Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([N:16]2[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18][CH2:17]2)[N:4]=1.C(O)(C(F)(F)F)=O.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]([NH:37][CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=3[C:33]([F:32])([F:42])[F:43])=[O:23])[CH2:20][CH2:21]2)[N:4]=1
Reactant: CNc1nc(N2CCC(C(=O)O)CC2)nc(N2CCN(C)CC2)n1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(N2CCN(C)CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
A solution of 1-[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid as the TFA salt (44.7 mg, 0.100 mmol, 1.00 equiv), 2-trifluoromethyl benzylamine (26.6 mg, 0.150 mmol, 1.50 equiv) and DMAP (3.3 mg, 0.26 equiv) in dichloromethane (1 ml) was cooled in an ice bath. 1-Ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI, 32 mg, 0.17 mmol, 1.7 equiv) was added. The reaction mixture was stirred at room temperature for 2 h. The solution was diluted with dichloromethane (1 ml) and washed with saturated sodium bicarbonate and water. The solvent was removed, and the residue was purified by reverse-phase HPLC to give the title compound (66 mg, 82.5% yield). MS (ES+): m/e 493.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([N:15]2[CH2:20][CH2:19][O:18][C:17]3[CH:21]=[N:22][CH:23]=[CH:24][C:16]2=3)=[O:14])[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]=1[O:8]C.[Cl-].[Li+].N1CCNCC1.C(=O)([O-])O.[Na+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([N:15]2[CH2:20][CH2:19][O:18][C:17]3[CH:21]=[N:22][CH:23]=[CH:24][C:16]2=3)=[O:14])[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]=1[OH:8]
Reactant: COc1c(Cl)cc(C(=O)N2CCOc3cnccc32)cc1[N+](=O)[O-]
Agent: C1CNCCN1
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)c(O)c([N+](=O)[O-])c1)N1CCOc2cnccc21
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
In a 25 ml flask, (3-chloro-4-methoxy-5-nitro-phenyl)-(2,3-dihydro-pyrido[3,4-b][1,4]oxazin-1-yl)-methanone (176 mg, 0.441 mmol), lithium chloride (42.7 mg, 1.006 mmol), piperazine (65 mg, 0.755 mmol) and N,N-dimethyl formamide (5 ml) were added and stirred at 1000 for 30 minutes. Lithium chloride (42.7 mg, 1.006 mmol) was further added thereto and then stirred at 1000 for 2 hours. After neutralizing with saturated solution of sodium hydrogen carbonate to pH 8 to 9, the mixture was adjusted to pH 6 again by using 1N hydrochloric acid to form solid. The resulting solid was filtered and recrystallized from methanol and tetrahydrofuran to obtain the target compound 36 as yellow solid (153 mg, 91%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8].[H-].[Na+].[C:12]1([C:22]([C:24]2[C:31]([CH3:32])=[CH:30][C:27]([CH2:28]Br)=[CH:26][C:25]=2[CH3:33])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O.C(O)(=O)C>[NH2:1][C:2]1[N:6]([CH2:28][C:27]2[CH:26]=[C:25]([CH3:33])[C:24]([C:22]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)=[O:23])=[C:31]([CH3:32])[CH:30]=2)[N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1nn[nH]c1N
Reactant: Cc1cc(CBr)cc(C)c1C(=O)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Cn2nnc(C(N)=O)c2N)cc(C)c1C(=O)c1cccc2ccccc12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A solution of 5-amino-l,2,3-triazole-4-carboxamide (182 mg, 1.43 mmol) in 5 ml of dry dimethylformamide (DMF) is treated with 50% sodium hydride dispersion in mineral oil (70mg). The reaction mixture is warmed to 45° C. and stirred for 1 hour. To this mixture, a solution of 4-(1-naphthoyl)-3,5dimethylbenzyl bromide (0.43 g, 1.2 mmol) in 5 ml of dry DMF is added. The reaction mixture is stirred at 45° C. for an additional 20 minutes and then stirred at room temperature for 1 hour. The reaction mixture is added slowly to water containing a small quantity of glacial acetic acid. The mixture is extracted with methylene chloride and the combined extracts washed with brine and dried with anhydrous sodium sulfate. Solvent is removed and the crude mixture of two triazoles is chromatographed on silica gel to give the titled compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:2].[NH2:10][C:11](N)=[O:12]>>[C:11](=[O:12])([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[NH2:10]
Reactant: CCc1ccc(O)cc1
Reactant: NC(N)=O
Product: CCc1ccc(OC(N)=O)cc1
Yield: 88 %

