Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([I:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: O=c1[nH]c2ccc(I)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccc(I)cc2[nH]1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
5-Iodo-1,3-dihydro-2H-1,3-benzimidazol-2-one (7 g) [see Preparation 24] was added to a solution of phosphoryl chloride (135 ml). The reaction mixture was then heated to 120° C. and stirred for 2 hours, after which time the phosphoryl chloride was removed under reduced pressure and the residue diluted with water. The residual aqueous solution was neutralised with aqueous potassium hydrogen carbonate solution and the product extracted with 90:10, by volume, dichloromethane:methanol, dried over magnesium sulphate and the solvent removed under reduced pressure to afford 2-chloro-6-iodo-1H-1,3-benzimidazole (3.68 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:21][O:20][C:11]1[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=1[C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:33][CH:34]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(OCCN4CCOCC4)cc3)nc12

Procedure:
[8-(2-methoxy-5-trifloromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.150 g, 0.5 mmol), and 4-(morpholin-4-yl-ethoxy)-phenylamine (0.130 g, 0.58 mmol) in a manner analogous to Example 2d. Product was isolated as a foam (0.19 g, 81%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=6.8 Hz, 1H), 7.96 (s, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.55 (d, J=5.7 Hz, 1H), 7.51-7.46 (m, 2H), 7.12 (d, J=7.9 Hz, 1H), 6.94-6.89 (m, 1H), 6.77 (d, J=6.8 Hz, 1H) 6.71 (s, 1H) 6.65 (d, J=7.9 Hz, 1H), 4.15-4.03 (m, 2H), 3.89 (s, 3H), 3.78-3.71 (m, 4H), 2.86-2.76 (m, 2H), 2.64-2.56 (m, 4H). MS=514 (MH)+.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]([OH:11])=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][N:2]2[CH2:3][CH2:4][O:5][CH2:6][CH2:7]2)[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[O:15])=[CH:35][CH:36]=1
Reactant: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCOCC1
Agent: Cl
Product: O=C(CN1CCOCC1)N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 55 %

Procedure:
Proceeding as in Example 1, but substituting 2-morpholin-4-ylacetic acid hydrochloride and (S)-2-amino-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 210, (S)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-morpholinoacetamido)propanamide (60 mg, 55%). 1H-NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 8.00 (s, 1H), 7.37-7.25 (m, 5H), 7.10-6.90 (m, 7H), 4.79-4.73 (m, 1H), 4.63 (m, 2H), 4.00-3.80 (m, 6H), 3.20-3.10 (s, 2H), 2.60-2.45 (m, 4H). MS (EI) for C28H29F2N3O5 found 526 (MH+).
Reaction SMILES: [C:1]([N:4]([CH2:8][C:9]1[C:18]2[O:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([CH3:25])[C:14](=[O:26])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH2:5][CH2:6][Cl:7])(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:7].[C:1]([N:4]([CH2:8][C:9]1[C:18]2[O:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([CH3:25])[C:14](=[O:26])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH2:5][CH2:6][N:38]1[CH2:37][CH2:36][N:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[O:28][CH3:27])[CH2:40][CH2:39]1)(=[O:3])[CH3:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(=O)N(CCCl)Cc1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(CCN(Cc2cccc3c(=O)c(C)c(-c4ccccc4)oc23)C(C)=O)CC1
Product: Cl
Reaction time: 2 h
Yield: 57.9 %

