Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][N:22]([C:24]4[CH:25]=[N:26][C:27]([O:34][CH3:35])=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=O)(C)(C)C.[ClH:36].C(OCC)C>C(Cl)Cl>[ClH:36].[ClH:36].[CH3:35][O:34][C:27]1[N:26]=[CH:25][C:24]([N:22]2[CH2:21][CH2:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([O:13][C@H:10]4[CH2:11][CH2:12][NH:8][CH2:9]4)[C:15]=3[CH2:23]2)=[CH:29][C:28]=1[C:30]([F:33])([F:31])[F:32]
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 128 %

Procedure:
(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 1.69 mmol) in CH2Cl2 (5 mL) was added 2M anhydrous HCl in diethyl ether (25.3 mL, 50.5 mmol) and the mixture stirred at rt for 3 h. The resulting precipitate was filtered and washed with diethyl ether to give 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine dihydrochloride as a yellow solid (1.01 g, 128% yield). [M+H]+=396.0, Rt(4)=0.71 min. The free base can be generated by partitioning the dihydrochloride salt between dichloromethane and 1N sodium hydroxide solution(aq), separating the organic phase and evaporating in vacuo. [M+H]+=396.0, Rt(4)=0.71 min.
Reaction SMILES: C(O)[C:2](N)(CO)[CH2:3][OH:4].[Cl-].[Cl-].[Ca+2].C[C@@H]([C@@H]1[C@@]2(C)[C@@H](O)C[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4C[C@@H](O)[C@H]3[C@@H]2CC1)C[CH2:15][C:16]([NH:18][CH2:19][CH2:20][S:21]([O-:24])(=[O:23])=[O:22])=[O:17].[Na+].C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>O>[CH2:2]1[N:18]([CH2:19][CH2:20][S:21]([OH:24])(=[O:22])=[O:23])[CH2:16][CH2:15][O:4][CH2:3]1.[OH2:17]
Reactant: NC(CO)(CO)CO
Reactant: C[C@H](CCC(=O)NCCS(=O)(=O)[O-])[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Product: O=S(=O)(O)CCN1CCOCC1

Procedure:
Prelysis solution: The solution is prepared according to Graves, L, et al. (1993). Universal Bacterial DNA isolation procedure. In Diagnostic molecular microbiology: principles and applications, D. Persing, T. Smith, F. Tenover and T. White, eds. (Washington, D.C.: American Society for Microbiology). The solution, which is freshly prepared and maintained on ice, contains: 0.25 ml of 2M Tris (pH 7.0), 3.1 ml of pancreatic lipase (prepared by dissolving 6.1 mg of pancreatic lipase (Sigma) in 59.8 ml of water and adding 1.2 ml of 0.1M CaCl2; stored at −20° C. in 3.1 ml aliquots), 0.3 ml of 1% sodium taurocholate (Difco), 0.5 ml of 0.1M CaCl2, 5.25 ml of sucrose, and 0.05 g of lysozyme.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[C:13]([CH2:15][CH2:16][O:17][C:18]([N:20]1[C:29]2[C:24](=[N:25][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:27][CH:28]=2)[C@@H:23]([N:34]([CH2:41][C:42]2[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[C:44]([C:52]([F:55])([F:54])[F:53])[CH:43]=2)[C:35]2[N:36]=[N:37][N:38]([CH3:40])[N:39]=2)[CH2:22][C@H:21]1[CH2:56][CH3:57])=[O:19])#[N:14].Cl>C1(C)C=CC=CC=1>[N:1]1[NH:2][N:3]=[N:14][C:13]=1[CH2:15][CH2:16][O:17][C:18]([N:20]1[C:29]2[C:24](=[N:25][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:27][CH:28]=2)[C@@H:23]([N:34]([CH2:41][C:42]2[CH:43]=[C:44]([C:52]([F:55])([F:54])[F:53])[CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=2)[C:35]2[N:36]=[N:37][N:38]([CH3:40])[N:39]=2)[CH2:22][C@H:21]1[CH2:56][CH3:57])=[O:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OCCC#N
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OCCc1nn[nH]n1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 66.1 %

Procedure:
Add sodium azide (16 mg, 0.24 mmol) and triethylamine hydrochloride (33 mg, 0.24 mmol) to a solution of (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid 2-cyano-ethyl ester (77 mg, 0.12 mmol) in toluene (2.4 mL). Stir the mixture at 80° C. for 1.5 h and at 100° C. overnight. Add more sodium azide (24 mg, 0.36 mmol) and triethylamine hydrochloride (50 mg, 0.36 mmol) and stir the mixture for 8 h at 100° C. Add more sodium azide (24 mg, 0.36 mmol) and triethylamine hydrochloride (50 mg, 0.36 mmol) and stir the mixture for 6 h at 100° C. Cool down to room temperature. Add 1 M HCl and extract the aqueous phase with dichloromethane. Wash the organic layers with water and brine, then dry over Na2SO4, filter, and concentrate. Purify the crude material by silica gel chromatography (elution with dichloromethane/methanol) to afford the title compound (55 mg, 66%). MS (ES+): 694 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH3:10][NH:11][C:12]1[NH:20][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]=2[N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:17]2[CH:18]=[CH:19][C:14]3=[N:13][C:12]([NH:11][CH3:10])=[N:20][C:15]3=[CH:16]2)=[CH:4][CH:5]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CNc1nc2ccncc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nc2ccn(Cc3ccc(F)cc3)cc-2n1
Temperature: 60 °C

