Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH3:20])=[O:18])[C@@H:14]([NH2:21])[C@H:12]1[OH:13].[C:22]([O:26][C:27]([NH:29][CH:30]([C:39](O)=[O:40])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH3:20])=[O:18])[C@@H:14]([NH:21][C:39](=[O:40])[CH:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28])[C@H:12]1[OH:13]
Reactant: COC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1N
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(Cl)c1)C(=O)O
Product: COC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1NC(=O)C(Cc1cccc(Cl)c1)NC(=O)OC(C)(C)C
Yield: 54.2 %

Procedure:
Methyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-[N-tert-butoxycarbonyl-β-(3-chlorophenyl)-D,L-alanylamino]-β-D-ribofuranuronate (312 mg) was prepared by reacting methyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronate (294 mg) prepared in Example 62 with N-tert-butoxycarbonyl-β-(3-chlorophenyl)-D,L-alanine (300 mg) according to a similar manner to that of Example 64, mp. 115°-125° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[O:6][C:5](=[O:9])[NH:4][C:3]=1[CH3:10].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[C:7](=[O:8])[O:6][C:5](=[O:9])[N:4]([CH3:11])[C:3]=1[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Cc1[nH]c(=O)oc(=O)c1Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cc1c(Cl)c(=O)oc(=O)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
At room temperature, 2.11 g of 5-chloro-4-methyl-2H-1,3-oxazine-2,6(3H)-dione, 2.07 g of potassium carbonate and 1.3 ml of methyl iodide were sequentially added to 40 ml of acetone, then the mixture was stirred for 3 hours under heat refluxing condition. To the reaction mixture was added 0.5 ml of methyl iodide, and the mixture was further stirred for 2 hours under heat refluxing condition. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The resulting solid was dried to obtain 1.74 g of 5-chloro-3,4-dimethyl-2H-1,3-oxazine-2,6(3H)-dione represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.C(N(S(F)(F)[F:32])CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([F:32])([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccncc2)C1
Solvent: ClCCl
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(F)c2ccncc2)C1
Temperature: 2.5 °C

Procedure:
1-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol (300 mg) was dissolved in DCM (10 mL) and the solution was cooled to 0 to 5° C. Diethylaminosulfur trifluoride (0.3 mL) was added and the reaction mixture was allowed to warm to RT for 30 min The reaction mixture was quenched with saturated aqueous sodium bicarbonate, the organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH3:11].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(F)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1cccc(F)c1CBr

Procedure:
3-Fluoro-2-methyl-benzoic acid methyl ester (4.3 g, 26 mmol), N-bromosuccinimide (5.0 g, 28 mmol) and AIBN (2,2′-azobisisobutyronitril) (420 mg, 2.6 mmol) were stirred at 80° C. for 10 hours in carbon tetrachloride (45 ml). The reaction solution was mixed with water and chloroform, washed with saturated sodium bicarbonate aqueous solution and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the extract under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 5.1 g (21 mmol, 81% in yield) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16](/[CH:17]=[N:1]/[C@H:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][OH:4])=[CH:15][CH:14]=1
Reactant: COc1ccc(C=O)cc1
Reactant: N[C@@H](CO)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=N/[C@@H](CO)c2ccccc2)cc1

Procedure:
A solution of (2R)-2-amino-2-phenylethanol (148 g, 1.08 mol) and 4-methoxybenzaldehyde (147 g, 1.08 mol) in toluene (2 L) was heated at reflux to remove water by Dean-Stark trap for 3 hr. The mixture was concentrated and the residue was dried which gave the title compound XIa (265 g, 96%) as a white solid, which was used for next reaction without further purification.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1B(O)O>>[CH3:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Reactant: Cc1ccncc1B(O)O
Product: Cc1ccncc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12