Procedure:
A mixture of 5 g of Intermediate XXXIII and 5.3 g of 1-(2-methoxyphenyl)-piperazine in 75 ml of dimethylformamide was stirred at 95 C for 2 hours. After cooling to 20°-25° C., the reaction mixture was poured into 200 ml of water, made alkaline with potassium carbonate and extracted with ethyl acetate. The organic phase was washed with water and dried on anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane:methanol (100:0.2). Salification of the pure base with ethanolic hydrogen chloride and recrystallization from methanol gave 4.4 g of the title compound, melting at (200) 227-°228° C. and containing one equivalent of methanol.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[NH2:13][C:14]1[S:15][CH:16]=[C:17]([CH3:19])[N:18]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:13][C:14]3[S:15][CH:16]=[C:17]([CH3:19])[N:18]=3)[N:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1ccc2ccnc(Cl)c2n1
Reactant: Cc1csc(N)n1
Product: Cc1csc(Nc2nccc3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=257.2 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-2-methyl-[1,7]naphthyridine (Example E) and 2-amino-4-methylthiazole.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)([O-:3])=[O:2].Br[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(C(C)=O)C>[CH2:22]([O:21][C:19]([C:18]1[N:15]=[C:12]2[N:11]([CH:17]=1)[C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[CH:14][S:13]2)=[O:20])[CH3:23]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1nc(-c2ccccc2[N+](=O)[O-])cs1
Solvent: CCC(C)=O
Product: CCOC(=O)c1cn2c(-c3ccccc3[N+](=O)[O-])csc2n1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
4-(2-Nitro-phenyl)-thiazol-2-ylamine (1.60 g, 7.2 mmol) was mixed with 50 mL of methyl ethyl ketone along 0.90 mL of ethyl bromopyruvate (7.2 mmol) and stirred under reflux for 24 hours. Another equivalent of ethyl bromopyruvate (0.90 mL, 7.2 mmol) was added and the reaction mixture was stirred under reflux for another 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by chromatography (Isco, gradient elution, CH2Cl2 to 95% CH2Cl2, 5% MeOH) to afford 1.2 g of 3-(2-nitro-phenyl)-imidazo[2,1-b]thiazole-6-carboxylic acid ethyl ester (52% yield).
Reaction SMILES: [C:1]([CH:4]([CH:10](C)[C:11](=O)[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].C([O-])(=O)C.[NH4+:23]>>[CH3:2][C:1]1[NH:23][C:11]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C(C)=O)C(C)C(=O)c1ccsc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: CCOC(=O)c1cc(-c2ccsc2)[nH]c1C
Yield: 96.3 %

Procedure:
Using ethyl 2-acetyl-3-methyl-4-oxo-4-(3-thienyl)butanoate (1.86 g) and ammonium acetate (626 mg), a procedure as in Reference Example 14 was performed to give the title compound as a brown oil (yield 1.57 g, 91%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH3:7])=[O:3].[OH:8][OH:9].[OH-:10].[Na+].[Na+].[Cl-]>>[CH2:5]([O:4][C:2]([O:8][O:9][C:2]([O:4][CH2:5][CH2:6][CH3:7])=[O:10])=[O:3])[CH2:6][CH3:7]
Reactant: [OH-]
Reactant: CCCOC(=O)Cl
Reactant: OO
Agent: [Cl-]
Agent: [Na+]
Product: CCCOC(=O)OOC(=O)OCCC

Procedure:
Using the apparatus (i.e., both centrifuges 18 and 30) and procedure of Example I (except that the temperature of reactor 14 is 25 ± 1° C.), NPP is prepared at the rate of 50 pph in an average assay of greater than 98% from 85 pph of n-propyl chloroformate, 31 pph of 50% aqueous H2O2, 169 pph of 20% NaOH and 50 pph of saturated NaCl solution.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[CH:5][C:4]=1F)#[N:2].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[SH:25].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CS(C)=O>[C:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[CH:5][C:4]=1[S:25][C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[Cl:17])#[N:2]
Reactant: Cc1nccn1Cc1ccc(C#N)c(F)c1
Reactant: Sc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nccn1Cc1ccc(C#N)c(Sc2ccc(Cl)cc2Cl)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of the product From Step C (417 mg, 1.94 mmol) and 2,4-dichlorothiophenol (348 mg, 1.94 mmol) in 7.0 mL of DMSO was added cesium carbonate (1.26 g, 3.88 mmol). The reaction was warmed to 60° C. under argon and stirred for three hours. The solution was poured into EtOAc and washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was purified by silica gel chromatography (3-4% MeOH/CH2Cl2) to provide the product as a brown foam.
Reaction SMILES: [CH:1]1([C:7]2[CH:28]=[CH:27][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[CH:24]=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29](Cl)(=[O:33])[C:30](Cl)=[O:31].[CH2:35]1[CH2:40][CH2:39][N:38]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>ClCCl>[N:38]1([CH:41]2[CH2:46][CH2:45][N:44]([C:29](=[O:33])[C:30]([C:24]3[N:16]4[C:15]([CH2:14][N:13]([C:11](=[O:12])[C:10]5[CH:27]=[CH:28][C:7]([CH:1]6[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]6)=[CH:8][CH:9]=5)[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[CH2:17]4)=[CH:26][CH:25]=3)=[O:31])[CH2:43][CH2:42]2)[CH2:39][CH2:40][CH2:35][CH2:36][CH2:37]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: ClCCl
Product: O=C(C(=O)N1CCC(N2CCCCC2)CC1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.1 %

