Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][NH:5][C:6](=[O:42])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31](C(OC(C)(C)C)=O)[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([C:11]4[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=4)[O:8][CH2:7][C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:43])=[O:42])[N:24]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CN(C)CCNC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCNC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-(2-(2-(dimethylamino)ethylamino)-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.18 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-(dimethylamino)ethyl)acetamide. (19 mg, 0.039 mmol, 22%).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH3:13][C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[NH:15]1>>[CH3:13][C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: CCOC(=O)c1ccc(I)cc1
Product: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1

Procedure:
By reaction and treatment in the same manner as in Preparation Example 18 and using ethyl 4-iodobenzoate (1.4 mL) and (R)-4-methyloxazolidin-2-one (860 mg) described in Preparation Example 25, the title compound (0.9 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2=[CH:21][CH:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:19]2[CH:18]=[CH:17]1>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:25]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[O:16][CH:17]=[CH:18][C:19]=23)=[O:26])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Reactant: O=C(O)c1cccc2occc12
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2cccc3occc23)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with benzofuran-4-carboxylic acid (M. A. Eissenstat et al. J. Med. Chem. 1995, 38, 3094-3105). LC-MS (acidic): tR=1.00 min; [M+H]+=357.1. 1H-NMR (CDCl3): δ=0.58 (bs, 1H); 0.80-0.86 (m, 1H); 1.52 (s, 9H); 1.52-1.59 (m, 1H); 1.79 (bd, J=13.3 Hz, 1H); 2.51-2.60 (m, 1H); 3.24-3.30 (m, 1H); 3.60-3.64 (m, 2H); 4.45-4.52 (m, 1H); 7.32 (t, J=7.9 Hz, 1H); 7.47 (bs, 1H); 7.61 (d, J=8.2 Hz, 1H); 7.65 (d, J=7.5 Hz, 1H); 7.70 (bs, 1H); 8.43 (bs, 1H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH3:28])[C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:12][C:13](COS(C)(=O)=O)=[N:14][CH:15]=1)=[O:9].C(Cl)Cl.[OH2:41]>>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH3:28])[C:8]([C:10]1[C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:12][C:13]([CH2:28][N:7]2[CH2:8][CH2:10][O:41][CH2:5][CH2:6]2)=[N:14][CH:15]=1)=[O:9]
Reactant: O
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(COS(C)(=O)=O)nc1-c1ccccc1
Solvent: ClCCl
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(CN2CCOCC2)nc1-c1ccccc1
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of 0.40 g (0.73 mmol) methanesulfonic acid 5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-phenyl-pyrimidin-2-ylmethyl ester in 5 ml CH2Cl2 0.095 ml (1.10 mmol) morpholine were added. The reaction mixture was stirred for 16 hrs. at RT. The reaction mixture was poured into H2O and extracted three times with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 10:1) to give 0.33 g (88%) 2-morpholin-4-ylmethyl-4-phenyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a pale yellow waxy solid, MS (ISP): 539.3 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15](C(O)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=CC=1.C(=O)=O>>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc(-c2ccccc2)nc2ccccc12
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Product: c1ccc(-c2ccc3ccccc3n2)cc1
Temperature: 200 °C

Procedure:
