Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[OH-].[K+].Cl.O>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(Br)ccc1C(=O)O
Temperature: 65 °C

Procedure:
A solution of methyl 4-bromo-2-methoxybenzoate (1 g, 4.08 mmol) in 20 ml of MeOH was treated with 4.08 ml of a 2 N solution of potassium hydroxide and refluxed at 65° C. for 2.5 hours. MeOH was removed in vacuo and the remaining water was taken-up in 100 ml of EtOAc and quenched with 30 ml of 1 N HCl (3.5 eq.) and 100 ml of water. Layers were separated and the aqueous layer was extracted twice with EtOAc. Organics were combined, dried over sodium sulfate, and concentrated under reduced pressure to a yellow-white solid (950.7 mg crude).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[C:35]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)(=[O:37])[CH3:36]>>[C:35]([C:38]1[CH:43]=[C:42]([C:23]2[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:22]=2[O:21][C:16]2[CH:15]=[C:14]([CH:19]=[C:18]([CH3:20])[CH:17]=2)[O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=2)[CH:41]=[CH:40][CH:39]=1)(=[O:37])[CH3:36]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: CC(=O)c1cccc(-c2cc(C(F)(F)F)ccc2Oc2cc(C)cc(Oc3ccc(CCC(=O)O)c(C)c3)c2)c1
Yield: 72 %

Procedure:
The compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester is reacted with 3-acetyl phenyl boronic acid as in Example 38 to afford 0.186 g (72%) of the title compound. 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C32H28O5F3 549.1888, found 549.1880.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH3:10].[C:18]([O-])([O-])=O.[K+].[K+].CI>O>[F:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([O:15][CH3:18])=[O:14])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH3:10]
Reactant: COCc1ccc(NC(C)(C)C(=O)O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COCc1ccc(NC(C)(C)C(=O)OC)cc1F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The title compound was prepared according to General Method 5. A mixture of 2-(3-fluoro-4-(methoxymethyl)phenylamino)-2-methylpropanoic acid (1 g, 4.1 mmol), anhydrous K2CO3 (0.858 g, 6.2 mmol) and methyliodide (0.880 g, 6.2 mmol) was stirred at 60° C. for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3), organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product that was purified by silica gel chromatography (eluant 30% ethyl acetate-hexane) to obtain methyl 2-(3-fluoro-4-(methoxymethyl)phenylamino)-2-methylpropanoate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.CN1CCOCC1.[CH2:55]([N:57]1[CH2:61][CH2:60][CH2:59][CH:58]1[CH2:62][NH2:63])[CH3:56]>ClCCl>[CH2:55]([N:57]1[CH2:61][CH2:60][CH2:59][CH:58]1[CH2:62][NH:63][C:18]([C:17]1[CH:16]=[C:15]([CH:10]2[C:9]([CH3:24])([CH3:25])[CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[NH:11]2)[CH:23]=[CH:22][CH:21]=1)=[O:19])[CH3:56]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Reactant: CCN1CCCC1CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCN1CCCC1CNC(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Reaction time: 0.5 h
Yield: 122.7 %

