Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[C:8]([O-])([O-:10])=[O:9].[K+].[K+].C(=O)=O.Cl>O>[Cl:1][C:2]1[N:3]=[C:4]([C:8]([OH:10])=[O:9])[NH:5][C:6]=1[Cl:7]
Reactant: O=C([O-])[O-]
Reactant: Clc1nc[nH]c1Cl
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1nc(Cl)c(Cl)[nH]1
Temperature: 200 °C
Reaction time: 10 h
Yield: 75.1 %

Procedure:
A mixture of 137 g (1 mol) of 4,5-dichloroimidazole, 414 g (3 mol) of K2CO3 and 1,000 ml of carbon dioxide was stirred in an autoclave at 200° C. under autogenous pressure for 10 hours. The solid output was pulverized, suspended in 2 1 of water and brought to pH 3-4 with concentrated hydrochloric acid while being cooled with ice. The resulting precipitate was filtered off and recrystallized from water to give 136 g (75%) of 4,5-dichloroimidazole-2-carboxylic acid (Compound No. 1); mp. 240° C. (dec.).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1[OH:35])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(Cl)Cl.[CH2:39]([O:41][C:42]([C:44]1[CH:45]=[C:46]([N:50]2[C:54]([SH:55])=[N:53][N:52]=[N:51]2)[CH:47]=[CH:48][CH:49]=1)=[O:43])[CH3:40].S(Cl)(Cl)(=O)=O>ClCCl>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[CH:34]=[C:33]([S:55][C:54]2[N:50]([C:46]3[CH:47]=[CH:48][CH:49]=[C:44]([C:42]([O:41][CH2:39][CH3:40])=[O:43])[CH:45]=3)[N:51]=[N:52][N:53]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1[OH:35])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1ccc2ccccc2c1O
Reactant: CCOC(=O)c1cccc(-n2nnnc2S)c1
Agent: ClSCl
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1cc(Sc2nnnn2-c2cccc(C(=O)OCC)c2)c2ccccc2c1O
Reaction time: 5 h
Yield: 77.5 %

Procedure:
22.8 g of 2-(2-tetradecyloxyphenyl)carbamoyl-1-naphthol was dissolved in 100 ml of dichloromethane and to the solution was added dropwise at room temperature a dichloromethane solution of the sulfenyl chloride prepared from 25 g of 1-(3-ethoxycarbonylphenyl)-5-mercaptotetrazole and 13.5 g of sulfuryl chloride. After the completion of the addition, the mixture was stirred for 5 hours and the dichloromethane solution was washed with an aqueous solution of sodium hydrogencarbonate and then with water. The dichloromethane was distilled off under reduced pressure and the residue was crystallized from methanol to obtain 26.9 g of 2-(2-tetradecyloxyphenyl)carbamoyl-4-[1-(3-ethoxycarbonylphenyl)-5-tetrazolylthio]-1-naphthol. Yield: 74.3%. Melting Point: 88° to 90° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=3[CH3:24])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[CH2:32]([NH:34][CH2:35][CH2:36]O)[CH3:33].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(OCC)C>[CH2:32]([NH:34][CH2:35][CH2:36][O:23][C:19]1[CH:18]=[C:17]([CH3:24])[C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][C:6]3[CH:5]=[CH:4][C:3]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:2]([F:1])[CH:7]=3)[CH:11]=2)=[C:21]([CH3:22])[CH:20]=1)[CH3:33]
Reactant: CCNCCO
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCNCCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)OCC)c(F)c3)c2)c(C)c1
Yield: 89.3 %