Procedure:
To a stirred solution of 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Example 4 (1.0 g) in dichloromethane (20 mL) was added oxalyl chloride (0.34 g). The reaction mixture was allowed to stir at room temperature for three hours, and then 4-(1-piperidino) piperidine (0.91 g) was added. After stirring overnight at room temperature, the mixture was washed with water and saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol® and the eluate refluxed with the slow addition of hexane to provide the title compound as pale pink crystals (0.43 g), m.p. 190–195° C.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].F[C:15]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:16]=1[NH:17][S:18]([CH3:21])(=[O:20])=[O:19].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH:1]([NH:4][CH2:5][CH2:6][O:7][C:15]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:16]=1[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])([CH3:3])[CH3:2]
Reactant: CC(C)NCCO
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)NCCOc1ccc([N+](=O)[O-])cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
2-(Isopropylamino)ethanol (24,0 g) solution in dimethylformamide (70 ml) was added with potassium tert-butoxide (21.9 g) in an ice bathing. After being stirred for 1 hour at room temperature, the reaction mixture was cooled down to 5° C. and added drop-wise with 2′-fluoro-5′-nitromethanesulfonanilide (21.8 g) in dimethylformamide (30 ml). After being stirred for 3 hours at room temperature, the reaction mixture was added into ethyl acetate (500 ml) and solids formed were collected by filtration and washed with ethyl acetate (100 ml). Solids obtained were dissolved into water (200 ml) and the solution was adjusted to pH=7 with 2N HCl . Resultant crystals were collected by filtration, washed with water, and dried under vacuum to obtain 2′-[2-(isopropylamino)ethoxy]-5′-nitromethanesulfonanilide (26.1 g) as white crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O.CO>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1ccccc1N

Procedure:
The appropriate 2-nitrobenzoic acid was initially reacted in analogy to general methods 2 and 5 with the particular amine to give a 2-nitrobenzamide. Subsequently, 4 mmol of the 2-nitrobenzamide were hydrogenated in 50 ml of THF and 50 ml of methanol in the presence of a spatula tip of 10% palladium on carbon at RT under atmospheric pressure. The catalyst was filtered off with suction, the reaction mixture was concentrated, and the appropriate 2-aminobenzamide was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[N+:11]([O-:14])(O)=[O:12].[CH3:15][C:16](OC(C)=O)=[O:17]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:16](=[O:17])[CH3:15])=[CH:4][C:3]=1[N+:11]([O-:14])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CCO)cc1
Product: CC(=O)OCCc1ccc(N)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
2-(4-Aminophenyl)ethanol (186) (Aldrich, 26,164-5) (2.4 g, 17.5 mmol) was dissolved in Ac2O (12 mL) and chilled to 0° C. before addition of concentrated HNO3 (2.5 mL). The colorless solution turned red as it was stirred at 0° C. After stirring for 10 min, the reaction was quenched by addition of ice cold water (50 mL). The resulting biphasic mixture was stirred for 0.5 h to provide for 187 as a solid. The solid was recovered by filtration and recrystallized from methanol to give 187 (2.13 g) as a crystalline solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:7][C:8]1[C:9]([CH2:15][CH3:16])=[N:10][NH:11][C:12]=1[CH2:13][CH3:14].[H][H].Br[CH2:24][C:25]#[N:26]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:7][C:8]1[C:12]([CH2:13][CH3:14])=[N:11][N:10]([CH2:24][C:25]#[N:26])[C:9]=1[CH2:15][CH3:16]
Reactant: N#CCBr
Reactant: CCc1n[nH]c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(CC#N)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Yield: 94 %

