Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:17]2[C:12](=[C:13]([O:26]C(=O)C)[C:14]([O:22]C(=O)C)=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[S:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[CH3:2].[OH-].[Na+].C(O)(=O)C>CC(C)=O>[C:1]([N:4]1[C:17]2[C:12](=[C:13]([OH:26])[C:14]([OH:22])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[S:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c2c(c3ccccc3c1OC(C)=O)N(C(C)=O)c1ccccc1S2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CC(=O)N1c2ccccc2Sc2c(O)c(O)c3ccccc3c21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 28 %

Procedure:
To a suspension of 12-acetyl-5,6-diacetoxy-12H-benzo[a]phenothiazine (450 mg) in acetone (10 ml) there was added 2N aqueous sodium hydroxide solution (10 ml) and the resulting mixture was stirred at room temperature for 45 minutes. It was then made slightly acidic by the addition of 10% aqueous acetic acid solution and the insolubles filtered and washed with water. The solid was swished in ethyl acetate to afford pure title compound (100 mg), m.p. 258°-260° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:34]1[CH2:39][CH:38]=[C:37]([C:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)[CH2:36][CH2:35]1>C1COCC1.CN(C=O)C>[NH:42]1[C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40]([C:37]2[CH2:38][CH2:39][N:34]([CH2:12][CH:13]3[O:27][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]5)[CH2:35][CH:36]=2)=[CH:41]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Temperature: 25 °C

Procedure:
To a solution of (2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (7.02 g, 18.1 mmole) and potassium carbonate (5.71 g, 41.3 mmole) in 250 mL of 1:1 THF/DMF was added 10.7 g (54.5 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole. The mixture was heated at reflux under nitrogen for 6 hours. After cooling to room temperature, the mixture was concentrated to dryness under vacuum and the residue column chromatographed on silica gel using first methylene chloride to elute impurities and then 3% methanol in methylene chloride to elute the product. The product-containing fractions were concentrated in vacuum and the residue recrystallized from ethanol/ethyl acetate to give 4.45 g of the (S)-enantiomer of the title compound as a yellow solid (m.p. 210° C.).
Reaction SMILES: [CH:1]([C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8])=O.[C:16]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:18][CH2:19][CH3:20])=[O:17]>O1CCOCC1>[CH2:19]([O:18][C:16]([CH:21]=[CH:1][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8])=[O:17])[CH3:20]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1C=O
Solvent: C1COCCO1
Product: CCOC(=O)C=Cc1c(C)oc2c([N+](=O)[O-])cccc12
Yield: 84.2 %

Procedure:
A solution of 3-formyl-2-methyl-7-nitrobenzo[b]furan (200 mg) and (carboethoxymethylene)triphenylphosphorane (434 mg) in dioxane (3 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel. The obtained oil was crystallized from diisopropyl ether to give 3-(2-ethoxycarbonylethenyl)-2-methyl-7-nitrobenzo[b]furan (226 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH2:13][CH2:14][OH:15])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>C(Cl)Cl>[CH3:23][S:24]([O:15][CH2:14][CH2:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccccc1OCC1CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccccc1OCC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
2-Cyclopropylmethyloxy-1-(2-hydroxyethyloxy)benzene (2.7 g, 13.0 mmol), prepared as in Example 1, Step (a), and triethylamine (2.7 mL, 19.5 mmol) were dissolved in methylene chloride (20 mL) and the solution was cooled in an ice bath. Methanesulfonyl chloride (1.2 mL, 15.5 mmol) in methylene chloride (10 mL) was added dropwise to the solution and the mixture was stirred at 0° C. for 30 minutes. Water was added and the mixture was stirred vigorously at room temperature for 15 minutes. The mixture was extracted into methylene chloride. The organic phase was separated, washed with 2N hydrochloric acid and then brine, and dried over magnesium sulfate. Evaporation gave 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate (3.7 g, 12.9 mmol) as a white solid, m.p. 90°-91° C.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[S:11][C:12]2[C:17]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])=[N:16][C:15]([S:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:14][C:13]=2[N:32]=1.C(#N)C.C(Br)(Br)[Br:37]>>[Br:37][C:10]1[S:11][C:12]2[C:17]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])=[N:16][C:15]([S:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:14][C:13]=2[N:32]=1
Reactant: BrC(Br)Br
Reactant: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc2nc(N)sc12
Agent: CC(C)CCON=O
Solvent: CC#N
Product: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc2nc(Br)sc12
Yield: 38 %