Procedure:
The same method as step (6-1) of Example 6 was carried out with the exception of using 39.0 kg of 4-ethyl phenol (Tokyo Chemical Industry Co., Ltd., Japan) instead of 4-phenyl phenol, using 1057 g of urea and carrying out the reaction for 12 hours. When a portion of the reaction liquid was removed and analyzed by liquid chromatography, the formation of (4-ethylphenyl) carbamate was confirmed. The yield was about 88% based on the charged amount of urea.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([I:31])=[C:25]([CH:30]=1)[CH2:26][N:27]=[N+]=[N-].O>C1COCC1>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([I:31])=[C:25]([CH:30]=1)[CH2:26][NH2:27]
Reactant: [N-]=[N+]=NCc1cc(Cl)ccc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
PPh3 (1.46 g, 5.58 mmol) was added to a stirred solution of 5-chloro-2-iodobenzylazide (0.55 g, 1.86 mmol) in THF (17.5 mL), and water (3.5 mL) were combined and stirred at room temperature. After 16 hr, the mixture was warmed to 80° C. for 3 h. The reaction was then concentrated and the residue was partitioned between ether and 1N HCl. The aqueous layer was adjusted to pH=8 with NaHCO3, saturated with NaCl and then extracted into CH2Cl2. The CH2Cl2 layer was washed with brine, dried (Na2SO4) and evaporated to give 5-chloro-2-iodobenzylamine (428 mg): 1H NMR (CDCl3, 400 MHz) δ 3.83 (s, 2H), 6.95 (dd, J=2.6, 8.4 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][N:7]=1.[C:8]1(=[O:17])[O:16][C:13]([CH3:15])([CH3:14])[O:12][C:10](=[O:11])[CH2:9]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:14][C:13]1([CH3:15])[O:16][C:8](=[O:17])[C:9](=[C:3]2[CH2:4][CH2:5][CH2:6][NH:7]2)[C:10](=[O:11])[O:12]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC1=NCCC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC1(C)OC(=O)C(=C2CCCN2)C(=O)O1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
A solution of 5-Methoxy-3,4-dihydro-2H-pyrrole (5.35 g, 54.0 mmol), isopropylidene malonate (7.78 g, 54.0 mmol), triethylamine (1.35 mL, 9.7 mmol) and benzene (55 mL) is refluxed under nitrogen overnight. The reaction is cooled to RT and concentrated and the crude product is recrystalized from EtOH (95 mL) to give the title compound as a white solid (8.13 g, 38.5 mmol). 1H NMR (CDCl3, 300 MHz) 3.73(t, 2H), 3.35(t, 2H), 2.20-2.08(m, 2H), 1.66(s, 6H).
Reaction SMILES: [Li+].[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([NH:24][CH2:25][C:26]([O-])=[O:27])[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][CH:7]=[N:6]1)([CH3:4])[CH3:3].C([N:31]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C>[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[C:17]4[CH:20]=[CH:21][C:22]([NH:24][CH2:25][C:26]([NH2:31])=[O:27])=[CH:23][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:11]=2)=[N:8][CH:7]=[N:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(NCC(=O)[O-])cc1OCC2
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(NCC(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.3 %

