Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:8]([CH:12]=1)[C:9]([OH:11])=O)=[O:3].Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[NH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:8]([CH:12]=1)[C:9]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:11])=[O:3]
Reactant: NC(=O)c1ccc(Oc2cccc(F)c2)c(C(=O)O)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(C(N)=O)ccc2Oc2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-(Aminocarbonyl)-2-(3-fluorophenoxy)benzoic acid (step 5) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.60 (1H, d, J=2.4 Hz), 8.05 (1H, dd, J=8.6, 2.4 Hz), 7.91 (2H, d, J=8.4 Hz), 7.83 (1H, d, J=7.2 Hz), 7.42–7.27 (3H, m), 7.00–6.77 (5H, m), 6.12 (1H, br.s), 5.32–5.22 (1H, m), 3.89 (3H, s), 1.51 (2H, d, J=7.0 Hz); MS (ESI) m/z 437 (M+H)+, 435 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[CH2:4][NH:3]1.[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1>N1C=CC=CC=1.CCOCC>[CH3:1][C:2]1([CH3:5])[CH2:4][N:3]1[S:12]([C:9]1[CH:10]=[CH:11][C:6]([CH3:16])=[CH:7][CH:8]=1)(=[O:14])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)CN1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2CC2(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.2 %

Procedure:
To a solution of 2,2-dimethylaziridine (5.42 g; 0.076 mole; sold by Polysciences, Inc., Warrington, PA) in pyridine (100 mL) cooled in an ice bath, is added p-toluenesulfonyl chloride (21.81 g; 0.114 mole) in one portion. The reaction is stirred at 0° C. for 2 hours; diluted with ether (400 mL); washed with cold 10% H3PO4 (2×150 mL), with a saturated NaHCO3 solution (3×150 mL) and brine (1×150 mL); and dried over MgSO4. Rotary evaporation of the solution affords a yellowish solid which is crystallized from ethyl acetate to yield the product 2,2-dimethyl-N-p-toluenesulfonyl-aziridine (4.48 g). 1H NMR (CDCl3):1.53 (6H, s), 2.45 (5H, m), 7.2-8.0 ppm (4H, m, aromatics).
Reaction SMILES: [NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[C:5](F)[CH:4]=1.[CH3:16][S:17](C1C=C(C=CC=1)C#N)(=[O:19])=[O:18]>>[OH:15][N:14]=[C:2]([C:3]1[CH:12]=[CH:11][CH:6]=[C:5]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:4]=1)[NH2:1]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Reactant: CS(=O)(=O)c1cccc(C#N)c1
Product: CS(=O)(=O)c1cccc(C(N)=NO)c1
Yield: 75 %

Procedure:
The title compound was obtained following procedure described for Intermediate 1 step 2 but starting from 3-methylsulfonylbenzonitrile (3.03 g; 16.72 mmol) to give the title compound as a white powder (2.69 g, 75%). 1H NMR (DMSO-d6, 300 MHz) δ 9.88 (s, 1H), 8.21 (t, J=1.68 Hz, 1H), 8.00 (dt, J=1.44, 7.93 Hz, 1H), 7.91 (dt, J=1.49, 7.80 Hz, 1H), 7.66 (t, J=7.84 Hz, 1H), 6.03 (s, 2H), 3.23 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CO.OS(O)(=O)=O.[C:22]([O-])(O)=O.[Na+]>O>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:22])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1cccc2c(O)ncnc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc2c(O)ncnc12
Temperature: 50 °C

Procedure:
A 1 L round bottom flask was charged with 4-hydroxyquinazoline-8-carboxylic acid (A), MeOH (300 mL), and H2SO4 (10 mL). The reaction was heated to 50° C. for 2 days. Upon cooling to room temperature, the reaction mixture was neutralized with NaHCO3 and diluted with water. The methanol was removed in vacuo, and the precipitate was collected, washed with water and heptanes, then dried to give methyl 4-hydroxyquinazoline-8-carboxylate (18.3 g, 65%, over 2 steps combining both isomers from A and B).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH:15]([Br:16])[CH2:14][CH2:13][C:12]3[N:11]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:10]=[CH:9][C:8]2=3)[O:4]1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.N1C=CC=CC=1>ClCCl>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([O:1][CH2:2][CH:3]2[CH2:7][O:6][C:5]3([CH:15]([Br:16])[CH2:14][CH2:13][C:12]4[N:11]([S:17]([C:20]5[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=5)(=[O:19])=[O:18])[CH:10]=[CH:9][C:8]3=4)[O:4]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CO)O2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COC3(O2)c2ccn(S(=O)(=O)c4ccc(C)cc4)c2CCC3Br)cc1
Reaction time: 10 h
Yield: 87 %