Procedure:
To a solution of ethyl 3-{2-fluoro-4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (0.50 g, 1.18 mmol), 2-ethylaminoethanol (0.10 mL, 1.30 mmol) and tributylphosphine (0.44 mL, 1.78 mmol) in tetrahydrofuran (10 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.45 g, 1.78 mmol) at room temperature with stirring. The reaction mixture was stirred at room temperature for 16 hrs. An equivalent amount of the aforementioned reagents (2-ethylaminoethanol, tributylphosphine and 1,1′-(azodicarbonyl)dipiperidine) were added and the mixture was further stirred at the same temperature for 16 hrs. Diethyl ether was added to the reaction mixture and insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (gradient cycle A) to give a colorless oil. The obtained oil was dissolved in ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate, washed with water and saturated brine, dried and concentrated under reduced pressure to give the title compound (0.52 g, yield 58%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].[F:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([CH2:21][O:22][C:23]3[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=3)[NH2:26])=[N:18]2)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([CH2:21][O:22][C:23]3[CH:24]=[C:25]([NH:26][C:6](=[O:8])[CH2:7][C:2]([CH3:9])([CH3:1])[C:3]([OH:5])=[O:4])[CH:27]=[CH:28][CH:29]=3)=[N:18]2)=[CH:13][CH:12]=1
Reactant: Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1
Reactant: CC1(C)CC(=O)OC1=O
Product: CC(C)(CC(=O)Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1)C(=O)O

Procedure:
The title compound is prepared analogously to the compound described in Example 20 from 2,2-dimethylsuccinic acid anhydride and 3-(7-fluoro-2-quinolinylmethoxy)aniline; colourless crystals of m.p. 209°-210°.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([CH2:32][OH:33])[CH:29]=[CH:30][CH:31]=2)O1>>[OH:33][CH2:32][C:28]1[CH:27]=[C:26]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][N:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CC1(C)OB(c2cccc(CO)c2)OC1(C)C
Reactant: O=C(Nc1cc2cnc(Cl)cc2cn1)C1CC1
Product: O=C(Nc1cc2cnc(-c3cccc(CO)c3)cc2cn1)C1CC1

Procedure:
The title compound was prepared following a procedure similar to example 162 using N-(7-chloro-2,6-naphthyridin-3-yl)cyclopropanecarboxamide and (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][Cl:11])=[CH:5][C:4]=1[CH3:12].[CH2:13]([O:15][P:16]([O:20]CC)[O:17][CH2:18][CH3:19])[CH3:14]>>[Cl:11][CH2:10][C:6]1[CH:5]=[C:4]([CH3:12])[C:3]([CH2:2][P:16]([O:17][CH2:18][CH3:19])([O:15][CH2:13][CH3:14])=[O:20])=[CH:8][C:7]=1[CH3:9]
Reactant: CCOP(OCC)OCC
Reactant: Cc1cc(CCl)c(C)cc1CCl
Product: CCOP(=O)(Cc1cc(C)c(CCl)cc1C)OCC
Temperature: 130 °C

Procedure:
2,5-Bis(chloromethyl)-p-xylene (25 mmol) and triethylphosphite (10 mmol) were combined and heated to 130° C. under a nitrogen atmosphere for 24 hours. The reaction mixture was chromatographed on silica gel (175 gm). The column was eluted with dichloromethane until the excess starting material eluted. The eluting solvent was then changed to 5% ethanol/dichloromethane whereupon the product eluted The appropriate fractions were pooled and concentrated on a rotatory evaporator to give the product as an oil.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25]1)=[O:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Yield: 91.9 %

Procedure:
To a solution of tert-butyl 3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate 37 (0.15 g, 0.34 mml) in methanol (15 mL) was added 5% Pd/C (0.3 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate 38 (0.11 g, 91%) as a colorless foam.
Reaction SMILES: CC(N([C@H](C)C([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[C:25]3[C:26]([CH3:30])([CH3:29])[CH2:27][O:28][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1)=O)C(=O)[O-])(C)C.CC(OC(N[C@@H](C(O)=O)C)=O)(C)C.[CH3:45][C:46]([O:49][C:50]([NH:52][C@H:53]([CH2:57][CH3:58])[C:54]([OH:56])=O)=[O:51])([CH3:48])[CH3:47]>>[CH3:29][C:26]1([CH3:30])[C:25]2[C:20]([O:19][C:16]3[N:15]=[CH:14][C:13]([NH:12][C:54]([C@H:53]([NH:52][C:50](=[O:51])[O:49][C:46]([CH3:45])([CH3:47])[CH3:48])[CH2:57][CH3:58])=[O:56])=[CH:18][CH:17]=3)=[CH:21][CH:22]=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@H](C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1)N(C(=O)[O-])C(C)(C)C
Agent: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1