Procedure:
A mixture of [2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-acetic acid lithium salt (130 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (82 mg, 0.42 mmol), 1-hydroxybenzotriazole hydrate (55 mg, 0.42 mmol) and DIPEA (0.42 mL, 1.4 mmol) in DMF (2 mL) was stirred at RT for 5 min before ammonium chloride (55 mg, 1.05 mmol) was added and the reaction stirred at RT for 18 h. The mixture was concentrated in vacuo and the resultant residue triturated with water. The solid was filtered off, washed with water then dried in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 444 (48 mg, 37%). LCMS: RT=2.10 min, [M+H]+=368. 1H NMR 400 MHz (DMSO-d6) δ: 8.12 (1 H, d, J=8.80 Hz), 7.88 (1 H, d, J=0.63 Hz), 7.77 (1 H, s), 7.37 (1 H, br, s), 7.11 (1 H, br, s), 6.45 (1 H, dd, J=8.84, 2.36 Hz), 6.32 (1 H, br, t), 6.10 (1 H, d, J=2.33 Hz), 5.92 (1 H, m), 4.42 (4 H, m), 3.63 (2 H, d, J=5.84 Hz), 1.47 (6 H, d, J=6.60 Hz)
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])[O:6][CH:7]=1)[CH3:2].[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:39].[CH2:1]([C:3]1[N:4]=[C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])[O:6][CH:7]=1)[CH3:2]
Reactant: CCc1coc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1coc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
A solution of tert-butyl 4-{1-[(4-ethyl-1,3-oxazol-2-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (780 mg; compound B5) in DCM (20 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (3 ml, 4.0 M) according to the procedure described in example B28 to afford the title compound as a solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC[N:12]1[C:16]([C:17]2[CH:18]=[C:19]([CH:24]=[C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])=[N:15][N:14]=[N:13]1)C>>[N:27]1([C:25]2[CH:24]=[C:19]([CH:18]=[C:17]([C:16]3[NH:15][N:14]=[N:13][N:12]=3)[CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CCOCn1nnnc1-c1cc(C(=O)OC)cc(N2CCCC2)c1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(-c2nnn[nH]2)cc(N2CCCC2)c1
Reaction time: 2 h

Procedure:
A trifluoroacetic acid (5 mL) solution of methyl 3-{[ethoxymethyl]tetrazol-5-yl}-5-pyrrolidin-1-ylbenzoate (127 mg) was stirred at room temperature for 2 hours and then at 80° C. for 2 hours. The reaction liquid was concentrated under reduced pressure, the residue was purified through reversed-phase high-performance liquid chromatography [acetonitrile/water+0.1% trifluoroacetic acid] to obtain the title compound as a yellow powder.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@@:16]1([CH2:26][C:27]#N)[CH2:25][C:20]2([CH2:24][CH2:23][CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.C[OH:30].O>C1(C)C=CC=CC=1>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@@:16]1([CH2:26][CH:27]=[O:30])[CH2:25][C:20]2([CH2:24][CH2:23][CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: N#CC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Reactant: CO
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: O=CC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
1.0 M DIBAL solution in toluene (3.0 ml, 3 mmol) was added drop-wise to a solution of 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (350 mg, 1.4 mmol) in 7 mL toluene at −78° C. The resulting mixture was stirred at −78° C. until completion (1.5 h). The reaction was then quenched with 5 eq of MeOH (0.28 mL) and 0.1 mL water, stir while warming, 175 mg NA2SO4 added, stir at room temp. 2 h to give 310 mg (80%) of 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetaldehyde. LCMS m/z 250.6 (M+1) observed.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:24]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccco1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccco4)nc23)CC1
Yield: 31.9 %

Procedure:
Beginning with 0.200 gm (0.87 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.171 mL (1.74 mMol) 2-furoyl chloride, 0.090 gm (32%) of the title compound was recovered as a crystalline solid from methanol/ethyl acetate by the procedure described in Example 16.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[O:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]1[CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28]>>[N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH:4]([NH:7][S:27]([CH2:26][CH2:25][N:16]2[C:15](=[O:14])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:24])(=[O:28])=[O:29])[CH2:5][CH2:6]1
Reactant: NC1CCN(c2ccncc2)CC1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)NC1CCN(c2ccncc2)CC1

Procedure:
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (3,4,5,6-tetrahydro-2H[1,4′]bipyridinyl-4-yl)-amide was prepared by an analogous procedure as described for example 1 i) starting from 638 mg (3.6 mmol) 3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylamine and 985 mg (1 equiv.) 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride. The product was obtained in crude form as a light yellow foam. Yield: 860 mg MS (ES+): m/e=415.
Reaction SMILES: [Mg].Cl[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH2:10][O:11][C:12]([CH3:15])([CH3:14])[CH3:13].BrCCBr.ClC1C=CC=CC=1F.[CH2:28]([O:30][C:31](=[O:37])[C:32](OCC)=[O:33])[CH3:29].Cl>C1COCC1.O>[F:9][C:5]1[C:4]([CH2:10][O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:3]([C:32](=[O:33])[C:31]([O:30][CH2:28][CH3:29])=[O:37])[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)(C)OCc1c(F)cccc1Cl
Agent: Cl
Agent: Fc1ccccc1Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Solvent: BrCCBr
Product: CCOC(=O)C(=O)c1cccc(F)c1COC(C)(C)C
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 243.7 %