Procedure:
To a solution of 4'-hydroxymethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-[1,3]-dioxolane (100 parts) in dichloromethane (2000 parts) is added a solution of p-toluenesulfonyl chloride (1.1 molar equivalent) and pyridine (1.2 molar equivalents) in dichloromethane (500 parts), and the mixture is kept at room temperature for 10 hours. The mixture is evaporated, and the residue is dissolved in ethyl acetate, washed with water, dried and evaporated to give 4'-p-toluenesulfonyloxymethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-[1,3]dioxolane in 87% yield. The physical constants are given in Table I, No. 18.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[CH2:43]([O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@H:29]([NH:28][C:2]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=3)[NH:4][C:3]2=[O:12])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:37][CH:38]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 4.58 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 86-3 (5.02 mmol, crude form) as starting materials, 1.09 g (Isomer A, yellow solid) and 1.67 g (Isomer B, colorless amorphous) of the respective diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:38]1[CH2:42][CH2:41][CH2:40][CH:39]1[CH2:43]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([O:1][CH2:43][CH:39]3[CH2:40][CH2:41][CH2:42][O:38]3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Reactant: OCC1CCCO1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(OCC2CCCO2)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (150 mg, 0.59 mmol), triphenylphosphine (150 mg, 0.59 mmol), tetrahydro-2-furanmethanol (60 mg, 0.59 mmol) in CH2Cl2 (8 mL) at rt was slowly added a solution of diisopropyl azodicarboxylate (200 mg, 1.0 mmol) in CH2Cl2 (3 mL). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21]CC)=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:24]1[NH:25][C:26](=[O:37])[C:27]2[N:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH3:36])[C:28]=2[N:29]=1)[CH3:2].[OH-].[K+]>C(O)C>[C:19]([CH:16]1[CH2:15][CH2:14][N:13]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:24]3[NH:25][C:26](=[O:37])[C:27]4[N:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH3:36])[C:28]=4[N:29]=3)[CH:6]=2)(=[O:12])=[O:11])[CH2:18][CH2:17]1)([OH:21])=[O:20]
Reactant: CCCc1ccnc2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCC(C(=O)OCC)CC4)ccc3OCC)nc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1ccnc2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCC(C(=O)O)CC4)ccc3OCC)nc12
Yield: 18 %

Procedure:
A mixture of 2-[2-ethoxy-5-(4-ethoxycarbonyl-piperidinosulphonyl)phenyl]-8-n-propylpyrido[3,2-d]pyrimidin-4(3H)-one (Example 4; 0.55 g, 0.001 mol), potassium hydroxide (0.146 g, 0.0026 mol) and ethanol (35 ml) was stirred under reflux for 5 hours, then allowed to cool. The solvent was evaporated under vacuum, and the residue chromatographed twice on ion-exchange resin (Bio-rad AG50W-X8 H+, 27.5 g) using a pyridine in water elution gradient (2-50% pyridine). Crystallisation of the product from aqueous ethanol gave the title compound as a colourless solid (0.09 g, 8%), m.p. 262°-264° C. Found: C,57.51; H,5.68; N,11.10. C24H28N4O6S requires C,57.58; H,5.64; N,11.19%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C@H:13]([CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:30].[Li+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C@H:13]([CH2:18][I:30])[CH2:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2Cc3ccc(NC(=O)OC(C)(C)C)cc3C2)cc1
Reactant: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C[C@@H](CI)C2
Yield: 78.2 %