Procedure:
To a suspension of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (100 mg, 0.29 mmol, 1.0 eq.) in dichloromethane (6.7 ml) was added N-hydroxybenzotriazole (59.7 mg, 0.44 mmol, 1.5 eq.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (169.7 mg, 0.88 mmol, 3.0 eq.), followed by 4-methylmorpholine (89.5 mg, 0.88 mmol) and the resultant mixture was stirred at room temperature for 40 min. Then (1-ethylpyrrolidin-2-yl)methanamine (0.33 mmol, 1.1 eq.) was added to the flask and the reaction mixture was stirred for an additional 30 min, LC-MS showed the reaction was complete. The reaction was quenched with water, separated, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layers were washed with 2% sodium hydroxide aqueous solution (twice) and brine (3 times), dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 160 mg of methyl 2-(3-((1-ethylpyrrolidin-2-yl)methylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow oil, which was purified by column chromatography (dichloromethane: methanol=8:1) to afford 45 mg desired product as a yellow powder, yield: 34.0%.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[CH3:24][S:21]([C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([OH:25])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18])(=[O:23])=[O:22]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(S(C)(=O)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A solution of 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.17 g, 3.01 mmol) in tetrahydrofuran (12 mL) was treated with a 0.8M aqueous lithium hydroxide solution (5.6 mL, 4.52 mmol). The reaction mixture was stirred at 25° C. for 3 h. The resulting reaction mixture was partitioned between water (75 mL) and ethyl acetate (75 mL) and then treated with a 1N aqueous hydrochloric acid solution (10 mL). The layers were shaken and separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (1.10 g, 98%) as a white foam which was used without further purification: mp 64-68° C. (foam to gel); FAB-HRMS m/e calcd for C16H22O6S2 (M+H)+375.0936, found 375.0932.
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[CH:7]=[CH:6][N:5]([CH3:8])[N:4]=1.ClC(Cl)C1N(C)N=CC=1.[FH:19].[FH:20].F.C(N(CC)CC)C.[OH-].[Na+]>>[F:19][CH:2]([F:20])[C:3]1[CH:7]=[CH:6][N:5]([CH3:8])[N:4]=1
Reactant: Cn1ccc(C(Cl)Cl)n1
Reactant: F
Agent: Cn1nccc1C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: Cn1ccc(C(F)F)n1
Yield: 89.4 %

Procedure:
3-Dichloromethyl-N-methylpyrazole (40.0 g; 0.21 mol; 84.8% pure according to GC analysis) comprising, as minor component, 5-dichloromethyl-N-methylpyrazole was stirred with triethylamine trishydrofluoride (199 g, 1.23 mol) at 160° C. under intrinsic pressure (<1 bar) for 1 h. The reaction mixture was vented and poured onto ice (500 g), made alkaline using aqueous sodium hydroxide solution and extracted three times with methyl tert-butyl ether (100 ml). The organic phases were combined, washed successively with hydrochloric acid (dilute, 100 ml) and a saturated aqueous NaCl solution (100 ml), dried over magnesium sulfate and freed from the solvent under reduced pressure. The residue obtained was 3-difluoromethyl-1-methylpyrazole (24.8 g, yield: 78%) in a purity of 85.4% (according to GC analysis) comprising, as minor component, 5-difluoromethyl-N-methylpyrazole.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH2:22](C1CC2C(=CC=CC=2)C1N)[CH3:23]>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]2[CH2:22][CH3:23])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCC1Cc2ccccc2C1N
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2c3ccccc3CC2CC)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 2-ethylindan-1-amine and making non-critical variations provided the title compound as a yellow oil. MS (ESI+) for m/z 296.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]([CH3:12])[OH:11])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:13]([Si:17]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23]OS(C1C=CC(C)=CC=1)(=O)=O)([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:13]([Si:17]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:11][N:10]([CH3:12])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])([CH3:14])([CH3:15])[CH3:16]
Reactant: CN(O)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCOCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(OCCOCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
In a oven dried flask (50 mL) was added NaH (60% disepersion in mineral oil) 481 mg (12.03 mmol) under argon. The dispersion was washed 3 times with pentane to remove the mineral oil. To the pure NaH was added 5 mL THF (dry). N-BOC-N-methyl hydroxyl amine (a) 1.53 mg (10.43 mmol) in 5 mL THF was added slowly. The reaction mixture was left for ½ an hour until no more gas production could be seen. The solution was put on ice-bath and stirred for ½ an hour after which 4 g (8.02 mmol) of 4-toluene-sulfonic acid 2-[2-(tert-butyl-diphenyl-silanyloxy)-ethoxy]-ethyl ester (c) was added dropwise. The solution was left on ice-bath for ½ an hour and then stirred over-night at RT. The solvents were removed under reduced pressure, and the residue was dissolved in EtOAc (200 mL) and poured into a separatory funnel. The organic layer was washed with 0.1 M NaOH (5×50 mL), H20 (50 ml), 0.1 m KHSO4, and brine (50 ml) and the dried with MgSO4. After removal of the solvent, the residue was purified using flash chromatography on a Companion Combiflash using a gradient of methanol in DCM (methanol: 0-20% over 19 minutes). Structure confirmed by NMR.
Reaction SMILES: NC1C=CC(N2CCC[C@H](C(N3CCN(C)CC3)=O)C2)=CC=1OC.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([N:36]2[CH2:41][CH2:40][CH:39]([N:42]3[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]3)[CH2:38][CH2:37]2)[CH:30]=[CH:31][C:32]=1[N+:33]([O-])=O>>[NH2:33][C:32]1[CH:31]=[CH:30][C:29]([N:36]2[CH2:41][CH2:40][CH:39]([N:42]3[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]3)[CH2:38][CH2:37]2)=[CH:28][C:27]=1[O:26][CH3:25]
Reactant: COc1cc(N2CCC(N3CC[C@@H](O)C3)CC2)ccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Product: COc1cc(N2CCC(N3CC[C@@H](O)C3)CC2)ccc1N