Procedure:
[7-(4-Methyl-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine and 4-methylpyridine-3-boronic acid in an analogous manner to Example 1031b. Product isolated as a yellow solid (55 mg, 48%). m.p.=191-193° C.; LCMS (m/e) 387 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.76-8.69 (m, 2H), 8.59-8.52 (m, 1H), 7.37 (d, 2H, J=7.40 Hz), 7.31-7.26 (m, 1H), 6.88-6.84 (m, 1H), 6.84-6.75 (m, 3H), 6.67 (s, 1H), 3.89-3.81 (m, 4H), 3.12-3.04 (m, 4H), 2.31 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1)(=O)[CH3:8].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:7]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1)[CH3:8]
Reactant: CC(=O)N1CCC(CN)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN1CCC(CN)CC1
Yield: 83.6 %

Procedure:
Lithium aluminum hydride (1.06 g) was suspended in tetrahydrofuran (70 ml) and the resultant suspension was stirred under nitrogen atmosphere under ice cooling. Next, 1-acetyl-4-aminomethylpiperidine (4.14 g). dissolved in tetrahydrofuran (30 ml) was added thereto and the resultant mixture was stirred at room temperature for 10 min and heated under reflux overnight. Then the reaction mixtures were ice-cooled and water (1.06 ml), a 5 N aqueous solution of sodium hydroxide (1.06 ml) and further water (3.18 ml) were successively added thereto. After stirring, the mixture was diluted with ethyl acetate and the insolubles were filtered off. The residue was purified by NH-silica gel column chromatography (chloroform/methanol system) to give the title compound (3.15 g) as a pale brown oil.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][NH2:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:16](OCC)(=[O:24])[C:17]#[C:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>C(O)C>[F:1][C:2]1[C:7]([N:8]2[C:16]([OH:24])=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: NNc1cccnc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(O)n(-c2cccnc2F)n1
Temperature: 25 °C
Yield: 33.7 %

Procedure:
To a solution of 2-fluoro-3-hydrazinopyridine (30.0 g) in ethanol (472 mL) were added sodium carbonate (65.2 g) and diethyl but-2-ynedioate (40.2 g). After refluxing for 18 hr, the mixture was cooled to room temperature, treated with 2 mol/L hydrochloric acid, and extracted twice with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was suspended in diethyl ether, and the obtained solid was collected by filtration and dried under reduced pressure to give the title compound as a yellow solid (yield 20.0 g, yield 34%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=O)[CH2:6][CH2:5]2.[N:13](OCCC(C)C)=O.Cl.O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH2:7][CH:6]([NH2:13])[CH2:5]2
Reactant: CC(C)CCON=O
Reactant: O=C1CCc2cc(F)c(F)cc21
Agent: Cl
Solvent: CO
Solvent: O
Product: NC1Cc2cc(F)c(F)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (4.60 g, 27.4 mmol) in MeOH (90 mL) at 40° C. was added isoamyl nitrite (4.17 g, 35.6 mmol) followed by concentrated HCl (2.7 mL). Upon heating for 45 min the solution was cooled to room temperature and water was added. Precipitated solid was collected by filtration and rinsed thoroughly with water affording 3.97 g of a light orange solid. The solid was dissolved in HOAc (100 mL), conc HCl (8 mL) was added, followed by 10% Pd/C (1.07 g). The mixture was hydrogenated under 50 psi H2 for 24 hr using a Parr hydrogenation apparatus, and filtered through a bed of Celite (CHCl3 wash). The filtrate was concentrated in vacuo and the residue was dissolved in water. The aqueous solution was basified with solid K2CO3, extracted with CHCl3 (3×), combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (MeOH/CH2Cl2) affording the title compound as a brown oil. 1H NMR (400 MHz, CDCl3) δ 6.95 (t, 2H, J=8.9 Hz), 3.83 (m, 1H), 3.10 (dd, 2H, J=15.8 & 6.8 Hz), 2.60 (dd, 2H, J=15.8 & 5.0 Hz); (M+H) 170, 0.68 min (LC/MS method A).
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[C:11]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[N:12][CH:13]=[C:14]([CH:18]=3)[C:15](O)=[O:16])[CH:8]=[CH:9][C:2]=12.[F:25][C:26]([F:35])([F:34])[C:27]1[N:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[C:11]([O:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[N:12][CH:13]=[C:14]([CH:18]=3)[C:15]([NH:33][CH2:32][C:30]3[O:29][N:28]=[C:27]([C:26]([F:35])([F:34])[F:25])[N:31]=3)=[O:16])[CH:8]=[CH:9][C:2]=12
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc3nonc3c2)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(-c2ccc3nonc3c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-benzo[1,2,5]oxadiazol-5-yl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (example CH) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; MS (ESI) 489.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=1[NH2:7].[NH2:13][CH2:14][CH2:15][C:16](O)=O.[ClH:19]>O>[OH2:1].[ClH:12].[ClH:19].[OH:1][CH2:2][CH2:3][N:4]1[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=[C:16]1[CH2:15][CH2:14][NH2:13].[OH:1][CH2:2][CH2:3][N:4]1[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=[C:16]1[CH2:15][CH2:14][NH2:13].[ClH:12].[ClH:12]
Reactant: Nc1ccc(Cl)cc1NCCO
Reactant: NCCC(=O)O
Agent: Cl
Solvent: O
Product: NCCc1nc2ccc(Cl)cc2n1CCO
Reaction time: 24 h