A 1-liter capacity flask equipped with N2 -bleeding tube, thermometer, paddle stirrer, and condenser was charged with 2-phenyl-4-quinolinecarboxylic acid, 227.7 g (0.90 mol), quinoline 200.0 g, and cupurons oxide 20.0 g (0.14 mol). The flask was heated with stirring to 200° C., and maintained at 200° C. for 1 hour. CO2 started to evolve at about 120° C. The mixture was cooled to room temperature, and filtered by suction using filter aid and ether. Ether was evaporated from the filtrate in a vacuum evaporator, and the residue was subjected to fractional distillation under vacuum. A fraction was collected at 140° C./0.2 mmHG-155° C./0.5 mmHg which was 99+% pure 2-phenylquinoline by GC, NMR. M.p. 80°-84° C. The yield was 82.0 g (44%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH2:17][N+:18]([O-])=O)[CH2:12][C:13](OC)=[O:14])=[CH:8][CH:9]=2)[N:4]([CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:3]=1.[H][H]>CO.[Ni]>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[CH2:17][NH:18][C:13](=[O:14])[CH2:12]3)=[CH:8][CH:9]=2)[N:4]([CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:3]=1
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc2c(C)cn(CCCc3ccccc3)c2c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cc1cn(CCCc2ccccc2)c2cc(C3CNC(=O)C3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A solution of methyl 3-(3-methyl-1-{3-(phenyl)propyl}-1H-indol-6-yl)-3-nitromethyl-propionate (0.296 g, Reference Example 38) in methanol (100 ml), under argon, was treated with excess Raney® nickel. The argon atmosphere was replaced by hydrogen at 1 atmosphere then the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite. The filtrate was evaporated and the residual crude methyl 3-(3-methyl-1-{3-(phenyl)propyl}-1H-indol-6-yl)-3-aminomethyl-propionate was dissolved in sodium hydroxide solution (15 ml, 1N). After stirring at room temperature for 1 hour the reaction mixture was extracted three times with ethyl acetate (15 ml). The combined extracts were dried over sodium sulphate then evaporated. The residue was subjected to preparative layer chromatography on silica using a mixture of ethyl acetate and hexane (1:1, v/v) as eluent to yield the title compound (0.198 g) as an oil. NMR (CDCl3): δ 2.05-2.15(m); 2.30(s); 2.55-2.60(m); 2.65-2.70(m); 2.85-2.95(m); 3.30-3.40(m); 3.60-3.70(m); 3.90-4.00(m); 4.40-4.60(m); 6.80-7.40(m). M+332.1941.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH3:19])[CH:5]=1.FC(F)(F)S(O[C:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=1)(=O)=O>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=2)=[C:6]([CH3:19])[CH:5]=1
Reactant: COc1cccc(C2=C(OS(=O)(=O)C(F)(F)F)CCCC2)c1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Product: COC(=O)c1ccc(C2=C(c3cccc(OC)c3)CCCC2)c(C)c1
Yield: 53.4 %

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Example 28, Step A (0.300 g, 1.09 mmol) and 2-(3-methoxy-phenyl)-cyclohex-1-en-1-yl trifluoromethanesulfonate (0.441 g, 1.31 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 0 to 5% ethyl acetate in hexane, afforded the title compound (0.196 g) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([O:34]C)=[O:33])=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([OH:34])=[O:33])=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1ccc(Cn2c(C(=O)OC)c(-c3cccc(CO)c3)c3cc(Cl)ccc3c2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1c(-c2cccc(CO)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of 6-chloro-4-(3-hydroxymethylphenyl)-2-(4-methoxycarbonylbenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (130 mg) in methanol (4.0 ml) was added 1N sodium hydroxide (390 μl), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 3 with 1N hydrochloric acid and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/1) to give the title compound (92 mg) as a colorless powder. 1H-NMR (CDCl3) δ: 3.23 (3H, s), 4.76 (2H, s), 5.41 (1H, d, J=15.6 Hz), 5.48 (1H, d, J=15.6 Hz), 7.18-7.30 (3H, m), 7.35 (2H, d, J=8.7 Hz), 7.42-7.47 (2H, m), 7.52 (1H, dd, J=2.1, 8.4 Hz), 8.02 (2H, d, J=8.7 Hz), 8.48 (1H, d, J=8.4 Hz). HPLC analysis: purity 97.9% (retention time: 3.84 min). MS (ESI+): 478 (M+H), 480.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([OH:12])=O)[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:23]([CH2:25][C:26]([NH:28][C@H:29]([C:36]([NH:38][C@H:39]([C:52]([O:54][CH3:55])=[O:53])[CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27])[CH3:24].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([N:23]([CH2:25][C:26]([NH:28][C@H:29]([C:36]([NH:38][C@H:39]([C:52]([O:54][CH3:55])=[O:53])[CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27])[CH3:24])=[O:12])[OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CNCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CN(C)C(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
