Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][C:9]([F:27])=[CH:10][CH:11]=2)[C:6]1=O)C.[ClH:32].[NH2:33][N:34]([CH2:42][CH3:43])C(=O)OC(C)(C)C>C(O)C>[ClH:32].[CH2:42]([N:34]1[C:6]2[C:7]3[CH:8]=[C:9]([F:27])[CH:10]=[CH:11][C:12]=3[O:13][C:14]3([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[C:5]=2[CH:4]=[N:33]1)[CH3:43]
Reactant: CCN(N)C(=O)OC(C)(C)C
Reactant: CCOC(OCC)C1C(=O)c2cc(F)ccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCO
Product: CCn1ncc2c1-c1cc(F)ccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a solution of tert-butyl 3-(diethoxymethyl)-6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (1.3 g, 3.0 mmol) in ethanol (10.4 mL) was added hydrochloric acid (11.1 mL of 4 M, 44.6 mmol) (4 M in dioxane). The reaction mixture was allowed to stir at 25° C. for 2 hours. The solvent was removed under vacuum, and the obtained solid was azeotroped with ethanol (3×30 mL). The resulting beige-white solid was fully dissolved in ethanol (10.40 mL) at 25° C. prior to the addition of tert-butyl N-amino-N-ethyl-carbamate (571.2 mg, 3.6 mmol). The solution was allowed to stir at 25° C. overnight. To the thick beige-white slurry that formed was added hydrochloric acid (3.7 mL of 4 M in dioxane, 14.9 mmol). The mixture was heated at 60° C. to yield a clear yellow solution. After 1 hour at 60° C., a thick white slurry developed. The slurry was allowed to slowly, cool to 25° C. over 4 hours, and solids were collected by vacuum filtration. The cake was rinsed with a 10% solution of EtOH in hexanes (2×). Residual solvent was further removed under reduced pressure providing 1-ethyl-8-fluoro-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride (880 mg, 82%). ESI-MS m/z calc. 287.1. found 288.1 (M+1)+. Retention time 0.79 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.52 (dd, J=9.4, 2.8 Hz, 1H), 7.47 (s, 1H), 7.26-7.13 (m, 2H), 5.24 (s, 1H), 4.47 (q, J=7.2 Hz, 2H), 3.30-3.12 (m, 4H), 2.18-2.01 (m, 4H), 1.37 (t, J=7.2 Hz, 3H).
Reaction SMILES: N[C@H](C(O)=O)C(C)C.[OH-].[Na+].[CH3:11][S:12]([O-:14])=[O:13].[Na+].Br[C:17]1[CH:18]=[C:19]([C:29]([NH:31][CH2:32][C:33]2[C:34](=[O:41])[NH:35][C:36]([CH3:40])=[CH:37][C:38]=2[CH3:39])=[O:30])[C:20]2[CH:21]=[N:22][N:23]([CH:26]([CH3:28])[CH3:27])[C:24]=2[CH:25]=1>O.CS(C)=O>[CH3:39][C:38]1[CH:37]=[C:36]([CH3:40])[NH:35][C:34](=[O:41])[C:33]=1[CH2:32][NH:31][C:29]([C:19]1[C:20]2[CH:21]=[N:22][N:23]([CH:26]([CH3:28])[CH3:27])[C:24]=2[CH:25]=[C:17]([S:12]([CH3:11])(=[O:14])=[O:13])[CH:18]=1)=[O:30]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CS(=O)[O-]
Agent: CC(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(S(C)(=O)=O)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a 10 mL microwave vial containing a stirring mixture of L-valine (8.42 mg, 0.072 mmol), NaOH (0.024 mL, 0.072 mmol), and DMSO (1.6 mL) were added sodium methanesulfinate (0.065 g, 0.539 mmol) copper(I) iodide (6.85 mg, 0.036 mmol) and 1-Ethyl-3-methylimidazoliym bromide (0.014 g, 0.072 mmol). After stirring for 15 min, 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (0.15 g, 0.359 mmol) was added. The reaction vial was sealed and the mixture was stirred with heating at 90° C. (heat block) for 18 h. The contents were then irradiated (microwave) at 130° C. for 2 hr. After cooling to RT, the reaction mixture was poured onto 50 mL of water and stirred. The contents were extracted with hot 30% THF/EtOAc (2×) (need to heat to break up emulsion). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluent: 5-75% chloroform (containing 10% 2M ammonia in methanol) and dichloromethane. The isolated product was concentrated from DCM and MTBE, and dried under hi vacuum. The title compound was collected as 75 mg (49%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, J=6.57 Hz, 6H) 2.13 (s, 3H) 2.22 (s, 3H) 3.30 (s, 3H) 4.38 (d, J=4.80 Hz, 2H) 5.23 (quin, J=6.57 Hz, 1H) 5.90 (s, 1H) 8.02 (d, J=1.01 Hz, 1H) 8.45 (s, 1H) 8.52 (s, 1H) 8.77 (t, J=4.80 Hz, 1H) 11.56 (s, 1H); LCMS: (M+H)+=417.1.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:17][O:16][P:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][CH2:13]2)=[C:4](Cl)[N:3]=1.[OH2:23].[OH-:24].[Na+:25]>C(O)C>[NH:3]1[C:4](=[O:23])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][CH:12]([CH2:17][OH:16])[CH2:13][CH2:14][P:15]([O:19][CH2:20][CH3:21])(=[O:24])[O-:18])[C:9]=2[N:10]=[C:2]1[NH2:1].[Na+:25]
Reactant: O
Reactant: [OH-]
Reactant: CCOP1(=O)CCC(Cn2cnc3c(Cl)nc(N)nc32)CO1
Agent: [Na+]
Solvent: CCO
Product: CCOP(=O)([O-])CCC(CO)Cn1cnc2c(=O)[nH]c(N)nc21