Procedure:
Sodium hydride (60% dispersion in oil, 470 mg, 11.8 mmol) was added to a stirred solution of 4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole (3 g, 10.5 mmol, Example 3) in dry N,N-dimethylformamide (20 ml) at 0° C. under nitrogen. The mixture was stirred for 5 minutes during which time hydrogen was evolved and then bromoacetonitrile (0.81 ml, 11.6 mmol) was added. The yellow solution turned dark brown and a precipitate formed. Further dry N,N-dimethylformamide (5 ml) was added to aid dissolution and after 45 minutes the reaction mixture was quenched by the addition of water (1 ml). The mixture was partitioned between water (150 ml) and diethyl ether (2×150 ml). The combined organic layers were washed with water (50 ml) and brine (100 ml), dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane to provide the title compound (3.2 g) as a yellow powder, m.p. 70–72° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([N:24]=[C:25]=[S:26])[CH2:5][O:6][Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:28][CH:29]1[CH2:32][NH:31][CH2:30]1>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:27])[C@@H:4]([NH:24][C:25]([N:31]1[CH2:32][CH:29]([OH:28])[CH2:30]1)=[S:26])[CH2:5][O:6][Si:7]([C:20]([CH3:23])([CH3:21])[CH3:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC1CNC1
Reactant: COC(=O)C(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N=C=S
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=S)N1CC(O)C1
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of 3-(t-butyldiphenylsilyloxy)-2-isothiocyanatopropionic acid methyl ester (13.4 g, 33.5 mmol) (obtained as described in Reference Example 70(1)) in tetrahydrofuran (245 ml) was added a solution of 3-hydroxyazetidine (4.90 g, 67.1 mmol) (obtained as described in Reference Example 31(1)) in water (50 ml) at room temperature and the mixture was stirred overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene and toluene:acetonitrile (3:1) as the eluant to afford (2S)-3-(t-butyldiphenylsilyloxy)-2-[(3-hydroxyazetidine-1-carbothioyl)amino]propionic acid methyl ester (9.60 g, yield 61%) as an yellow solid.
Reaction SMILES: C[Si](C[Li])(C)C.[Li].ClC[Si](C)(C)C.[CH3:14][C:15]1[C:16](=O)[C:17]([CH3:25])([CH3:24])[CH2:18][CH:19]2[C:23]=1[O:22][CH2:21][O:20]2.[O:27]1CCC[CH2:28]1>CCCCC>[CH2:25]=[CH:17][CH2:18][CH2:19][C:23]([OH:27])=[O:22].[CH3:14][C:15]1[C:16](=[CH2:28])[C:17]([CH3:25])([CH3:24])[CH2:18][CH:19]2[C:23]=1[O:22][CH2:21][O:20]2
Reactant: CC1=C2OCOC2CC(C)(C)C1=O
Reactant: C1CCOC1
Agent: C[Si](C)(C)CCl
Agent: [Li]
Agent: [Li]C[Si](C)(C)C
Solvent: CCCCC
Product: C=C1C(C)=C2OCOC2CC1(C)C
Product: C=CCCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
The solution of trimethylsilylmethyllithium (about 0.43 mol) prepared from 8.7 g (1.25 mol) of lithium powder and 74 ml (61.6 g, 0.5 mol) of chloromethyltrimethylsilane in 450 ml of pentane was placed in a 750 ml four-necked sulphonation flask provided with a magnetic stirrer, dropping funnel, condenser and argon gasification. Then a solution of 60.0 g (0.33 mol) of 4,6,6-trimethyl-5,6,7,7a-tetrahydro-1,3-benzodioxol-5-one in 75 ml of tetrahydrofuran was added dropwise thereto at −20° C. within 30 minutes. The mixture was warmed slowly to room temperature and subsequently the pentane was distilled off up to the boiling point 62° C. over a Vigreux column. The pentane, which was distilled off, was replaced continuously with 500 ml of tetrahydrofuran. Finally, the mixture was heated at reflux for 12 hours under GC control. Subsequently, it was cooled to 0° C., 200 ml of water were added dropwise, the phases were separated and the aqueous phase was extracted three times with 100 ml of pentane each time. The entire organic phase was washed with 150 ml of saturated sodium bicarbonate solution and sodium chloride solution, dried over anhydrous sodium sulphate, filtered and concentrated. This gave 67.5 g of a yellow oil, which was distilled over a 10 cm packed column. At a boiling temperature of 38° C./0.04 mbar (4 Pa) there were obtained 49.0 g (82% yield) of 4,6,6-trimethyl-5,6,7,7a-tetrahydro-5-methylidene-1,3-benzodioxol as a colorless oil. The analytical data of the product were the same as those of the product of Example 7.
Reaction SMILES: [CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[C:31]([CH2:42]Br)[CH:30]=1)=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[C:31]([CH2:42][O:24][C:21]2[CH:20]=[CH:19][C:18]([C:8]3[CH:9]=[N:10][C:11]4[N:12]([N:13]=[CH:14][C:15]=4[C:16]#[N:17])[C:7]=3[CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:23][CH:22]=2)[CH:30]=1)=[O:28]
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(CBr)c1
Reactant: N#Cc1cnn2c(C3CCCCC3)c(-c3ccc(O)cc3)cnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(COc2ccc(-c3cnc4c(C#N)cnn4c3C3CCCCC3)cc2)c1