254 mg of Z-Sta-OH (see stage 1.12), 297 mg of H-Sar-His-Lys(Boc)-OMe, 97 mg of HOBt×H2O and 196 mg of DCCI are dissolved, in this sequence, in 3 ml of DMF and the whole is left to stand for 20 hours at room temperature. The DCH which has crystallised out is filtered off, the filtrate is concentrated to dryness, heated for 1 hour at 60° in 7 ml of methanol/glacial acetic acid/H2O (94:3:3), and this solution is again concentrated to dryness. The oily residue is purified by chromatography over 75 g of silica gel (Merck No. 60, 230-400 mesh) by elution with CHCl3 /MeOH (9:1). The pure fractions are dissolved in ethyl acetate, washed with NaHCO3 solution and with H2O and, by concentration of the organic phase, Z-Sta-Sar-His-Lys(Boc)-OMe is obtained in amorphous form (honey); Rf (F)=0.15; Rf (I)=0.5.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]([CH3:12])=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[Cl:10].I[CH3:14].O>CN(C=O)C>[Cl:10][C:9]1[C:4]([NH2:3])=[C:5]([CH3:12])[C:6]([O:11][CH3:14])=[CH:7][CH:8]=1
Reactant: CI
Reactant: Cc1c(O)ccc(Cl)c1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)c(N)c1C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
NaH, 60% (0.236 mol) was stirred in DMF (500 ml), at room temperature. 3-amino-4-chloro-2-methylphenol (0.236 mol) was added portionwise (exothermic temperature rise to 32° C.). The reaction mixture was stirred for 30 minutes, allowing the temperature to drop to room temperature. Iodomethane (0.236 mol) was added dropwise. The reaction mixture was stirred for one hour at room temperature. Water was added (at first, slowly). This mixture was extracted with toluene. The separated organic layer was dried, filtered and the solvent evaporated, yielding 40.5 g 6-chloro-3-methoxy-2-methylbenzenamine (interm. 22) (quantitative yield; used in next reaction step, without further purification).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]3[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[CH2:33][C:34](=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36]>C(#N)C>[CH2:38]([O:37][C:35]([C:34]1[N:1]=[C:2]2[CH:7]=[C:6]([NH:8][C:9]([C:11]3[N:23]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:14]4=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=[C:13]4[CH:12]=3)=[O:10])[CH:5]=[CH:4][N:3]2[CH:33]=1)=[O:36])[CH3:39]
Reactant: Nc1cc(NC(=O)c2cc3cc(C(F)(F)F)cnc3n2Cc2cccc(F)c2)ccn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CC#N
Product: CCOC(=O)c1cn2ccc(NC(=O)c3cc4cc(C(F)(F)F)cnc4n3Cc3cccc(F)c3)cc2n1
Yield: 53.8 %

Procedure:
The compound is prepared according to a process similar to that described in step 15.3, by reacting 0.197 g (0.46 mmol) of N-[2-aminopyrid-4-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, prepared according to the protocol described in step 15.2, with 0.179 g (0.92 mmol) of ethyl 3-bromo-2-oxopropionate in 5 mL of acetonitrile. 130 mg of the expected product are obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:13]([O:15]C)=[O:14])[CH3:8].O.[OH-].[Li+]>CO.O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:13]([OH:15])=[O:14])[CH3:8]
Reactant: COC(=O)c1cc(C)cc(CN(C)Cc2ccco2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CN(C)Cc2ccco2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-{[(2-furylmethyl)(methyl)amino]methyl}-5-methylbenzoate (180 mg, 0.66 mmol) in methanol (2 mL), tetrahydrofuran (1 mL), and water (1 mL) is added lithium hydroxide (277 mg, 6.6 mmol), and the reaction mixture stirred at room temperature for 2 h. The reaction mixture is concentrated under reduced pressure, dissolved in methylene chloride, filtered, and the filtrate concentrated under reduced pressure to provide the title compound. ESI MS m/z 258 [M+H]+.