Procedure:
2-Amino-6-chloro-9-[(2-ethoxy-2-oxo-1,2-oxaphosphorinan-5-yl)-methyl]purine (VSC 655) and its 7 isomer (100 mg, 0.29 mmol), dissolved in ethanol (4 ml), water (4 ml), and 2M aqeous sodium hydroxide (0.90 mmol) was kept at 37° C. for 18 h. The solution was neutralized by addition of weakly acidic Amberlite cation exchange resin, filtered, and evaporated to dryness to give 113 mg (quantitative yield) of a crude product.
Reaction SMILES: C[C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])(C)N1.[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15]>C(N(CC)CC)C>[C:4]1([CH:9]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][CH:7]=[CH:2][CH:10]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: CC(=O)CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)C=Cc1ccccc1

Procedure:
The title compound was prepared by the method of Example 6 (that is, using 2,2,6,6-tetramethylpiperidine as base instead of triethylamine) using 2,4-pentanedione instead of ethyl acetoacetate. The material prepared by this procedure was identical to that prepared by the method of Example 30, as indicated by the reverse phase chromatographic method described in Example 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:24]=3)[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C(=O)O)c1ccc(F)cc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)c3ccc(F)cc3)CC2)c1

Procedure:
Example 64 was prepared from 2-(4-fluorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 440.4 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9].[ClH:14].[CH3:15][C:16]1([CH3:31])[O:21][C:20]2[CH:22]=[C:23]([CH:26]=[CH:27][C:28]([OH:30])=O)[CH:24]=[N:25][C:19]=2[NH:18][CH2:17]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[ClH:14].[CH3:31][C:16]1([CH3:15])[O:21][C:20]2[CH:22]=[C:23](/[CH:26]=[CH:27]/[C:28]([N:2]([CH3:1])[CH2:3][C:4]3[O:5][C:6]4[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=4[C:8]=3[CH3:9])=[O:30])[CH:24]=[N:25][C:19]=2[NH:18][CH2:17]1
Reactant: CC1(C)CNc2ncc(C=CC(=O)O)cc2O1
Reactant: CNCc1oc2ccccc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OC(C)(C)CN3)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl-(3-methyl-benzofuran-2-ylmethyl)-amine (88 mg, 0.5 mmol) in DMF (5 mL) were added in sequential order 3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid hydrochloride (107 mg, 0.46 mmol), 1-hydroxybenzotriazole (68 mg, 0.5 mmol), diisopropylethylamine (240 uL, 1.38 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (100 mg, 0.5 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water added with rapid stirring. The product was extracted with ethyl acetate (3×10 mL), dried with sodium sulfate, filtered and concentrated. The free base was re-solvated in methylene chloride (5 mL) and a solution of 4M HCl in dioxane (1 mL) was added to precipitate the hydrogen chloride salt as a pale yellow solid (84 mg, 43%): 1H NMR (400 MHz, DMSO-d6) δ 8.94 (1s, 1H), 8.01-8.06 (m, 2H), 7.47-7.58 (m, 3H), 7.16-7.25 (m, 3H), 4.73-4.94 (rotamers, 2s, 2H), 3.42 (s, 2H), 3.04 (s, 3H), 2.42 (s, 3H), 1.34 (s, 6H); MS (ESI) m/e 392 (C23H25N3O3+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][N:9]1[CH3:19].O1CCCC1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[CH:10][N:9]1[CH3:19]
Reactant: CCOC(=O)c1cn(C)n(-c2ccccc2Cl)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(C(=O)O)c(=O)n1-c1ccccc1Cl
Yield: 92 %