Procedure:
Alkylation of 7-cyclohexyl-6-(4-hydroxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile with 2-bromomethyl-4′-chloro-biphenyl-4-carboxylic acid methyl ester was carried out in dimethylformamide (DMF) using cesium carbonate and following a previously described experimental procedure to give 4′-chloro-2-[4-(3-cyano-7-cyclohexyl-pyrazolo[1,5-a]pyrimidin-6-yl)-phenoxymethyl]-biphenyl-4-carboxylic acid methyl ester. This compound was converted to its corresponding tetrazole 4′-chloro-2-{4-[7-cyclohexyl-3-(1H-tetrazol-5-yl)-pyrazolo[1,5-a]pyrimidin-6-yl]-phenoxymethyl}-biphenyl-4-carboxylic acid methyl ester (475) via a previously described procedure. Finally, 4′-chloro-2-{4-[7-cyclohexyl-3-(1H-tetrazol-5-yl)-pyrazolo[1,5-a]pyrimidin-6-yl]-phenoxymethyl}-biphenyl-4-carboxylic acid (490) was obtained following a standard LiOH saponification protocol.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:7][OH:8])[CH2:4][CH2:5][OH:6].CO[C:11](OC)([CH3:13])[CH3:12].C(N(CC)CC)C>O1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:6][CH2:5][CH2:4][CH:3]1[CH2:7][O:8][C:11]([CH3:13])([CH3:12])[O:1][CH2:2]1
Reactant: COC(C)(C)OC
Reactant: OCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CCO)CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
To a solution of 1,4-dihydroxy-2-hydroxymethylbutane (12 g, 100 mmol) in tetrahydrofuran (25 ml), 2,2-dimethoxypropane (13.5 g, 110 mmol) and p-toluenesulphonic acid monohydrate (0.57 g, 3 mmol) were added. The solution was stirred for 0.5 hour at room temperature and was then neutralised by addition of triethylamine. The solvent was removed and the residue purified by column chromatography on silica gel eluting with chloroform.-methanol mixtures to afford 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan as a clear colourless liquid (6.5 g, 41%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([O:11][CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH2:1]([NH:8][C:9](=[O:10])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:14]1[CH2:15][CH2:16][C:12](=[O:11])[CH2:13]1
Reactant: O=C(NCc1ccccc1)OC1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)NCc1ccccc1
Product: O=C1CCNC1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a solution of 31.6 g (0.14 mmol) of 3-pyrrolidinol benzyl carbamate, from Step 1, in 275 mL of DMSO cooled to 0° C. was added 159.25 mL (1.12 mmol) of triethylamine. To this solution, maintained at 0° C. with stirring, was added dropwise over a one hour period a solution of 68.18 g (0.42 mmol) of sulfur trioxide pyridine complex in 250 mL of DMSO. The solution was stirred an additional half-hour at 0° C., then the ice bath was removed and the reaction allowed to proceed for 20 hours at room temperature. The DMSO solution was then poured into 1 L of 20% sodium chloride solution and the product was extracted with three washings of methylene chloride. The methylene chloride solution was washed with 20% NaCl solution to remove excess DMSO, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by evaporation. The dark liquid residue was distilled in a kugelrohr apparatus (140°-160° C. @ 5 Torr) and further purified by chromatography on silica gel (solvent 0.5-2.0% methanol in chloroform) to afford the title compound, MS M/Z 220 (M+H); NMR: d 2.61 (t,2H, J=7.5 Hz), 3.82 (s, 2H), 3.85 (t, 2H, J=7.5 Hz), 5.18 (s, 2H), 7.37 (m, 5H).