Procedure:
The title compound was made in a similar fashion to the preparation of Intermediate 60 replacing N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-alanine with (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (66.6 mg). This afforded 78 mg of the title compound.
Reaction SMILES: O.[OH:2][C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:14])(=[O:13])[N:5]([CH3:15])[C:4]=1[C:16]1[NH:20][N:19]=[N:18][N:17]=1.O[C:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2S(=O)(=O)N(C)C=1C1NN=NN=1.C(=O)([O-])[O-].[K+].[K+].C(Br)C1C=CC=CC=1.Cl>CN(C)C=O>[OH:2][C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:13])(=[O:14])[N:5]([CH3:15])[C:4]=1[C:16]1[N:20]=[N:19][N:18]([CH2:22][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:26]=2)[N:17]=1
Reactant: CN1C(c2nnn[nH]2)=C(O)c2ccccc2S1(=O)=O
Agent: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(c2nnn(Cc3ccccc3)n2)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 144.8 %

Procedure:
To a solution of 4-hydroxy-2-methyl-3-(5-tetrazolyl)-2H-1,2-benzothiazine 1,1-dioxide hemihydrate (18.0 g) and potassium carbonate (4.32 g), in N,N-dimethylformamide (63 ml) was added benzylbromide (7.81 ml). After being stirred for 16 hours at room temperature, the mixture was poured into 1N HCl (500 ml) with stirring. The resulting solids were filtered off and washed with water (100 ml) and then with petroleum ether (50 ml). The wet solids were recrystallized from toluene (150 ml) to give 4-hydroxy-3-[(2-benzyl)tetrazol-5-yl]-2-methyl-1,2-benzothiazine 1,1-dioxide (16.70 g). The mother liquor contains the said compound and its 1-benzyl isomer. It was concentrated to an oil (6.03 g), which was treated with acetic anhydride (30 ml) at 110° C. for 1.5 hours, concentrated and crystallized in toluene (30 ml), to afford 4-acetoxy-3-[(2-benzyl)-tetrazol-5-yl]-2-methyl-1,2-benzothiazine 1,1-dioxide (1.31 g). The resulting mother liquor was concentrated to a viscous oil, diluted with toluene (10 ml) and seeded. The resulting crystals were filtered off and recrystallized from toluene (24 ml) to give 4-acetoxy-[(1-benzyl)tetrazol-5-yl]-2-methyl-1,2-benzothiazine 1,1-dioxide (0.602 g).
Reaction SMILES: [CH3:1][C@@:2]1([C:13]([OH:15])=O)[CH2:6][CH2:5][C@H:4]([C:7](=[O:10])[NH:8][CH3:9])[C:3]1([CH3:12])[CH3:11].C(Cl)(=O)C>C(OCC)(=O)C>[CH3:1][C@:2]12[C:3]([CH3:12])([CH3:11])[CH:4]([CH2:5][CH2:6]1)[C:7](=[O:10])[N:8]([CH3:9])[C:13]2=[O:15]
Reactant: CNC(=O)[C@H]1CC[C@@](C)(C(=O)O)C1(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: CN1C(=O)C2CC[C@@](C)(C1=O)C2(C)C

Procedure:
To a solution of step 1 intermediate (4.5 g, 21 mmol) in ethyl acetate, acetyl chloride (5.25 mL, 73 mmol) was added and refluxed for 24 hours. After the reaction, ethyl acetate was removed under reduced pressure, crude material purified by column, using ethyl acetate and hexane. (3.7 g) 1H NMR (400 MHz, CDCl3) δ ppm: 0.8 (s, 3H), 0.9 (s, 3H), 1.1 (s, 3H), 1.60-1.61 (m, 1H), 1.71-1.83 (m, 1H), 1.88-1.95 (m, 1H), 2.11-2.2 (m, 1H), 2.65 (d, 1H), 2.91 (s, 3H). m/z (M+H): 196.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[CH2:27][N:26]([CH2:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[CH2:25][CH2:24][CH2:23][C:22]=4[CH:37]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[ClH:38]>CCOCC>[ClH:38].[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[CH2:27][N:26]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:24][CH2:23][C:22]=4[CH:37]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(CCC(=O)OC(C)(C)C)C4)no2)cc1C#N
Agent: Cl
Solvent: CCOCC
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(CCC(=O)O)C4)no2)cc1C#N
Temperature: 50 °C
Yield: 84.9 %