Procedure:
In the same manner as in Reference Example 65 and using ethyl 2-(2-chlorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (2.8 g, 9.9 mmol), tetrahydrofuran (6 mL), methanol (5 mL) and 4N aqueous sodium hydroxide solution (8 mL) as starting materials, the title compound (2.3 g, 91%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:13]([O:19]C[I:21])(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].O1CCOC[CH2:23]1>>[IH:21].[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]([CH:15]([CH3:23])[C:14]([CH3:17])([CH3:16])[C:13]([OH:19])=[O:18])[C:2](=[NH:1])[S:3][C:4]=2[CH:10]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: COc1ccc2nc(N)sc2c1
Reactant: C1COCCO1
Product: COc1ccc2c(c1)sc(=N)n2C(C)C(C)(C)C(=O)O
Product: I

Procedure:
A solution of 2-amino-6-methoxy benzothiazole (8.5 g) and iodomethyl pivalate (11.5 g) in dry dioxan (120 ml) was stored at room temperature for 7 days. The resulting solid was collected and dried to give the sub-title product (14 g), mp 191°-3° as a hemi-solvate with dioxan (n.m.r.).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][Mg+].[Br-]>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:19])[CH3:29])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[S:14]2)[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg+]
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2C[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)[C@H]1O[C@@H]2SC(N(C)C(=O)OC(C)(C)C)=N[C@@H]2C[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a solution of tert-butyl ((3aR,5S,6S,7aR)-6-(benzyloxy)-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.920 g, 2.26 mmol) in anhydrous THF (20 mL) at 15° C. was added a solution of MeMgBr (1.4 M in THF/toluene, 4.1 mL, 5.7 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 h, and then quenched with saturated aqueous NaHCO3 solution (30 mL). The mixture was extracted with EtOAc (2×30 mL), and the combined extracts were dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (MeOH/DCM, 0:4 to 1:4), affording tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-(1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.350 g, 37%) as a white foam; 1H NMR (400 MHz, CDCl3) for this material indicated that it contained two diastereomers with a ratio of 1:2. Also isolated was the deprotected side product 1-((3aR,5R,6S,7aR)-6-(benzyloxy)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)ethanol (0.300 g, 41%) as a white solid; 1H NMR (400 MHz, CDCl3) for this material indicated that it contained two diastereomers with a ratio of 1:1.4.
Reaction SMILES: [Si]([O:8][C@H:9]([C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([NH:55][CH:56]=[O:57])[CH:49]=1)[CH2:10][NH:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:27][CH2:26]2)=[O:22])=[C:15]([CH3:47])[CH:14]=1)(C(C)(C)C)(C)C.ClCCl.F.F.F.C(N(CC)CC)C>C(OCC)(=O)C>[CH:56]([NH:55][C:50]1[CH:49]=[C:48]([C@@H:9]([OH:8])[CH2:10][NH:11][CH2:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:27][CH2:26]3)=[O:22])=[C:15]([CH3:47])[CH:14]=2)[CH:53]=[CH:52][C:51]=1[OH:54])=[O:57]
Reactant: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(NC=O)c1
Agent: F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CNC[C@H](O)c1ccc(O)c(NC=O)c1
Temperature: 25 °C