Procedure:
A mixture of 9.7 g. (52 mmole) 2-(2-hydroxyethylamino)-4-chloroaniline, 6.9 g. (78 mmole) β-alanine, 46 ml. concentrated hydrochloric acid and 54 ml. of water is heated at reflux with stirring for 24 hrs. After cooling, the solution is concentrated, and made basic with 10% aqueous sodium hydroxide. Continuous liquid-liquid extraction of the aqueous solution with ethyl acetate affords 9.9 g. of the product, which is converted to it hydrochloride salt. The product has a m.p. of 196°-200° C. after recrystallization from methanol/ethyl acetate.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([N:9]3[CH2:49][CH2:48][C:12]4[N:13]=[C:14]([C:27]5[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]6[C:28]=5[C:29]([CH3:47])=[N:30][N:31]6[S:37]([C:40]5[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=5)(=[O:39])=[O:38])[N:15]=[C:16]([N:17]5[CH2:22][CH2:21][C@@H:20]([O:23][CH3:24])[C:19]([CH3:26])([CH3:25])[CH2:18]5)[C:11]=4[CH2:10]3)[N:6]([CH3:50])[N:5]=2)[CH2:3][CH2:2]1.[Cl:51]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:51][C:8]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]([CH3:50])[C:7]=1[N:9]1[CH2:49][CH2:48][C:12]2[N:13]=[C:14]([C:27]3[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]4[C:28]=3[C:29]([CH3:47])=[N:30][N:31]4[S:37]([C:40]3[CH:41]=[CH:42][C:43]([CH3:44])=[CH:45][CH:46]=3)(=[O:39])=[O:38])[N:15]=[C:16]([N:17]3[CH2:22][CH2:21][C@@H:20]([O:23][CH3:24])[C:19]([CH3:25])([CH3:26])[CH2:18]3)[C:11]=2[CH2:10]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(c2cc(C4CC4)nn2C)CC3)CC1(C)C
Solvent: ClCCl
Product: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(c2c(Cl)c(C4CC4)nn2C)CC3)CC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-6-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.062 g, 0.089 mmol) in DCM (2 mL) under an atmosphere of nitrogen was added N-chlorosuccinimide (0.012 g, 0.089 mmol). The mixture was left to stir for 1 h at rt. The reaction mixture was then directly purified by FCC (40-75% EtOAc/heptanes) to give the title compound. 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 8.08 (d, J=8.3 Hz, 1 H), 7.79 (d, J=8.3 Hz, 2 H), 7.45 (d, J=8.8 Hz, 1 H), 7.25 (d, J=8.3 Hz, 2 H), 4.32 (d, J=14.7 Hz, 1 H), 4.22 (d, J=14.4 Hz, 1 H), 3.67 (d, J=11.6 Hz, 1 H), 3.58 (s, 3 H), 3.52 (dq, J=12.8, 6.3 Hz, 2 H), 3.28-3.36 (m, 4 H), 3.09 (br. s., 1 H), 2.99 (br. s., 2 H), 2.92 (dd, J=8.6, 3.8 Hz, 1 H), 2.86 (d, J=11.6 Hz, 1 H), 2.72 (s, 2 H), 2.36 (s, 3 H), 2.25 (s, 3 H), 1.88-1.96 (m, 4 H), 1.78-1.88 (m, 1 H), 1.52-1.69 (m, 3 H), 0.94 (s, 3 H), 0.81-0.90 (m, 8 H); MS (ESI+) m/z 729.4 (M+H)+.
Reaction SMILES: O.[OH-].[Na+].[S:4](Cl)([C:7]1[CH:13]=[CH:12][C:10]([CH3:11])=[CH:9][CH:8]=1)(=[O:6])=[O:5].C(O)(=[O:17])C>O1CCCC1>[CH3:11][C:10]1[CH:9]=[CH:8][C:7]([S:4]([OH:17])(=[O:6])=[O:5])=[CH:13][CH:12]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84731.5 %