Procedure:
1,1-Dimethylethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]propanoate (Preparation 12) (70 mg, 0.139 mmol) was treated with HCl (1045 μl, 4.18 mmol) (4N in dioxan) and warmed at 50° C. for 1.5 hours. A white precipitate started to form. Ether (0.5 ml) was added and the white solid filtered off and washed with ether to give the title compound (57 mg) on drying. δH (400 MHz, d6DMSO) 1.39 (6H, d), 1.91-1.96 (2H, m), 2.82 (2H, m), 3.12-3.21 (4H, m), 3.56 (2H, m), 4.62 (2H, s), 4.96-5.02 (1H, m), 7.57 (1H, d), 7.71 (1H, d), 7.99-8.01 (2H, m), 8.41 (1H, dd), 8.52 (1H, d), 10.3 (1H, v. broad s), 12.8 (1H, v. broad s); MS (ES) C25H26N4O4 requires 446; found 447.0 [M+H]+.
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]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N(CC)CC)C.[N-:42]=[N+:43]=[N-:44].[Na+]>C1(C)C=CC=CC=1.CN(C)C=O>[CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]4[NH:44][N:43]=[N:42][N:17]=4)=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(-c3cnc4c(C#N)cnn4c3C3CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-c2ccc(-c3cnc4c(-c5nnn[nH]5)cnn4c3C3CCCCC3)cc2)cc1
Temperature: 25 °C
Yield: 15.2 %

Procedure:
To a solution of 42 mg (0.092 mmol) of 7-cyclohexyl-6-(4′-methanesulfonyl-biphenyl-4-yl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile in 1 mL of toluene and 1.2 mL of dimethylformamide (DMF) was added 76 mg (0.55 mmol) of triethylamine hydrochloride (Et3N—HCl), and 36 mg (0.55 mmol) of sodium azide and the resulting heterogeneous mixture was heated at 120° C. for 72 h, during which time 76 mg (0.55 mmol) of triethylamine hydrochloride (Et3N—HCl), and 36 mg (0.55 mmol) of sodium azide was added to the reaction mixture after every 24 h. The mixture was then cooled to rt, filtered and concentrated to a residue which was purified via reverse-phase chromatography to afford (after lyophilization) 7 mg (15% yield) of 7-cyclohexyl-6-(4′-methanesulfonyl-biphenyl-4-yl)-3-(1H-tetrazol-5-yl)-pyrazolo[1,5-a]pyrimidine as a white solid (90% purity, entry 443) as indicated by 1H-NMR; LC-MS calcd for C26H25N7O2S [M++H]+ 500.18; found 500.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:12][N:13]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[C:27]([C:29]4[C:34]([O:35][CH3:36])=[CH:33][C:32]([O:37][CH3:38])=[CH:31][C:30]=4[O:39][CH3:40])[CH:26]=[C:25]([C:41]([O:43]CC)=[O:42])[N:24]=3)[CH2:18][CH2:17][N:16]([CH2:46][C:47]3[N:52]=[C:51]([C:53]([O:55]CC)=[O:54])[CH:50]=[C:49]([C:58]4[C:63]([O:64][CH3:65])=[CH:62][C:61]([O:66][CH3:67])=[CH:60][C:59]=4[O:68][CH3:69])[CH:48]=3)[CH2:15][CH2:14]2)[CH:9]=[C:8]([C:70]2[C:75]([O:76][CH3:77])=[CH:74][C:73]([O:78][CH3:79])=[CH:72][C:71]=2[O:80][CH3:81])[CH:7]=1)=[O:5])C.[Cl-].[Dy+3:83].[Cl-].[Cl-]>>[Dy+3:83].[C:41]([C:25]1[N:24]=[C:23]([CH2:22][N:19]2[CH2:18][CH2:17][N:16]([CH2:46][C:47]3[CH:48]=[C:49]([C:58]4[C:63]([O:64][CH3:65])=[CH:62][C:61]([O:66][CH3:67])=[CH:60][C:59]=4[O:68][CH3:69])[CH:50]=[C:51]([C:53]([OH:55])=[O:54])[N:52]=3)[CH2:15][CH2:14][N:13]([CH2:12][C:10]3[N:11]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[C:8]([C:70]4[C:71]([O:80][CH3:81])=[CH:72][C:73]([O:78][CH3:79])=[CH:74][C:75]=4[O:76][CH3:77])[CH:9]=3)[CH2:21][CH2:20]2)[CH:28]=[C:27]([C:29]2[C:30]([O:39][CH3:40])=[CH:31][C:32]([O:37][CH3:38])=[CH:33][C:34]=2[O:35][CH3:36])[CH:26]=1)([OH:43])=[O:42]
Reactant: CCOC(=O)c1cc(-c2c(OC)cc(OC)cc2OC)cc(CN2CCN(Cc3cc(-c4c(OC)cc(OC)cc4OC)cc(C(=O)OCC)n3)CCN(Cc3cc(-c4c(OC)cc(OC)cc4OC)cc(C(=O)OCC)n3)CC2)n1
Agent: [Cl-]
Agent: [Dy+3]
Product: COc1cc(OC)c(-c2cc(CN3CCN(Cc4cc(-c5c(OC)cc(OC)cc5OC)cc(C(=O)O)n4)CCN(Cc4cc(-c5c(OC)cc(OC)cc5OC)cc(C(=O)O)n4)CC3)nc(C(=O)O)c2)c(OC)c1