Procedure:
To a mixture of 73 g (3.0 mole, 3 eq) of magnesium turnings in 700 mL of THF was added 40 g (0.25 mole) of 1-chloro-3-fluoro-2-[(1,1-dimethylethoxy)-methyl]benzene followed by 1 mL of 1,2-dibromoethane. The reaction mixture was heated at reflux temperature and over the next four hours another 1 mL of 1,2-dibromoethane was added in two portions. At the end of that time period, gas chromatography indicated Grignard formation had commenced. The remaining 177 g of the chlorofluorobenzene added over one hour, and the mixture was heated at reflux temperature for an additional 12 hours. The resulting cloudy dark brown mixture was cooled to 5° C. with an ice-bath and was added via nitrogen pressure cannulation to a solution of 163 mL (1.2 mole) of diethyloxalate in 300 mL of THF. The temperature during addition was maintained between -60° and -50° C. via dry ice/acetone bath cooling, and the addition was complete in 45 minutes. After allowing the mixture to warm to 0° C., 100 mL of 2N HCl was added, followed by 200 mL of water and concentrated HCl to bring the pH to 2. The THF was removed in vacuo, EtOAc was added, and the mixture washed with water, brine, and concentrated in vacuo to give a dark liquid. Distillation using a 5-tray Oldershaw column gave 172 g of ethyl 3-fluoro-2-[(1,1-dimethylethoxy)methyl]-α-oxo-benzeneacetate as a light yellow oil (bp 113-117° C./0.35 mm Hg.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][O:18]1)[N:6]=[C:5]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: Fc1ccc(-c2n[nH]c3ccc(Br)cc23)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
To a solution of 5-bromo-3-(4-fluorophenyl)-1H-indazole (8.00 g, 27.48 mmol) in dried tetrahydrofuran (80 mL) under nitrogen at ambient temperature was added 3,4-dihydro-2H-pyran (5.78 g, 68.7 mmol) and p-toluenesulfonic acid monohydrate (1.00 g, 5.26 mmol). The reaction mixture was stirred at room temperature for 24 hours. It was quenched with dichloromethane and washed with 5% sodium carbonate and brine. The dichloromethane layer was dried over magnesium sulfate and concentrated. Crystallization from diethyl ether and hexane provided the title compound (8.47 g, 82% yield). 1H NMR (CDCl3) δ 8.07 (t, 1H), 7.86-7.91 (m, 2H), 7.47-7.55 (m, 2H), 7.16-7.26 (m, 2H), 5.74 (dd, 1H), 4.05 (m, 1H), 3.76 (m, 1H), 2.60 (m, 1H), 2.08-2.21 (m, 2H), 1.66-1.83 (m, 3H); ES-MS (m/z) 377 [M+3]+, 375 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:11])=[CH:4][CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[O:11][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:4][CH:3]=1
Reactant: OC1CCc2ccc(Br)cc21
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1ccc2c(c1)C(OC1CCCCO1)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
6-Bromoindan-1-ol (3.01 g) and dihydropyrane (1.78 g) are dissolved in dichloromethane (50 ml), and thereto is added pyridinium p-toluenesulfonate (178 mg), and the mixture is stirred at room temperature for 1.5 hour. The reaction solution is washed with a saturated aqueous sodium hydrogen carbonate solution, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane/ethyl acetate) to give 6-bromo-1-tetrahydropyranyloxyindane (4.10 g).
Reaction SMILES: C[Sn](N=[N+]=[N-])(C)C.[CH3:8][CH2:9][CH2:10][CH2:11][C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:29]([C:30]4[N:34]=[N:33][N:32](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:31]=4)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:15]([CH2:54][OH:55])=[C:14]([Cl:56])[N:13]=1>>[CH3:8][CH2:9][CH2:10][CH2:11][C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]3[N:34]=[N:33][NH:32][N:31]=3)=[CH:20][CH:19]=2)[C:15]([CH2:54][OH:55])=[C:14]([Cl:56])[N:13]=1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: C[Sn](C)(C)N=[N+]=[N-]
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1