Procedure:
Toluene-4-sulfonic acid (S)-5-tert-butoxycarbonylamino-indan-2-ylmethyl ester (2.93 g, 7.02 mmol) was dissolved in DMF (60 mL) and heated and stirred at 70° C. with lithium iodide (4.7 g, 35.1 mmol) for 18 hours. Volatiles were removed under reduced pressure and the resulting residue was stirred with 100 mL of CH2Cl2 and solids removed by filtration. The filtrate was again evaporated, the residue was purified by flash column chromatography (10% of ethyl ether in hexanes) to yield a white solid as (S)-2-iodomethyl-indan-5-yl-carbamic acid tert-butyl ester (2.05 g, 78.5%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[CH:4]=[N:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[OH:17][C:7]1([C:5]2[CH:4]=[N:3][CH:2]=[N:1][CH:6]=2)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: OC1(c2cncnc2)CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2cncnc2)CC1
Yield: 97 %

Procedure:
A solution of 8-pyrimidin-5-yl-1,4-dioxaspiro[4,5]decan-8-ol (0.14 g, 0.59 mmol) in 10 mL of THF/1 N HCl (1:1) was stirred for 24 h at room temperature. The mixture was treated with Na2CO3 to pH 8 and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated to give 0.11 g of 4-hydroxy-4-pyrimidin-5-ylcyclohexanone in 79% yield. MS (EI) calcd: (M+H)+=192.1; found: 192.1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:16]([O:18]CC)=[O:17])[CH:6]([C:12]([F:15])([F:14])[F:13])[O:7]2.[OH-].[Li+].Cl>C1COCC1.CO.O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[CH:6]([C:12]([F:15])([F:14])[F:13])[O:7]2
Reactant: CCOC(=O)C1=Cc2c(F)cccc2OC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2c(F)cccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80104.6 %

Procedure:
To a solution of 290 mg (1.0 mmole) of ethyl 5-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 7 mLs of THF and 2 mL of methanol was added a solution of 85 mg of lithium hydroxide monohydate in 1.0 mL of water. The mixture was heated to reflux for 30 min and allowed to cool to rt. After stirring overnight, the mixture was treated with 75 mL of 1N HCl and extracted three times with diethyl ether. The combined extracts were washed with brine, dried and concd in vacuo to afford 210 g (80%) of a white solid: 1H NMR (d6-acetone/400 MHz) 5.86 (q, 1H, J=7.1 Hz), 6.88 (m, 2H), 7.44 (q, 1H, J=6.7 Hz), 7.93 (s, 1H); 19F NMR (d6-acetone/400 MHz) −120.9 (t, 1F, J=7.7 Hz), −79.4 (d, 3F, J=7.7 Hz); MS (ES+) 263 (M+l, 100); MS (ES−) 261 (M−1, 100); HRMS (ES−) m/z calcd for (C11H6F4O3) 261.0175, found 261.0193.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[O:24]([CH2:31][CH:32]1[CH2:34][O:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:34][CH:32]([OH:33])[CH2:31][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(Br)cc3c2C1
Reactant: c1ccc(OCC2CO2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(c3cc(Br)ccc3n2CC(O)COc2ccccc2)C1
Reaction time: 1 h
Yield: 21 %