Procedure:
Deprotection of compound 21 followed by treatment with dysprosium chloride as described in Example 20 yielded the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[C:3](Cl)=[O:4].N1C=CC=CC=1.[CH:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH2:18].O>ClCCl>[CH2:20]([O:19][CH:17]=[CH:18][C:3](=[O:4])[C:2]([F:10])([F:1])[C:6]([F:9])([F:8])[F:7])[CH2:21][CH2:22][CH3:23]
Reactant: C=COCCCC
Reactant: O=C(Cl)C(F)(F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCOC=CC(=O)C(F)(F)C(F)(F)F
Temperature: -10 °C
Reaction time: 15 h

Procedure:
With stirring at −10° C., 17.0 g (93.2 mmol) of pentafluoropropionyl chloride—dissolved in 20 ml of dichloromethane—were added to a mixture of 8.11 g (102 mmol) pyridine and 9.33 g (93.2 mmol) of butyl vinyl ether in 200 ml of dichloromethane. After the addition, stirring was continued at room temperature for a further 15 h. 200 ml of water were then added to the mixture, and the organic phase was separated off, dried and concentrated. This gave 18.9 g (82% of theory) of a yellowish oil.
Reaction SMILES: C([C:4]1[C:5](=[O:13])[O:6][C:7]([CH2:11][Br:12])=[CH:8][C:9]=1[OH:10])(=O)C.S(=O)(=O)(O)O>>[Br:12][CH2:11][C:7]1[O:6][C:5](=[O:13])[CH:4]=[C:9]([OH:10])[CH:8]=1
Reactant: CC(=O)c1c(O)cc(CBr)oc1=O
Agent: O=S(=O)(O)O
Product: O=c1cc(O)cc(CBr)o1

Procedure:
A mixture of 3-acetyl-6-bromomethyl-4-hydroxypyran-2-one (26 parts) and 90% sulphuric acid (73.4 parts) was heated at 125°-130° C. with rapid agitation for 20 minutes, then poured onto ice. The product was filtered off and washed with water (2×100 parts) and dried to give 6-bromomethyl-4-hydroxypyran-2-one (25.0 parts). The crude product was recrystallised from boiling chloroform to give 6-bromomethyl-4-hydroxy pyran-2-one (12.8 parts, 60%) melting point 77°-78° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=2)[N:11]=[N:10]1.Cl[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].[Cl-].[NH4+]>N1C=CC=CC=1>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:18][CH:19]=2)[N:11]=[N:10]1
Reactant: Fc1ccccc1-n1cc(C2=CCNCC2)nn1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: CC(C)OC(=O)N1CC=C(c2cn(-c3ccccc3F)nn2)CC1
Reaction time: 1 h