Procedure:
Isoamyl nitrite (0.3 ml) was added to a suspension of the product of example 32 step c) (0.23 g) in bromoform (15 ml) and acetonitrile (15 ml) at 50° C. Stirring was maintained for 10 min before concentrating to approximately, 3 ml. The residue was purified by column chromatography using 20% EtOAc/DCM as eluent to yield the subtitle compound as a yellow solid (102 mg, 38%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[S:9][C:8]=2[C:18]([O:20][CH3:21])=[O:19])[CH:4]=[N:3]1.OO.C1([OH:30])C=CC=CC=1>C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:30])[N:14]=[CH:15][C:10]=3[S:9][C:8]=2[C:18]([O:20][CH3:21])=[O:19])[CH:4]=[N:3]1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1sc2cnc(SC)nc2c1-c1cnn(C)c1
Agent: OO
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2cnc(S(C)=O)nc2c1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
230 mg of methyl 7-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylate, prepared by analogy with the method described in example 4, are added to a mixture of 25 equivalents of hydrogen peroxide (30% in water) and 1.49 g of phenol. The reaction medium is stirred for 30 minutes at ambient temperature and then heated at 50° C. for 1 hour. The reaction medium is diluted in ethyl acetate and washed with a saturated aqueous NaHCO3 solution and then with a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered, and then concentrated under vacuum so as to obtain the crude product, which is purified on silica, elution being carried out with a 0-10% gradient of methanol in dichloromethane so as to obtain 170 mg of methyl 7-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfinyl)thieno[3,2-d]pyrimidine-6-carboxylate in the form of a beige solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[NH:28]1[CH:32]=[CH:31][CH:30]=[N:29]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: c1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCn3cccn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=442.4 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-pyrazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:16][O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH:14]=[CH2:15]
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCC(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C

Procedure:
2-tert-Butoxycarbonylamino-pent-4-enoic acid (9.3 g, 43.3 mmol) in acetone (70 mL) is treated with solid potassium carbonate (11.9 g, 86.6 mmol) followed by methyl iodide (5.4 mL, 86.6 mmol). The resulting mixture is heated to reflux for 4 h and then allowed to cool to RT. The solvent is removed in vacuo and the crude residue is dissolved in EtOAc, washed with water, saturated sodium hydrogen carbonate solution, brine, dried (MgSO4) and concentrated in vacuo. The crude residue is purified by flash chromatography (SiO2, iso-hexane:EtOAc 7:3) to afford the title compound as a light-yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:30])[C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>>[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22](=[C:23](\[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][CH3:9])/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)/[C:21]2=[O:30])[CH:14]=1
Reactant: CSc1ccccc1I
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccccc3SC)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-iodo-2-methylsulfanyl-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 2.31 (s, 3H), 3.90 (s, 3H), 5.00 (dd, 2H), 6.03 (d, 1H), 6.60-6.64 (m, 2H), 7.04 (t, 1H), 7.26-7.30 (m, 2H), 7.33-7.56 (m, 9H), 7.95 (d, 1H), 8.01 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>ClCCl>[Br:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(N2CCNCC2)cn1
Reaction time: 16 h
Yield: 141.3 %

Procedure:
11.20 ml (150.77 mmol) of trifluoroacetic acid are slowly added to a suspension of 5.16 g (15.08 mmol) of 1,1-dimethylethyl 4-(6-bromo-3-pyridyl)-1-piperazine-carboxylate, obtained in step 7.2., in 70 ml of dichloromethane. Stirring is continued at room temperature for 16 hours. The reaction mixture is concentrated under reduced pressure, the residue is taken up in 40 ml of chloroform and 4 ml of aqueous sodium hydroxide solution (10M) are then slowly added. The aqueous phase is separated out and then extracted twice with chloroform. The organic phases are combined and are washed with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and the filtrate is concentrated under reduced pressure. 5.16 g of product are thus obtained in the form of an orange-colored oil that crystallizes at room temperature. This product is used without further purification in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10](Cl)(=[O:13])[CH2:11][CH3:12].[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[C:6]([C:10](=[O:13])[CH2:11][CH3:12])[CH:7]=1
Reactant: CCC(=O)Cl
Reactant: Cc1cc(O)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(=O)c1cc(Cl)c(C)cc1O
Temperature: 60 °C
Yield: 60 %

Procedure:
The 4-chloro-3-methyl-phenol (2 g, 10 mmol) and the propionyl chloride (1.8 mL, 20. mmol) were combined and the mixture was heated at 60° C. for 2 hours. The reaction was concentrated in vacuo to remove excess propionyl chloride to give an oil. To this was added aluminum trichloride (2.7 g, 20. mmol) and the mixture was heated at 180° C. for 30 minutes. The reaction mixture was then cooled to room temperature and slowly quenched with 1 N HCl while cooling in an ice bath. The reaction was partitioned between EtOAc and water. The organic layer was washed with 1 N HCl, water, brine, dried over magnesium sulfate and concentrated to give the crude product as a dark oil. The product was purified by chromatography on silica gel eluting with hexane:EtOAc gradient to give 1-(5-chloro-2-hydroxy-4-methylphenyl)propan-1-one as a solid (1.5 g, 60%). LCMS calculated for C10H12ClO2 (M+H)+: m/z=199.0. found: 198.9.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=1)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)Cl>>[CH2:1]([O:8][N:9]=[C:10]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=NOCc2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Sn]Cl
Product: COc1ccc(C(=NOCc2ccccc2)c2cccc(N)c2)cc1