Reaction SMILES: C(S)C.[CH2:4]([N:6]([CH2:37][CH3:38])[CH2:7][CH2:8][N:9]1[C:25](=[O:26])[C:24]2[C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:27]CC5C=CC=CC=5)[CH:21]=4)[NH:16][C:15]=3[C:14]([O:35][CH3:36])=[CH:13][C:12]=2[C:10]1=[O:11])[CH3:5].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:37]([N:6]([CH2:4][CH3:5])[CH2:7][CH2:8][N:9]1[C:25](=[O:26])[C:24]2[C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([OH:27])[CH:21]=4)[NH:16][C:15]=3[C:14]([O:35][CH3:36])=[CH:13][C:12]=2[C:10]1=[O:11])[CH3:38]
Reactant: CCN(CC)CCN1C(=O)c2cc(OC)c3[nH]c4ccc(OCc5ccccc5)cc4c3c2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCS
Solvent: CCOC(C)=O
Product: CCN(CC)CCN1C(=O)c2cc(OC)c3[nH]c4ccc(O)cc4c3c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
1.8 ml of ethanethiol and 0.47 ml of boron trifluoride-diethyl ether complex were added to 180 mg of N-(2-diethylaminoethyl)-6-benzyloxy-1-methoxycarbazole-3,4-dicarboximide. The mixture was stirred at room temperature overnight. Thereto were added 100 ml of ethyl acetate and 50 ml of an aqueous saturated sodium hydrogencarbonate solution. The mixture was stirred at room temperature for 10 minutes. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/methanol=40/1 to 10/1), followed by recrystallization from ethanol to obtain 26 mg (yield: 18%) of N-(2-diethylaminoethyl)-6-hydroxy- 1-methoxycarbazole-3,4-dicarboximide as yellow crystals.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][C@H:13]([O:15][CH2:16][C:17]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C@@H:12]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[O:47][CH3:48])=[CH:31][CH:30]=2)[C@H:11]([CH2:49][OH:50])[CH2:10]1)=O)(C)(C)C>CO>[CH3:48][O:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[CH2:40][O:39][CH2:38][CH2:37][CH2:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([C@@H:12]2[C@@H:13]([O:15][CH2:16][C:17]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:14][NH:9][CH2:10][C@H:11]2[CH2:49][OH:50])=[CH:34][CH:33]=1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2[C@H](CO)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2cc(OC)c3ccccc3c2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc([C@H]2[C@H](CO)CNC[C@@H]2OCc2cc(OC)c3ccccc3c2)cc1

Procedure:
In an analogous manner to that described in Example 13 (j) by cleavage of the BOC group using a solution of hydrogen chloride in methanol, starting from (3S,4R,5R)-3-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [Example 13 (h)] there was obtained (3S,4R,5R)-[4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yl]-methanol as a colorless foam; MS: 572 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]#[C:12][CH2:13][CH2:14]O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.O=P(Cl)(Cl)[Cl:24].O>N1C=CC=CC=1>[Cl:24][CH2:14][CH2:13][C:12]#[C:11][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[N:5]=[CH:4]2
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: Fc1c(C#CCCCl)ccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a mixture of 4-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (4.6 g, 16.0 mmol) in pyridine (50 mL), was added POCl3 (10.3 g, 67.3 mmol). The resulting solution was stirred at room temperature for 2 hours. Upon completion, the reaction solution was poured into water (250 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified on silica gel column (0˜10% EtOAc in petroleum ether) affording the title compound (2.62 g). 