Procedure:
A mixture of 5.6 parts of 1-(chloromethyl)-4-fluorobenzene, 5.2 parts of N-methyl-3H-imidazo[4,5-c]-pyridine-2-amine, 4.2 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred and heated first for 3 hours at 90°-100° C. and further overnight at 60° C. The reaction mixture was poured onto water and the product was extracted four times with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (92.5:7.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was boiled in 2-propanone, yielding 6 parts of 5-[(4-fluorophenyl)methyl]-N-methyl-5H-imidazo-[4,5-c-]pyridin-2-amine; mp. 209.5° C. (intermediate 97).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:25]1[C:26]([CH3:48])=[C:27]([C:34]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[N:42]=[C:41]([CH3:46])[NH:40][C:39]3=[O:47])=[O:35])[N:28]2[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]2>O.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:48][C:26]1[C:25]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[O:4])=[C:33]2[N:28]([C:27]=1[C:34]([C:36]1[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=1)[N:42]=[C:41]([CH3:46])[NH:40][C:39]3=[O:47])=[O:35])[CH:29]=[CH:30][CH:31]=[CH:32]2
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Cc1nc2ccc(C(=O)c3c(C)c(Br)c4ccccn34)cc2c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-c2c(C)c(C(=O)c3ccc4nc(C)[nH]c(=O)c4c3)n3ccccc23)c1
Temperature: 150 °C
Yield: 58.6 %

Procedure:
0.139 g (0.78 mmol) of [3-(methoxycarbonyl)phenyl]boronic acid, 0.321 g (1.29 mmol) of potassium phosphate dihydrate dissolved in 0.81 ml of water, and 0.0149 g (0.01 mmol) of tetrakis(triphenylphosphine)palladium are added, under an argon atmosphere at ambient temperature, to 0.256 g (0.65 mmol) of 6-[(1-bromo-2-methylindolizin-3-yl)carbonyl]-2-methylquinazolin-4(3H)-one in 9 ml of DMF. The reaction medium is microwave-heated at 150° C. for 15 minutes. After dilution with ethyl acetate, the organic phase is washed with a 1N aqueous solution of hydrochloric acid and then a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/2) mixture. 172 mg of a yellow solid are obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH2:8])[CH2:3]1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>C(Cl)Cl>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1CCCC(N)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: NC1CCCC(NS(=O)(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 1,3-diaminocyclohexane (1.14 g, 10 mmol, undetermined isomer mixture) in methylene chloride (50 mL) was cooled to 0° C. and phenylsulfonyl chloride (0.64 mL, 5 mmol) was added dropwise. The mixture was stirred at 0° C. for 4 h, then 1N sodium hydroxide solution (10 mL) was added and the mixture stirred an additional 5 min. The phases were separated, the organic phase was dried (K2CO3), filtered, and concentrated in vacuo. Toluene was added and the mixture re-concentrated to remove any remaining diamine, to give 0.77 g of a semi solid. 1H—NMR was consistent with the desired structure. MS (ion spray) 255 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>C(Cl)Cl>[CH:39]1([C:42]([NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]4[C:19](=[O:31])[N:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:21]([CH3:24])[C:22]=4[CH3:23])=[O:17])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[O:43])[CH2:41][CH2:40]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2)c(=O)n(-c2ccccc2)n1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (200 mg, 0.48 mmol) in DCM (5 mL) was added triethylamine (1 mL), followed by adding cyclopropanecarbonyl chloride (104.5 mg, 0.96 mmol) at 0° C. The reaction mixture was warmed to rt and stirred for 3 hours, then quenched with water (10 mL). The separated organic layer was added saturated aq. Na2CO3 (10 mL) and EtOH (30 mL). The mixture was stirred at rt for 30 minutes and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=80/1) to give the title compound as a white solid (130 mg, 56%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12
Reactant: COc1cccc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cccc(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of Example 51 (0.150 g, 0.290 mmoles) in dichloromethane (25 ml), BBr3 (1M in dichloromethane, 1.5 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as grey colour solid (0.110 g, 75% yield). MP: 282-285° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.69(s,1H), 8.06(s, 1H), 8.05(dd, J=8.0, 1.6 Hz, 1H), 7.86(dt, J=7.2,1.6 Hz, 1H), 7.68(t, J=8.2 Hz, 1H), 7.53 (dt, J=8.0,0.9 Hz, 1H), 7.34(t, J=8.0 Hz, 1H), 7.29 (br s, 1H), 7.06-6.84(m, 6H), 6.03(q, J=7.1 Hz, 1H), 1.89(d, J=7.1 Hz, 3H). Mass: 493.95(M+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH:20]1([N:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH2:13][CH:26]3[CH2:27][CH2:28][N:23]([CH:20]4[CH2:22][CH2:21]4)[CH2:24][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1CCN(C2CC2)CC1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: Clc1nc(N2CCOCC2)c2sc(CNCC3CCN(C4CC4)CC3)cc2n1
Yield: 57 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)methylamine was reacted with 1-cyclopropyltetrahydro-4(1H)-pyridinone using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether and methanol to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-cyclopropyl-piperidin-4-yl)methyl-amine as a solid (57% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was purified by mass directed chromatography (18% yield) to give 339. NMR (CDCl3, 400 MHz), 0.39-0.47 (4H, m), 1.58-1.66 (3H, m), 1.83 (2H, d, J=12.1), 2.19 (2H, t, J=9.9), 2.36 (3H, s), 2.54-2.58 (1H, m), 3.13 (2H, d, J=11.5), 3.88-3.92 (6H, m), 4.03-4.06 (4H, m), 5.22 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=481
Reaction SMILES: Cl[C@H:2]1[C@H:14]2[C@H:10]([N:11]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:13]2)[CH2:9][C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[Li].C[O:23]CCO>O>[C:15]1([C:12]2[O:13][C@H:14]3[CH:2]([OH:23])[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=4[CH2:9][C@H:10]3[N:11]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cl[C@@H]1c2ccccc2C[C@H]2N=C(c3ccccc3)O[C@@H]12
Reactant: COCCO
Agent: [Li]
Solvent: O
Product: OC1c2ccccc2C[C@H]2N=C(c3ccccc3)O[C@@H]12
Temperature: 90 °C