Procedure:
(R)-1-[1-(4-Amino-3-methoxy-phenyl)-piperidin-4-yl]-pyrrolidin-3-ol was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with (R)-1-[1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-yl]-pyrrolidin-3-ol (180 mg, 99%). LC/MS (E/I+) 292.16 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1cccc(I)c1
Product: Brc1cccc(-c2cccnc2)c1

Procedure:
In some embodiments, the process further comprises: reacting 1-bromo-3-iodobenzene with 3-pyridine boronic acid to form 3-(3-bromophenyl)pyridine.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:18]=[C:17]2[N:8]([C:9](=[S:19])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[OH:3][CH2:4][C:6]1[CH:18]=[C:17]2[N:8]([C:9](=[S:19])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1
Reactant: CCOC(=O)c1cc2c3ccccc3[nH]c(=S)n2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCc1cc2c3ccccc3[nH]c(=S)n2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1.37 g (0.005 mole) of 5,6-dihydro-5-thioxopyrazolo-[1,5-c]quinazoline-2-carboxylic acid ethyl ester prepared as described in Example 2 is suspended in 100 ml of dichloromethane and treated with 8 ml (0.011 mole) of 20% diisobutylaluminum hydride (Dibal). The resultant yellow solution is stirred at room temperature for 45 minutes, 2.0 ml (0.003 M) of Dibal solution is added and stirring continued for 17 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].[OH-].[Na+].Cl>CCO.O>[NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:13]([F:14])([F:15])[F:16]
Reactant: CCOC(=O)c1ccc(N)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 2 h

Procedure:
At RT a solution of 153 g (0.66 mol) ethyl 4-amino-3-trifluoromethyl-benzoate in 350 mL EtOH was added to a solution of 100 g (2.5 mol) NaOH in 250 mL water and the reaction mixture was stirred for 2 h at 45° C. EtOH was eliminated i. vac., the remaining aqueous solution was acidified with conc. HCl, the precipitated product was suction filtered, washed with water and dried in the air.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=1.BrC1C=CC([N+]([O-])=O)=CC=1[C:26](OCC)=[O:27].COC1C=CC(OC)=CC=1B(O)O>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>[CH3:22][O:21][C:5]1[CH:4]=[CH:3][C:2]([O:27][CH3:26])=[CH:7][C:6]=1[C:8]1[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(F)ccc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(OC)c(B(O)O)c1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(OC)ccc1OC
Yield: 69 %

Procedure:
This compound was prepared in a manner similar to that of methyl 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylate (EXAMPLE 107) from ethyl 2-bromo-5-nitrobenzoate (2.46 g, 9.46 mmol), (PPh3)4Pd (0.33 g, 0.28 mmol), and 2,5-dimethoxyphenylboronic acid (2.42 g, 13.3 mmol) to afford 2.08 g (69%) of methyl (2', 5'-dimethoxy-4-nitro-2-biphenylcarboxylate) as a white solid. Data for methyl (2',5'-dimethoxy-4-nitro-2-biphenylcarboxylate): 1H NMR (400 MHz, CDCl3) 8.70 (d, J=2.4, 1H), 8.37 (dd, J=8.4, 2.5, 1H), 7.52 (d, J=8.5, 1H), 6.92 (dd, J=8.8, 3.0, 1H), 6.84 (m, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.67 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH2:6]Br.C[N+]([O-:25])(C)C.CS(C)=O>>[CH3:1][O:2][C:3](=[O:20])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH:6]=[O:25]
Reactant: C[N+](C)(C)[O-]
Reactant: COC(=O)C(CCBr)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Product: COC(=O)C(CC=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-2,2-diphenyl-butyric acid methyl ester (0.10 g, 0.300 mmol) and trimethylamine N-oxide (0.09 g, 1.2 mmol) in dimethyl sulfoxide (0.5 mL, 7 mmol) was stirred overnight at room temperature. The reaction was quenched with cold brine. The crude product was extracted three times with dichloromethane, dried over a bed of Na2SO4, filtered, and concentrated to dryness to provide crude title compound which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH:8]([CH2:10][CH3:11])[CH3:9])=[CH:4][CH:3]=1.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]([CH2:10][CH3:11])[CH3:9])[C:21]([NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:22])=[CH:12][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCC(C)NCc1ccc(Br)cc1
Product: CCC(C)N(Cc1ccc(Br)cc1)C(=O)Nc1ccccc1
Yield: 90.7 %