Procedure:
To water (288 mL), sodium hydroxide (180 g, 4.5 mol, 5.0 eq) was added. At 0° C., methanol-d3 (32.4 g, 900 mmol, 1.0 eq) was added, and the solution of tosyl chloride (206 g, 1.1 mmol, 1.2 eq) in tetrahydrofuran (288 mL) was dropwise added slowly. The mixture was warmed to room temperature and stirred overnight. The mixture was neutralized to neutral by dropwise adding acetic acid (206 g) at 25° C., filtered and partitioned. The aqueous phase was extracted with ethyl acetate (100 mL). The filter cake was dissolved in water (300 mL) and extracted with ethyl acetate (200 mL). The organic phases were combined and washed with saturated sodium carbonate (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent in the filtrate was removed under reduced pressure to afford the title compound (160.5 g, purity 99%, yield 94%) as a pale yellow liquid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:32]=[C:31]4[C:27]([C:28]([CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])=[CH:29][N:30]4[CH3:33])=[CH:26][CH:25]=3)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:32]=[C:31]4[C:27]([C:28]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:29][N:30]4[CH3:33])=[CH:26][CH:25]=3)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)OC(C)(C)C)cn(C)c4c3)no2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)O)cn(C)c4c3)no2)cc1Cl
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
Trifluoroacetic acid (0.878 mL) was added to a solution of 1,1-dimethylethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoate (D18) (113 mg) in dichloromethane (1.5 mL) at RT. The resulting solution was stirred for 30 min. The reaction mixture was concentrated. The residue was recrystallized from dichloromethane/ether to afford 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoic acid (E6) (55 mg) as a white solid. MS (ES) C23H22ClN3O4 requires 439; found 440.0 (M+H+).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[O:17][N:16]=[C:15]([CH2:18][O:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1>ClCCl>[Cl:4][C:14]1[C:15]([CH2:18][O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[N:16][O:17][C:13]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CS(=O)(=O)OCc1cc(-c2cccc(Cl)c2)on1
Solvent: ClCCl
Product: CS(=O)(=O)OCc1noc(-c2cccc(Cl)c2)c1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Sulfuryl chloride (1 ml) was added to methanesulfonic acid 5-(3-chloro-phenyl)-isoxazole-3-ylmethyl ester (200 mg, 0.70 mmol) and then stirred at 60° C. overnight. The reaction mixture was diluted with dichloromethane, washed saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to afford methanesulfonic acid 4-chloro-5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester (219 mg, 97%, light brown solid). 1H NMR (CDCl3) d (ppm): 8.07 (m, 1H), 7.92 (m, 1H), 7.50 (m, 2H), 5.38 (s, 2H), 3.16 (s, 3H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([C:23]4[N:27]=[N:26][N:25](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:24]=4)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[C:8]([CH2:47][OH:48])=[C:7]([Cl:49])[N:6]=1.Cl.[OH-].[Na+]>CO>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][NH:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:47][OH:48])=[C:7]([Cl:49])[N:6]=1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 10 °C
Yield: 88.5 %