1H NMR (300 MHz, DMSO-d6): δ 8.13 (s, 1H), 7.58 (d, 1H), 7.43 (dd, 1H), 5.87 (dd, 1H), 3.90-3.69 (m, 2H), 3.83 (t, 2H), 2.98 (t, 1H), 2.41-2.29 (m, 1H), 2.06-1.94 (m, 2H), 1.78-1.70 (m, 1H), 1.60-1.54 (m, 2H); LCMS: 307 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([NH:20][CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[CH2:8][C@@H:7]1[CH2:36][CH3:37])=[O:5])[CH3:2].[C:38](OC(=O)C)(=[O:40])C.C([O-])=O.[Na+]>C(O)=O.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[C@H:9]([N:20]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:23]=2)[CH:38]=[O:40])[CH2:8][C@@H:7]1[CH2:36][CH3:37])=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1CC
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N(C=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1CC
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.4 %

Procedure:
A solution of cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 3E) (2.0 g, 3.65 mmol) in 20 mL of formic acid was treated with acetic anhydride (11.29 g, 111 mmol) and sodium formate (1.25 g, 18.5 mmol). After stirring for 24 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography using 10-15% ethyl acetate/hexanes as eluent to afford 1.8 g of the title product. MS m/z 571.2 (M++1); 1H NMR (˜5:1 mixture of formamide rotamers, CDCl3) δ 0.75 (t, 3H), 1.28 (t, 3H), 1.42 (m, 1H), 1.6-1.75 (M, 2H), 2.3 (bm, 1H), 4.15-4.3 (m, 2H), 4.3-4.4 (m, 1H), 4.5-4.7 (bm, 1H), 4.8-5.8 (bm, 2H), 7.14 and 7.08 (s, 1H), 7.5-7.6 (m, 2H), 7.74 (s, 2H), 7.80 and 7.86 (s, 1H), 8.47 and 8.62 (s, 1H).
Reaction SMILES: OC1C2N=C3CCNCCC3=C(C)C=2C=CC=1.[Cl:18]C(OCC)=O.[CH2:24]([O:26][C:27]([N:29]1[CH2:43][CH2:42][C:41]2[C:32](=[N:33][C:34]3[C:35]([O:45]C(OCC)=O)=[CH:36][CH:37]=[CH:38][C:39]=3[C:40]=2[CH3:44])[CH2:31][CH2:30]1)=[O:28])[CH3:25].[OH-].[K+]>>[ClH:18].[CH2:24]([O:26][C:27]([N:29]1[CH2:43][CH2:42][C:41]2[C:32](=[N:33][C:34]3[C:35]([OH:45])=[CH:36][CH:37]=[CH:38][C:39]=3[C:40]=2[CH3:44])[CH2:31][CH2:30]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)Oc1cccc2c(C)c3c(nc12)CCN(C(=O)OCC)CC3
Agent: Cc1c2c(nc3c(O)cccc13)CCNCC2
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)N1CCc2nc3c(O)cccc3c(C)c2CC1
Product: Cl
Yield: 22 %

Procedure:
7-Hydroxy-1,2,4,5-Tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 7-hydroxy-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63, and subsequent hydrolysis of the intermediate 7-(ethoxy-carbonyloxy)-1,2,4,5 -tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester with dilute potassium hydroxide at 30° C.
Reaction SMILES: [N:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][CH2:18][C:13]3=[N:12][C:4]=1[CH:5]=[N+:6]2[O-].ClC(Cl)(Cl)C([N:23]=C=O)=O>ClCCl>[N:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][CH2:18][C:13]3=[N:12][C:4]=1[C:5]([NH2:23])=[N:6]2
Reactant: [O-][n+]1cc2nc3n(c2c2ncccc21)OCCC3
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: Nc1nc2cccnc2c2c1nc1n2OCCC1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c][1,5]naphthyridine 5-oxide (0.13 g, 0.54 mmol) in dichloromethane (10 mL) was added trichloroacetyl isocyanate (0.08 mL, 0.67 mmol). After 1.5 hours, the solution was concentrated under reduced pressure and methanol (4 mL) and sodium methoxide (2 drops of a 25% w/w solution in methanol) were added with stirring. After 18 hours the solution was concentrated under reduced pressure. The resulting solid was recrystallized from methanol/ethyl acetate to provide 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c]-1,5-naphthyridin-6-amine.