Procedure:
A solution of tert-butyl 8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (449.7 mg, 1.28 mmol) and powdered potassium hydroxide (86.9 mg, 1.54 mmol) in acetone (4.0 ml) was stirred for 15 minutes before the addition of 2-(phenoxymethyl)oxirane (254 mg, 1.69 mmol). After 1 h the reaction was condensed, diluted with EtOAc and washed twice with water and then brine. The organic layer was then dried over Na2SO4, filtered and condensed. The crude mixture was purified by silica gel chromatography (1% MeOH/CH2Cl2+0.1% Et3N). Yield=21%. ESI (m/z): 546.6 (M+CHCOO−).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][C:5]=3[NH:6][C:7]=2[C:8]([Cl:11])=[CH:9][CH:10]=1.[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=O)=O)=CC=1>CN(C=O)C>[Br:1][C:2]1[C:3]2[C:4]3[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][C:5]=3[N:6]([CH2:30][CH2:31][C:32]3[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=3)[C:7]=2[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: CN1CCc2[nH]c3c(Cl)ccc(Br)c3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4c(Br)ccc(Cl)c42)CN(C)CC3)cn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9-bromo-6-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (500 mg, 1.67 mmol) in DMF (5 mL), sodium hydride (200 mg, 5.0 mmol) was added. After stirring at 60° C. for 30 min., 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (1.2 g, 4.2 mmol) was added to the reaction mixture and stirred at the same temperature for 1 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase HPLC to obtain the 9-bromo-6-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.39 (s, 1H), 8.12 (d, 1H), 7.66 (d, 1H), 7.26 (d, 1H), 7.1 (d, 1H), 4.67 (m, 4H), 3.7 (m, 2H), 3.27 (t, 2H), 3.18 (m, 2H), 3.15 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([Cl:36])=[O:35])=[CH:29][CH:28]=1>>[ClH:36].[ClH:36].[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:34](=[O:35])[O:33][C:30]4[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C(Cl)Oc1ccccc1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)Oc5ccccc5)c4)CC3)cccc2n1
Product: Cl
Yield: 59 %

Procedure:
The title compound was prepared in 59% yield according to the general procedure for the preparation of carbamates (Method D) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and phenyl chloridocarbonate.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.ClC(OC)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C.O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([N:30]=[N+:31]=[N-:32])=[O:17])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: COC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1ccc(-c2ccccc2C(=O)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 4'-ethylbiphenylcarboxylic acid (20 mmol) dissolved in 50 mL dry DMF was added 25 mmol of triethylamine and the mixture was cooled in an ice bath, added 38.5 mmol of methyl chloroformate dropwise at 0°-5° C., and then stirred at room temperature for 15 minutes. The mixture was cooled to 0° C. again, and a cold solution of 38.5 mmol of sodium azide dissolved in a minimum amount of water (<8 mL) was added as rapidly as possible (in one portion if possible) at <5° C. The reaction mixture was stirred at 0° C. for 1 hour and poured into 500 mL of ice-water. The resulting precipitate was filtered while still cold (<10 min), washed with cold water and dried under a stream of nitrogen to give the crude 4'-ethylbiphenylcarbonyl azide. The azide was used in place of 4'-ethylbiphenylisocyanate for the subsequent reactions according to the procedures exactly paralleling those described previously for Examples 1 through 3 to give the desired product as a colorless solid, mp 223°-224° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][CH:13]1[CH2:14][CH2:15][O:10][CH2:11][CH2:12]1
Reactant: OC1CCOCC1
Reactant: Oc1cc(F)cc(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cc(F)cc(OC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 3,5-difluorophenol (1.0 equiv.), tetrahydro-2H-pyran-4-ol (1.2 equiv.), and triphenylphosphine (2.0 equiv.) in THF (0.33 M) at 0° C. was added DIAD (2.0 equiv.) dropwise. The reaction mixture was stirred at rt overnight. The mixture was concentrated and purified by flash chromatography over silica gel (heptanes:ethyl acetate gradient) to give 4-(3,5-difluorophenoxyl)tetrahydro-2H-pyran in 90% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.72-1.84 (m, 2H), 1.96-2.09 (m, 2 H), 3.59 (ddd, J=11.64, 8.31, 3.52 Hz, 2 H), 3.90-4.04 (m, 2 H), 4.44 (tt, J=7.78, 3.77 Hz, 1 H), 6.32-6.53 (m, 3 H).
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1>CN(C=O)C.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[CH3:1][N:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[CH:3]1[CH2:4][CH2:5][N:6]([CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)[CH2:7][CH2:8]1
Reactant: CN(CCc1ccc(Oc2ccccc2)cc1)C1CCNCC1
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CCC(N(C)CCc3ccc(Oc4ccccc4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 54 h