Procedure:
In a similar manner to that described in Example (1b), the mixture (752 mg) of isomer A and B of 4-methoxyphenyl 3-nitrophenyl ketone O-benzyloxime and tin (II) chloride (1.97 g) were reacted, to afford a mixture of isomer A/isomer B=½ of the title compound as a yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([NH:18][C:19]2[S:20][CH:21]=[C:22]([C:24]3[C:32]4[C:27](=[N:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[N:23]=2)=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:7])=[O:6].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C=O)C>[N:33]1([CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([NH:18][C:19]3[S:20][CH:21]=[C:22]([C:24]4[C:32]5[C:27](=[N:28][CH:29]=[CH:30][CH:31]=5)[NH:26][CH:25]=4)[N:23]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)(=[O:7])=[O:6])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(Cc1cccc(NS(=O)(=O)CCCCl)c1)Nc1nc(-c2c[nH]c3ncccc23)cs1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(NS(=O)(=O)CCCN2CCCCC2)c1)Nc1nc(-c2c[nH]c3ncccc23)cs1
Temperature: 100 °C

Procedure:
The crude 2-[3-(3-chloro-propane-1-sulfonylamino)-phenyl]-N-[4-(1H-pyrrolo [2,3-b]pyridin-3-yl)-thiazol-2-yl]-acetamide was treated with neat piperidine and heated to 100° C. overnight. The reaction mixture was diluted with DMF and purified by preparative HPLC to give the desired compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:11][C:12]([NH2:15])([CH3:14])[CH3:13]>O1CCOCC1>[Br:1][C:2]1[C:3]([S:9][CH3:10])=[N:4][C:5]([NH:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[N:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: CSc1nc(Cl)ncc1Br
Solvent: C1COCCO1
Product: CSc1nc(NC(C)(C)C)ncc1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To 5-bromo-2-chloro-4-(methylthio)pyrimidine (3 g, 12.53 mmol) in dioxane (12.53 mL) was added 2-methylpropan-2-amine (7.93 mL, 75 mmol). The mixture was stirred at 100° C. overnight in a sealed vessel. The solvent was removed under reduced pressure and the residue was dissolved in 100 mL ethyl acetate and washed with 50 mL of a 1M aqueous solution of sodium hydrogen phosphate. The aqueous layer was back-extracted with 50 mL ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to give 5-bromo-N-tert-butyl-4-(methylthio)pyrimidin-2-amine (3.4 g, 12.31 mmol, 98% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.61-8.72 (m, 1H), 8.08 (s, 1H), 6.95-7.17 (m, 1H), 2.48 (s, 2H), 1.38 (s, 9H). MS (ESI) m/z 276.0 [M+1]+ and 278.2 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.CC1CCCCC=1.Cl([O-])=[O:27].[Na+].P([O-])(O)(O)=O.[Na+].Cl>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([OH:27])=[O:18])=[CH:13][C:11]=3[CH:12]=2)=[CH:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: Cc1ccc(-c2cc3cc(C=O)ccc3o2)cc1
Agent: CC1=CCCCC1
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc3cc(C(=O)O)ccc3o2)cc1
Reaction time: 3 h
Yield: 74 %

Procedure:
To a solution of 2-(4-methylphenyl)benzofuran-5-carbaldehyde (500 mg) and 1-methylcyclohexene (1.2 ml) in DMF (15 ml) was added a solution (9 ml) of sodium chlorite (80%, 1.5 g) and sodium dihydrogenphosphate (1.5 g) at room temperature, and the mixture was stirred for 3 hours. To the mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with sodium thiosulfate and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the precipitated crystals were collected by filtration, which were washed with diethylether to give colorless crystals of 2-(4-methylphenyl)benzofuran-5-carboxylic acid (395 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([NH2:47])[CH3:46])[CH:40]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:47][CH:45]([C:41]3[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=3)[CH3:46])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: CC(N)c1cccnc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)c4cccnc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 79 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (RS)-1-pyridin-3-yl-ethylamine: yield 79%.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][C:16]=2[CH2:28][N:29]2[CH2:33][CH2:32][O:31][C:30]2=[O:34])[CH:7]=1)C.[Li+].[OH-]>CO.O>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:35])=[O:3])[CH:11]=[CH:10][C:9]=2[O:12][CH3:13])=[C:16]([CH2:28][N:29]2[CH2:33][CH2:32][O:31][C:30]2=[O:34])[CH:17]=1)=[O:27]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)C(C)(C)C)cc2CN2CCOC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(NC(=O)C(C)(C)C)cc1CN1CCOC1=O
Temperature: 65 °C
Reaction time: 8 h