Procedure:
To a 1 L round-bottom flask was added biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(tert-butyldimethylsilanyloxy)-2-(3-formylamino-4-hydroxyphenyl)ethylamino]methyl}-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (21.5 g, 27.1 mmol) and dichloromethane (200 mL). The resulting mixture was stirred at room temperature until the ingredients dissolved and then triethylamine trihydrofluoride (8.85 mL, 54.2 mmol) was added and the resulting mixture was stirred at 25° C. for about 48 hours. The solvent was removed on a rotary evaporator to provide a thick paste. Dichloromethane (100 mL) and ethyl acetate (200 mL) were added to the paste and the resulting mixture was stirred for 30 minutes. The resulting slurry was slowly filtered under dry nitrogen and the filter cake was washed with a 1:2 mixture of dichloromethane and ethyl acetate (100 mL total), dried under nitrogen for 2 hours and then dried under vacuum overnight to provide biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester as a hydrofluoride salt (25 g, 96.9% purity) which was a hard clay-like solid. MS [M+H+] found 680.8.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[CH3:16].[CH:17](N1CCCCC1)=[O:18]>O1CCCC1.BrCBr>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:17]=[O:18])[C:10]=1[CH3:16]
Reactant: O=CN1CCCCC1
Reactant: Cc1c(Br)cccc1COC1CCCCO1
Solvent: BrCBr
Solvent: C1CCOC1
Product: Cc1c(C=O)cccc1COC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.2 g of Mg (magnesium shavings) in 15 ml of absolute tetrahydrofuran are initially introduced under a nitrogen atomsphere. A few drops of dibromomethane are added at 65° C. A solution of 14.25 g of 3-bromo-2-methylbenzyl tetrahydro-2-pyranyl ether in 50 ml of tetrahydrofuran is added dropwise while the temperature is kept at 65° C. The refluxed mixture is then stirred for 2 hours. A solution of 5.65 g of N-formylpiperidine in 10 ml of absolute tetrahydrofuran is added dropwise to the reaction mixture after the latter has been cooled to 0° C. Stirring is carried out for 20 hours at room temperature, the mixture is rendered slightly acidic with about 50 ml of 5% strength hydrochloric acid and extraction is carried out several times with ether. The combined ether extracts are washed with water, dried and evaporated down. The crude product (11 g) can be purified by column chromatography over silica gel using 97.5:2.5 toluene/acetone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7](Cl)[C:6]=2[CH:17]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[C:6]=2[CH:17]=1
Reactant: CN1CCNCC1
Reactant: ClC1c2ccccc2C=Cc2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C2c3ccccc3C=Cc3ccc(Br)cc32)CC1
Yield: 47.2 %