Procedure:
Dupont/Merck in their patents and papers always described that trityl losartan of the formula (7) is detritylated to get Losartan. They have used trimethyl tin azide or tri alkyl tin azides for the preparation of tetrazoles. The trityl Losartan of the formula (7) is reacted with mineral acid to give Losartan of the formula (1). The trityl Losartan of the formula (7) is prepared using trimethyl or trialkyl tin azide for the formation of tetrazole nucleus.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>ClCCl>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:15](=[O:16])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCNC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of 3-methylbutylamine (20 g, 229 mmol) in 840 ml of dichloromethane were added 35.6 ml triethylamine (255 mmol) and 28.8 ml of phenyl chloroformate (230 mmol) at 0° C. The mixture was stirred for three hours at room temperature. After distilling off the solvent under reduced pressure, 200 ml of ethyl acetate and 200 ml of water were added to the residue. The organic layers were separated and water layer was extracted with ethyl acetate (100 ml×3). The organic layers were combined, washed with water and saturated sodium chloride solution successively and dried over magnesium sulfate. The solvent was distilled off and the crystals separated out were collected by filtration, and washed with petroleum ether to give 39.5 g of phenyl 3-methylbutylcarbamate (83%) as colorless crystals.
Reaction SMILES: C([S:5][CH2:6][C:7]1([C:16]([NH:18][CH2:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[O:17])[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)(C)(C)C.C1(OC)C=CC=CC=1.S>FC(F)(F)C(O)=O>[SH:5][CH2:6][C:7]1([C:16]([NH:18][CH2:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[O:17])[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1
Reactant: CC(C)(C)SCC1(C(=O)NCC(=O)OCc2ccccc2)Cc2ccccc2C1
Agent: S
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)C1(CS)Cc2ccccc2C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.6 %

Procedure:
Dissolve N-[[2-[[(t-butyl)thio]methyl]-2,3-dihydro-1H-indene-2-yl]carbonyl]-glycine, benzyl ester (262 mg, 0.64 mmol) in trifluoroacetic acid (3 mL) and add excess anisole followed by mercuric acetate (203 mg, 0.64 mmol). Stir at room temperature for 18 hours then treat with gaseous hydrogen sulfide. Partition the mixture between methylene chloride/water (150 mL). Separate the organic phase and wash with dilute brine. Dry (MgSO4) and evaporate the solvent in vacuo to give a clear oil. Purify by silica gel chromatography (30% ethyl acetate/hexane) to give the title compound as a crystalline solid (213 mg, 94%); mp 92°-93° C. (methylene chloride/hexane).
Reaction SMILES: CO[C:3]1(OC)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]2[CH2:14][CH:6]2[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[CH2:14]1[CH:7]2[CH:6]1[C:5]1[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=1[C:3](=[N:22][OH:23])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=12
Reactant: COC1(OC)c2ccccc2C2CC2c2ccccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1c2ccccc2C2CC2c2ccccc21

Procedure:
A solution of 1.5 g (5.6 moles) of 1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one dimethylketal, 2.5 g of hydroxylamine hydrochloride in 20 ml of pyridine was held at reflux for 18 hr. The solvent was removed under reduced pressure and the residue was dissolved with a mixture of water and methylene chloride. The layers were separated and the organic layer was in turn washed with 10% hydrochloric acid, saturated sodium bicarbonate solution and saturated brine, dried and solvent removed to give 1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one oxime. All of the physical properties were identical to those obtained by Example 1A. Note: The oxime forms a solvate with methanol.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH3:3].Br[C:17]1[S:21][C:20]([NH2:22])=[N:19][N:18]=1>>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:17]1[S:21][C:20]([NH2:22])=[N:19][N:18]=1)[CH3:3]
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: Nc1nnc(Br)s1
Product: CN(C)Cc1cccc(OCCCNc2nnc(N)s2)c1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-[(dimethylamino)methyl]phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2amine.