Procedure:
The following procedure described in Example 1, process variant (a), 48 g (0.2 mole) of N-(4-bromobenzyl)-N-sec.-butylamine were reacted with 24 g (0.2 mole) of phenyl isocyanate. 65.5 g of N-(4-bromobenzyl)-N-sec.-butyl-N'-phenylurea were obtained. Yield: 91%. Melting point: 86°-88° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C@H:26]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:27]2)=[CH:21][CH:20]=1)[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]#[N:18])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[O-]CC.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:38])[C@H:5]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C@H:26]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:27]2)=[CH:21][CH:20]=1)[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]#[N:18])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc2ccc(C#N)cc2c1)c1ccc(O[C@H]2CCN(Cc3ccccc3)C2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H](Cc1ccc2ccc(C#N)cc2c1)c1ccc(O[C@H]2CCN(Cc3ccccc3)C2)cc1
Yield: 78.1 %

Procedure:
2-[4-[[(3S)-1-Benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionic acid ethyl ester (5 g, 9.9 mmol) was heated and dissolved in ethanol (15 ml), and the resultant solution was cooled to room temperature with stirring to settle crystals. Subsequently, sodium ethoxide (100 mg, 1.5 mmol) was added thereto, followed by stirring at the same temperature for one hour, then sodium ethoxide (100 mg, 1.5 mmol) was further added, followed by stirring for 15 hours. The crystals were collected through filtration to obtain 3.9 g of the title compound (77% yield). The obtained crystals had a diastereomer purity of 47% under HPLC analysis conditions.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:20][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[OH:21])=[O:5])[CH3:2].[CH2:22]1COCC1.C(N(C(C)C)CC)(C)C.[Si](C=[N+]=[N-])(C)(C)C>CO>[CH2:1]([O:3][C:4]([C:6]1[S:20][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[O:21][CH3:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc2c(c1O)CCN(C(=O)OCC)CC2
Reactant: C1CCOC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc2c(c1OC)CCN(C(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of step b) (2.3 g, 7.3 mmol) was dissolved in 60 mL of 1:1 MeOH:THF. Diisopropylethylamine (1.9 mL, 10.9 mmol) was added followed by TMSCHN2 (10.9 mL of 2M). The reaction was stirred overnight at room temperature then quenched carefully with 0.4 ML HOAc. After stirring ½ hour, the reaction was partitioned between DCM and 1M HCl (100 mL each). The organic layer was dried over MgSO4 and concentrated to give 2.75 g of the subtitle compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C@@H:9]2[CH:16]3[CH2:17][N:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)=[N:6][CH:7]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=C(C2SC(O[C@@H]3C4CN5CC(CC3C5)C4)=NC=2)C=N1.N>>[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:2]1[CH:3]=[CH:4][C:5]([O:8][C@@H:9]2[CH:16]3[CH2:17][N:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)=[N:6][CH:7]=1
Reactant: OB(O)c1cccs1
Reactant: Brc1ccc(OC2C3CC4CC2CN(C4)C3)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Agent: c1n[nH]cc1-c1cnc(OC2C3CC4CC2CN(C4)C3)s1
Product: c1csc(-c2ccc(OC3C4CC5CC3CN(C5)C4)nc2)c1