Procedure:
{3-[4-(2,2-Dimethyl-propionylamino)-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.57 mmol) was dissolved in MeOH and H2O, and treated with 1N aqueous LiOH. The reaction was stirred overnight at 65° C., and the mixture was then acidified and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]1[CH2:9][C@H:8]([OH:10])[CH2:7][CH2:6][N:5]1[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12].I[CH3:20].O>CN(C=O)C>[CH3:20][O:10][C@@H:8]1[CH2:7][CH2:6][N:5]([C@@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[C@H:4]([CH3:3])[CH2:9]1
Reactant: C[C@@H]1C[C@H](O)CCN1[C@H](C)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@@H]1CCN([C@H](C)c2ccccc2)[C@H](C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (710 mg, 17.7 mmol; 60% dispersion in mineral oil) was added to a solution of (2R,4R)-2-methyl-1-((R)-1-phenylethyl)piperidin-4-ol (1.95 g, 8.87 mmol) in DMF (47 mL) at 0° C. After 15 min, iodomethane (666 μL, 10.7 mmol) was added and the solution was allowed to warm to room temperature. After 1 h, water was slowly added at 0° C. The aqueous phase was extracted with a 4:1 mixture of EtOAc/n-heptane (3×). The combined organic layers were washed with brine (3×), dried over anhydrous sodium sulfate, filtered, and concentrated under reduce pressure. The residue was purified via FCC (0-30% EtOAc/heptane) to give the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (d, J=7.8 Hz, 2H), 7.35 (t, J=7.6 Hz, 2 H), 7.21-7.28 (m, 1 H), 4.33 (q, J=6.8 Hz, 1 H), 3.36 (s, 3 H), 3.11-3.22 (m, 1 H), 2.59-2.71 (m, 1 H), 2.49 (dt, J=11.9, 3.8 Hz, 1 H), 1.99-2.16 (m, 2 H), 1.85 (d, J=12.1 Hz, 1 H), 1.33-1.42 (m, 1 H), 1.28 (d, J=7.1 Hz, 4 H), 1.25 (d, J=6.3 Hz, 3 H); MS (ESI+) m/z 234.2 (M+H)+; [α]25D-49.17 (c 1.0, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:31](O)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: CCCCCCCO
Product: CCCCCCCOC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and 1-heptanol according to Method E. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.86 (t, J=6.98 Hz, 3H), 1.11-1.56 (m, 15H), 1.67-1.75 (m, 3H), 1.83 (ddd, J=25.98, 12.82, 3.89 Hz, 1H), 2.01-2.12 (m, 1H), 2.20-2.27 (m, 1H), 2.85-2.96 (m, 1H), 3.07-3.15 (m, 1H), 3.62 (ddd, J=13.76, 9.33, 4.56 Hz, 1H), 4.28 (t, J=6.58 Hz, 2H), 4.97 (dd, J=9.40, 5.64 Hz, 1H), 7.21 (dd, J=8.86, 2.15 Hz, 1H), 7.42 (d, J=2.15 Hz, 1H), 7.69 (d, J=8.86 Hz, 1H), 7.83 (dd, J=8.19, 1.48 Hz, 1H), 7.87 (s, 1H), 8.12 (d, J=8.32 Hz, 1H); ES-MS m/z 518 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.Cl.[NH2:14][C:15]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:21]([O:20][C:18]([C:15]1([N:14]2[C:8](=[O:9])[C:3]3[C:4](=[CH:10][CH:11]=[CH:12][C:2]=3[F:1])[C:5]2=[O:7])[CH2:17][CH2:16]1)=[O:19])[CH3:22]
Reactant: O=C1OC(=O)c2c(F)cccc21
Reactant: CCOC(=O)C1(N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(N2C(=O)c3cccc(F)c3C2=O)CC1

Procedure:
3-Fluorophthalic anhydride (2.0 g), ethyl 1-aminocyclopropane carboxylate hydrochloride (4.0 g) and triethylamine (4 ml) were stirred in chloroform (30 ml) for 0.5 h. Volatile material was evaporated and the residue was heated at 210° for 0.25 h in a nitrogen atmosphere; the residue was dissolved in THF (insoluble triethylame hydrochloride was discarded) and the ethereal solution was evaporated to dryness. This residue was recrystallised from dichloromethane/light petroleum (40°-60°) to give the title compound m.p. 164°.