH:42]=2)[CH:3]=1)[CH3:21]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
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: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 88 °C
Reaction time: 1 h
Yield: 164 %

Procedure:
A mixture of methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (580 g, 1.63 mol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (592 g, 1.95 mol), 1,4-dioxane (3.86 L), sodium carbonate (618 g, 5.83 mol), and water (771 ml) was degassed by bubbling nitrogen through the mixture at 20° C. for 20 minutes and treated with tetrakis(triphenylphosphine)palladium(0) (14.11 g, 12.21 mmol). The resulting mixture was degassed for an additional 20 minutes and then heated to 87-89° C. for 17 h. After cooling to 20° C., the mixture was diluted with ethyl acetate (5.80 L) and a solution of (R)-2-Amino-3-mercaptopropionic acid (232 g) in water (2.320 L). After stirring for 1 h at 20° C., the organic layer was separated and washed again with a solution of (R)-2-Amino-3-mercaptopropionic acid (232 g) in water (2.320 L). The aqueous layers were combined and extracted with ethyl acetate (5.80 L). The organic layers were combined, washed with a solution of sodium hydroxide (93 g) in water (2.32 L), and concentrated under vacuum at 35° C. to give the title compound as an orange oil (1.21 kg, 164% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1([CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O.COC(=O)CCC1(CC)CCCCC1=O.C(C12CCC(=O)[N:43]3C1=C([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=13)CCC2)C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1([CH3:13])[C:7]2[NH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:8]=2[CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)CCC1(C)CCCCC1=O
Reactant: CCC12CCCc3c1n(c1ccccc31)C(=O)CC2
Agent: CCC1(CCC(=O)OC)CCCCC1=O
Product: COC(=O)CCC1(C)CCCc2c1[nH]c1ccccc21

Procedure:
In the same manner but replacing 1-methyl-2-oxocyclohexanepropionic acid methyl ester with an equivalent amount of 1-ethyl-2-oxocyclohexanepropionic acid methyl ester, described in Example 6, 3a-ethyl-1,2,3,3a,4,5-hexahydro-6H-pyrido[3,2,1-jk]carbazol-6-one, mp 97°-99° C., and 1-ethyl-1,2,3,4-tetracarbazole-1-propionic acid methyl ester, νmaxCHCl3 1738 cm-1 are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:5]([OH:9])[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:19]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:9])[C:6]([O:8][CH3:19])=[O:7])[CH:10]=[CH:11][C:12]=1[OH:13]
Reactant: CO
Reactant: O=C(O)C(O)c1ccc(O)c(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1ccc(O)c(O)c1

Procedure:
3,4-Dihydroxymandelic acid is refluxed in methanol in the presence of sulfuric acid, to give methyl 2-(3,4-dihydroxyphenyl)-2-hydroxyacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].I[CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:12][CH3:13])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)cccc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cccc(Cl)c1C=O
Temperature: 80 °C

Procedure:
A mixture of commercially available 2-chloro-6-hydroxybenzaldehyde (2.000 g; 12.80 mmol), iodoethane (3.985 g; 25.50 mmol), and K2CO3 (2.119 g; 15.30 mmol) in anh. DMF (35 ml) was heated to 80° C., under nitrogen, for 1 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-chloro-6-ethoxybenzaldehyde as a yellow solid. LC-MS (conditions A): tR=0.75 min.; [M+H]+: 185.39 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17](I)([CH3:19])[CH3:18]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:17]([CH3:19])[CH3:18])[CH:7]=1
Reactant: COc1ccc(Br)cc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Br)cc1OC(C)C
Temperature: 20 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 5-bromo-2-methoxyphenol (0.200 g, 1 mmol) in DMF (4 mL) was added potassium carbonate (0.209 g, 1.5 mmol) and isopropyliodide (120 μL, 1.2 mmol), the reaction mixture was stirred at room temperature (20° C.) for 3 h. After this time the crude reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2×100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil (200 mg, 0.81 mmol, 82%). No further purification was required.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[CH3:16]O.Cl>>[OH:1][C:2]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:16])=[O:9])=[O:5]
Reactant: Cc1ccc(C(=O)CCC(=O)O)c(O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)CCC(=O)c1ccc(C)cc1O

Procedure:
3-(2-Hydroxy-4-methylbenzoyl)propionic acid was esterified with methanol-hydrogen chloride, in a similar manner to the procedure described in Example 1 (i), to give methyl 3-(2-hydroxy-4-methylbenzoyl)propionate, m.p. 61°-63°.