Procedure:
The free base of the title compound was prepared from the product of Example 10C (50 mg, 0.16 mmol) and 2-thiophene boronic acid (29 mg, 0.23 mmol; Aldrich) according to Method G, and converted to the p-toluenesulfonate salt using the procedure of Method H: 1H NMR (300 MHz, methanol-D4) δ ppm 1.92 (d, J=13.6 Hz, 2H), 2.19 (s, 1H), 2.32-2.46 (m, 6H), 2.55 (s, 2H), 3.57 (s, 2H), 3.68 (s, 4H), 5.46 (s, 1H), 6.93 (d, J=8.5 Hz, 1H), 7.10 (dd, J=5.1, 3.4 Hz, 1H), 7.22 (d, J=8.5 Hz, 2H), 7.37 (dd, J=15.3, 4.4 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H), 7.97 (dd, J=8.6, 2.5 Hz, 1H), 8.38 (d, J=2.7 Hz, 1H). MS (DCI/NH3) m/z=313 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:19])([CH3:18])[CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH2:13][CH2:12][CH2:11]2)=[O:6].Cl[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=O>C(O)C>[CH:17]1[C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([CH3:19])([CH3:18])[CH3:2])=[CH:9][C:10]2[CH2:11][CH2:12][CH2:13][N:14]3[C:15]=2[C:16]=1[C:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=13
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)CCCN2
Reactant: O=C1CCCCC1Cl
Agent: Cl
Solvent: CCO
Product: CC(C)(C)CC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCC1
Temperature: 150 °C
Yield: 32.5 %

Procedure:
A mixture of 3,3-dimethyl-N-1,2,3,4-tetrahydroquinolin-6-ylbutanamide hydrochloride (50 mg, 0.18 mmol) and 2-chlorocyclohexanone (28 mg, 0.21 mmol) in ethanol (2.5 mL) was heated in a microwave to 150° C. for 50 min. The reaction mixture was concentrated and the crude material was purified by flash column chromatography (elution with 20% ethyl acetate-hexane) to provide N-5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-2-yl-3,3-dimethylbutanamide (19 mg). MS (ESI) m/z 325; HPLC purity major: no impurities are detected at 210-370 nm window; and no impurities are detected at 252 nm (max. abs), RT=10.8 (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C1N2CN3CN(C2)CN1C3.[C:21](O)(=[O:23])C>>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:10])[C:4]([CH3:9])=[CH:5][C:6]=1[CH:21]=[O:23]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1cc(C=O)c(C)c(C)c1O
Temperature: 125 °C
Reaction time: 0.38 h
Yield: 90 %

Procedure:
A 500 ml three neck round bottom flask equipped with mechanical stirrer and pot thermometer, was charged with 50 g (0.36 mol) of 2,3,6-trimethyl-phenol, 200 ml glacial acetic acid and 20.61 g (0.14 mol) of hexamethylenetetramine. The reaction mass was refluxed for 2 hrs at 120-130° C. The completion of reaction was confirmed by TLC. 100 ml of acetic acid were distilled out at reflux temperature. The reaction mass was allowed to cool at 100° C. and 50 ml 20% sulphuric acid were slowly added over a period of 5-10 min. The mixture was stirred at 100° C. for 15-30 min. Heating was stopped and the reaction mass cooled to 20° C. in an ice bath. 500 ml process water were added and stirred for 10 min at 20-25° C. The reaction mass was filtered and washed with 300 ml process water. The crude product was dried at 60-80° C. under vacuum to afford 54 g (90%) of crude 2,3,5-trimethyl-4-hydroxy-benzaldehyde. Subsequently, a 1% one equivalent solution of sodium hydroxide was prepared in process water. 54 g of crude 2,3,5-trimethyl-4-hydroxy-benzaldehyde were added to it under stirring at room temperature. The mixture was stirred for 15-20 min and filtered. The residue was to be scraped as impurity. The filtrate was collected, acidified with 19.75 g of glacial acetic acid and filtered. The product was suck-dried under vacuum, dried at 60-80° C. for 3-4 hrs to give 48 g (80%) of pure 2,3,5-trimethyl-4-hydroxy-benzaldehyde as off-white amorphous solid (Table 1, no. 13). Melting point: 135-137° C. 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), δ 7.49 (s, 1H), δ 5.32 (bs, 1H), δ 2.58 (s, 3H), δ 2.28 (s, 3H), δ 2.22 (s, 3H).