Procedure:
In the last step, trityl losartan was suspended in methanol and cooled to ˜10° C. 3.4 N Hydrochloric acid was added to the slurry. After a period of time, the pH of the reaction mixture was raised to 13 with 10 N NaOH. Methanol was then distilled off while makeup water was added. After distillation, additional water and toluene were added. The toluene phase was separated and the aqueous phase was extracted once more with toluene. Ethyl acetate and acetic acid were then added to the aqueous phase. Losartan was recovered from the aqueous phase as a solid and further purified by slurrying in ethyl acetate. Losartan was obtained in 88.5% yield and 98.8% purity as determined by HPLC. This process is also described in U.S. Pat. Nos. 5,128,355 and 5,155,188.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[N:22][C:21]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:20]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:32][CH:31]=2)[CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[N:23]=[N:22][C:21]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[C:20]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:34][CH:35]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CCCCC2)nn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCCCC3)nn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.40 mmol, 0.08 g) in THF (0.45 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (0.54 mmol, 0.022 g) and continued stirring for 10 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 6-chloro-3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-pyridazine (0.27 mmol, 0.10 g) in THF (0.45 mL). After completion of addition, the reaction mixture was warmed to 65° C. and stirred for 2 hours. After cooling the reaction to room temperature, the reaction was quenched with water (1 mL) and extracted with ethyl acetate (1×2 mL). The ethyl acetate layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 4 g SiO2 cartridge eluting with an ethyl acetate/hexanes gradient to give 4-[6-cyclohexyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 81%). To a solution of 4-[6-cyclohexyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.22 mmol, 0.12 g) in DCM (1.5 mL) was added 4 N HCl in dioxane (0.5 mL) and the reaction was stirred for 30 min. The solvents were removed under reduced pressure and the residue was triturated with anhydrous ethyl ether (50 mL) and filtered to give 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.095 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.CS(O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)=O.CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>CCCCCC.CCOC(C)=O.O>[O:8]=[C:4]1[CH:3]=[C:2]([O:1][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:7]=[CH:6][NH:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=c1cc(O)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc[nH]c(=O)c2)CC1
Temperature: 25 °C
Yield: 16.5 %

Procedure:
To 4-hydroxypyridin-2(1H)-one (11.11 g, 100 mmol) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (27.9 g, 100 mmol) in a 100 mL round bottom flask was applied vacuum 5 minutes, vented to nitrogen, added DMSO (100 mL), and then added potassium carbonate (13.20 g, 220 mmol). Placed in a 90° C. oil bath under nitrogen for 4.5 hours. The reaction mixture was added to 1000 mL water and 1000 mL EtOAc, then washed EtOAc with additional water (4×500 mL), dried with MgSO4, filtered and concentrated to 27.3 g oily white solids. This material was slurried 200 mL refluxing EtOAc, allowed to cool to rt, filtered, and washed with 2×50 mL EtOAc then 2×50 mL of hexane to give product (4.86 g, 16.5 mmol, 17%) as a white crystalline powder. MS (ESI) 239.1 (M+1−56, indicating loss of t-butyl group the Boc group in the MS).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:26](O)[CH2:27][CH2:28][Cl:29]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:26][CH2:27][CH2:28][Cl:29])=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(O)cc2)C=CC=CC1
Reactant: OC(Br)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(OCCCCl)cc2)C=CC=CC1

Procedure:
Following the procedure described in example 47§D, but starting from 4′-hydroxybiphenyl-1-carboxylic acid ethyl ester (3 g), potassium carbonate (8.55 g) and 1-bromo-3-chloropropanol (6 mL) in N,N-dimethylformamide (30 mL) affords 4′-(3-chloropropoxy)biphenyl-1-carboxylic acid ethyl ester in quantitative yield used without further purification.