Procedure:
A solution of N-methyl-N-[2-(4-phenoxyphenyl)ethyl]-4-piperidinamine (about 0.7 mmol) in DMF (5 mL) and diisopropylethylamine (5 mL) was stirred as methyl 4-(bromomethyl)benzoate (163 mg, 0.71 mmol) was added. The reaction was stirred for 54 hours at ambient temperature. The reaction was diluted with ethyl acetate, washed with brine, dried, and concentrated to give methyl 4-[[4-[methyl[2-(4-phenoxyphenyl)ethyl]amino]-1-piperidinyl]methyl]benzoate; 1H NMR (CDCl3) 7.76 (d, 2H), 7.37 (d, 2H), 7.28 (td, 2H), 7.14 (d, 2H), 7.06 (dt, 1H), 6.95 (dt, 2H), 6.92 (dd, 2H), 3.84 (s, 3H), 3.55 (s, 2H), 2.87 (m, 2H), 2.71 (m, 3H), 2.51 (m, 1H), 2.01 (s, 3H), 1.98 (m, 2H), 1.76 (m, 2H), 1.62 (m, 2H) ppm.
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[O:12]([CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:8][N:6]1[C:5](=[O:9])[N:4]([CH3:10])[C:3](=[O:11])[C:2]([N:21]2[CH2:22][CH2:23][CH:19]([O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:20]2)=[N:7]1.[CH2:13]([OH:12])[CH2:14][CH2:15][CH3:16]
Reactant: Cn1nc(Br)c(=O)n(C)c1=O
Reactant: c1ccc(OC2CCNC2)cc1
Product: CCCCO
Product: Cn1nc(N2CCC(Oc3ccccc3)C2)c(=O)n(C)c1=O
Yield: 72 %

Procedure:
The compound 38 (solid) is prepared from the triazine 1b and from the intermediate 11b according to the synthesis method 1 in n-butanol (yield: 72%).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O-:10].[Na+].[CH3:12][OH:13]>>[C:2]1([CH2:1][C:9]([O:13][CH3:12])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: ClCc1ccccc1
Reactant: CO
Agent: [Na+]
Product: COC(=O)Cc1ccccc1
Reaction time: 2 h
Yield: 85 %

Procedure:
110 g (0.87 mole) of benzyl chloride and, simultaneously but separately, a solution of 46 g (0.85 mole) of sodium methylate in 130 g of methanol, were added gradually in the course of one hour, with vigorous stirring, to a solution of 160 g of methanol and 10 g of K[Fe(CO)3NO] (0.048 mole) under a carbon monoxide pressure of 1.7 bars, at 55° C. The reaction was complete after a further two hours. Conventional working up gave methyl phenylacetate in 85% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=O)[CH:8]=2)[O:3]1.[NH2:16][C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH:22]([CH2:28][OH:29])[C:23](=[O:27])[NH:24]2)=[CH:19][CH:18]=1>>[OH:29][CH2:28][CH:22]1[CH2:21][C:20]2[C:25](=[CH:26][C:17]([NH:16][C:12]([C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[O:3][C:2]([CH3:1])([CH3:15])[CH2:11][CH2:10]4)=[O:14])=[CH:18][CH:19]=2)[NH:24][C:23]1=[O:27]
Reactant: CC1(C)CCc2cc(C(=O)O)ccc2O1
Reactant: Nc1ccc2c(c1)NC(=O)C(CO)C2
Product: CC1(C)CCc2cc(C(=O)Nc3ccc4c(c3)NC(=O)C(CO)C4)ccc2O1

Procedure:
This material was prepared analogous to the procedures described for Example 2, steps (a-b). 2,2-Dimethyl-chroman-6-carboxylic acid (90 mg, 0.4 mmol, Maybridge) and 7-amino-3-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (85 mg, 0.44 mmol, prepared according to the procedure described in WO03049702) provided the title compound as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 381 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[CH3:25][S:26][CH2:27][CH2:28]Cl>>[CH3:25][S:26][CH2:27][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:9](\[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)/[CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1
Reactant: CSCCCl
Reactant: OCCC(=C(c1ccccc1)c1ccc(O)cc1)c1ccccc1
Product: CSCCOc1ccc(/C(=C(/CCO)c2ccccc2)c2ccccc2)cc1

Procedure:
The compound is prepared by using the method described in the example 1a starting from 4-(4-hydroxyphenyl)-3,4-diphenyl-but-3-en-1-ol (preparation described in U.S. Pat. No. 4,996,225) and 2-chloroethyl methyl sulfide.