Procedure:
1.00 gram (3.27 millimoles) of 3-bromo-5-chloro-5H-dibenzo[a,d]cycloheptene, 0.7 gram (about 7 millimoles) of N-methylpiperazine and 3 milliliters of dimethylformamide were stirred together at room temperature under an atmosphere of nitrogen for 60 hours. At the end of this period, water and aqueous sodium carbonate solution was added, and the resulting aqueous solution extracted with ether. The ether solution was washed five times with water, then with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed from the dried solution in vacuo to obtain a residue. The residue was triturated with acetonitrile and crystallized from acetonitrile. It was then purified by passing through a Still column using 3 percent methanol in chloroform as eluant, crystallized from acetonitrile, and the crystals dried over phosphorus pentoxide at 78° C./0.2 mm Hg for 17 hours to obtain 0.57 gram of 1-(3-bromo-5H-dibenzo[a,d]cyclohepten-5-yl)-4-methylpiperazine product, m.p. 128°-130° C. Elemental analyses were as follows:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[OH:20])[CH:8]=3)[N:3]3[N:35]=[N:36][N:37]=[C:2]3[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(O)(c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A mixture of intermediate 15 (0.0224 mol) and sodium azide (0.067 mol) in DMF (120 ml) was stirred at 90° C. for 2 hours, brought to room temperature, poured out into ice water and stirred. The precipitate was filtered, washed with water and taken up in DCM. The organic layer was washed with water, separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-40 μm) (eluent: toluene/iPrOH/NH4OH 90/10/1). The pure fractions were collected and the solvent was evaporated, yielding 9 g (80%) of 5-(3-chlorophenyl)-α-(4-methoxyphenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-α]quinazoline-7-methanol (intermediate 16), mp 200° C.
Reaction SMILES: C1(N(CCCN2C(=O)[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=O)C2C=CC=CN=2)C=CC=CC=1.[H-].[Na+].[NH2:30][CH2:31][CH2:32][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.[H][H].C(Br)C1C=CC=CC=1>CS(C)=O.O>[NH2:30][CH2:31][CH2:32][N:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:18][C:19]1[CH:20]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: NCCNc1ccccn1
Reactant: O=C1c2ccccc2C(=O)N1CCCN(c1ccccc1)c1ccccn1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: NCCN(Cc1ccccc1)c1ccccn1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
2-Bromopyridine (15.8 g), ethylene diamine (30 g) and pyridine (10 ml) were heated together under reflux for 3 hr. The mixture was stripped to remove the excess of ethylene diamine and the residue taken up in water. The pH was adjusted to 14 and extracted with chloroform. The extracts were dried (K2CO3), stripped and the residue distilled at reduced pressure to give 2-(2-aminoethylamino) pyridine, 8.24 g (60%) bp 80° C., 0.01 mm Hg. (ii) A mixture of sodium hydride (0.53 g) and 2-(aminoethylamino)pyridine (2.74 g) in DMSO (30 ml) was heated slowly to 85° C. under nitrogen. After the evolution of hydrogen had ceased the solution was cooled to room temperature and benzyl bromide (2.37 ml) added dropwise keeping the temperature below 30° C. After a further 1 hr, water (200 ml) was added, the mixture extracted with ether and the extract washed with 2N hydrochloric acid. The pH of the aqueous layer was adjusted to 4.5 and extracted with chloroform. The pH was further raised to 14 and extracted with ether. After drying (K2CO3) and stripping, the final ether extract gave 2-[N-(2-aminoethyl)-N-benzylamino]pyridine (2.58 g) as an oil which was used without further purification.
Reaction SMILES: C[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:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:16]=1)[C:9]([CH3:29])([CH3:28])[CH2:8]2)=[O:4].[OH-].[Na+]>CO.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:10]2[C:9]([CH3:28])([CH3:29])[CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[NH:11]2)=[CH:16][C:17]=1[NH:22][C:23](=[O:27])[CH:24]([CH3:25])[CH3:26]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)C(C)C)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C(=O)Nc1cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)ccc1F

Procedure:
A mixture of methyl-2-(4-fluoro-3-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (183 mg, 0.46 mmol), sodium hydroxide (312 mg, 7.8 mmol) in methanol/water (10 mL/4 mL) was heated to reflux for 1.5 h. LC-MS indicated that the starting material was consumed completely. The solvent was removed in vacuo and the residue was acidified with 2M hydrochloric acid solution to Ph=5. The precipitated white solid was collected by filtration and dissolved in acetone, dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give 2-(4-fluoro-3-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, which was purified by recrystallization from dichloromethane/methanol/Hexant to afford 140 mg of off-white crystal. Yield: 79.3%. LC-MS (M+1)=385.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH:7]1[NH:11][CH2:10][CH2:9][S:8]1.C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>ClCCCl>[Cl:23][CH2:24][C:25]([N:11]1[CH2:10][CH2:9][S:8][CH:7]1[CH2:6][O:5][C:4]1[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=1[O:2][CH3:1])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: COc1ccccc1OCC1NCCS1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccccc1OCC1SCCN1C(=O)CCl
Reaction time: 1 h

Procedure:
A solution of 2-(o-methoxyphenoxymethyl)thiazolidine (100 g) in 1,2-dichloroethane (250 ml) cooled at 10° is heated, under stirring, with triethylamine (68 ml) and a solution of α-chloroacetylchloride (36.2 ml) in 1,2-dichloroethane (50 ml) is added dropwise. After 1 hour, the mixture is washed with water, dried on Na2SO4 and evaporated to dryness. Subsequent crystallization from propan-2-ol gives 3-α-chloroacetyl-2-(o-methoxyphenoxymethyl)thiazolidine m.p. 87°-88° C. (100 g).