Procedure:
4-[1-(2-Fluorophenyl)-1H-[1,2,3]-triazol-4-yl]-1,2,3,6-tetrahydropyridine hydrochloride (22.7 mg) prepared in the above 1) was dissolved in 0.5 ml of pyridine and 0.06 ml of isopropyl chloroformate was added thereto followed by stirring for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution and the product was extracted with ethyl acetate, dried over sodium sulfate and the solvent was evaporated in vacuo. The resulting residue was separated and purified by a thin-layer chromatography (ethyl acetate/hexane=1/1) to give 4.9 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:12](O)=[O:13].CO>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1F
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(CCO)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
To a solution of 2-(2-fluoro-5-nitrophenyl)acetic acid (2.0 g, 10 mmol) in THF (50 mL) was added borane dimethyl sulfide complex solution (4.0 g, 25 mmol). The reaction was warmed to 60° C. stirred for about 12 hr. After cooling down to RT, CH3OH (20 mL) was slowly added to the reaction, concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography on silica gel (200-300 mesh, PE/EA=2/1) to afford the product as a colorless oil (1.6 g, 86.1%). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (t, J=3.2, 6.4 Hz, 1 H), 8.19-8.14 (m, 1 H), 8.45 (t, J=9.2 Hz, 1 H), 4.80 (t, J=5.6 Hz, 1 H), 3.66 (dt, J=5.6, 6.4 Hz, 1 H), 2.86 (t, J=6.4 Hz, 2 H). MS (ESI) m/e [M+1]+ 186.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.N>O>[O:22]=[C:19]1[CH:20]=[CH:21][N:2]([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=3)=[CH:5][CH:4]=2)[CH:17]=[CH:18]1
Reactant: O=c1ccocc1
Reactant: Nc1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: Cl
Agent: N
Solvent: O
Product: O=c1ccn(-c2ccc(-c3ccc(=O)[nH]n3)cc2)cc1

Procedure:
A stirred mixture of 6-(4-aminophenyl)-3(2H)-pyridazinone hydrochloride (1.5 g), 4H-pyran-4-one (0.71 g), and water (20 ml), was heated under reflux for 2 hours. The pH of the hot solution was adjusted to 8 with aqueous ammonia and the mixture was cooled to give the crude product, 1.84 g, m.p. 338°-340° C. Recrystallisation from aqueous ethanol gave the title compound, 1.4 g, m.p. 339°-341° C.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[CH3:15][C:16]1[O:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[C:19]([C:21](O)=[O:22])[N:20]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:21]([C:19]2[N:20]=[C:16]([CH3:15])[O:17][C:18]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[O:22])[CH:9]=[N:8]1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2C)o1
Product: Cc1nc(C(=O)Nc2cnn(CCCCC(C)(F)F)c2)c(-c2ccccc2C)o1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 2-methyl-5-o-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=403.22.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][OH:18])=[O:6])[CH:2]=[CH2:3].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][O:18][S:26]([C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])=[O:6])[CH:2]=[CH2:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (13.4 g: 50 mmole) in dichloromethane (50 ml), p-chlorobenzenesulfonyl chloride (12.66 g: 60 mmole) is added in a nitrogen atmosphere at room temperature and a solution of triethylamine (8.69 ml: 62.5 mmole) in dichloromethane (10 ml) is further added dropwise. The mixture is stirred at room temperature overnight. The reaction mixture is successively washed with aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (toluene-ethyl acetate) to give crude (2S,4R)-1-allyloxycarbonyl-2-p-chlorobenzenesulfonyloxymethyl-4-methanesulfonyloxypyrrolidine (23.73 g) as oil. Yield: 105%.