Procedure:
To a solution of (±)-(3aR,9R, 9aR)-9-chloro-3a, 4,9,9a-tetrahydro-2-phenyl-naphth[2,3-d]oxazole (360 mg) in 2-methoxyethanol (10 ml) was added a solution of lithium hydroxyde monohydrate (67 mg) in water (2 ml). The mixture was warmed at 90° C. for 1/2 hour and the title compound was precipitated by addition of water. Filtration, washing with water and drying in vacuo gave the title compound as a yellow solid (205 mg).
Reaction SMILES: [Li+].[CH3:2][C:3]1[C:4]([C:24]([O-])=[O:25])=[CH:5][C:6]2[O:10][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:7]=2[CH:23]=1.C[N+](C)=C(N(C)C)O[N:31]1[C:35]2C=[CH:37][CH:38]=[CH:39][C:34]=2N=N1.F[P-](F)(F)(F)(F)F.N1CCCCC1>CN(C)C=O>[CH3:2][C:3]1[C:4]([C:24]([N:31]2[CH2:37][CH2:38][CH2:39][CH2:34][CH2:35]2)=[O:25])=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:8][C:7]=2[CH:23]=1
Reactant: Cc1cc2c(cc1C(=O)[O-])OC(c1ccccc1)(c1ccccc1)O2
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1cc2c(cc1C(=O)N1CCCCC1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 20 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of 6-methyl-2,2-diphenyl-1,3-benzodioxole-5-carboxylic acid lithium salt (101.5 mg, 0.3 mmol) in N,N-dimethylformamide (3 mL) was added N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)-uronium-hexafluorophosphate (114 mg, 0.3 mmol, 1.0 eq.). The reaction mixture was stirred 1 h at 20° C. Piperidine (26 mg, 0.3 mmol, 1.0 eq.) was added and the reaction mixture was stirred 20 h at 20° C. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine and then dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography afforded the title compound (73 mg, 61%) as a light yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:14][N:15]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:16](=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][N:15]([CH:19]1[CH2:20][CH2:21][N:22]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[CH2:23][CH2:24]1)[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)N(C)C1CCNCC1
Reactant: Fc1ccc(OCCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)N(C)C1CCN(CCCCOc2ccc(F)cc2)CC1

Procedure:
A mixture containing 0.1 mole of the compound obtained in stage A, 0.1 mole of the compound obtained in stage C and 0.1 mole of potassium carbonate in 250 cm3 of acetone is heated to reflux.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:7]([O:8][CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[C@H:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[N+:29]([O-])=O)[CH2:3]1>CCO.[Pd]>[NH2:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[C@H:4]1[CH2:5][C@@H:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C@@H:7]([O:8][CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[C@@H:2]([CH3:1])[CH2:3]1
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OCCS(C)(=O)=O
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of (+/−)-tert-butyl (1R,5S,6S)-5-methyl-6-(2-(methylsulfonyl)ethoxy)-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.) in degassed EtOH (0.17 M) was added Pd/C (0.3 equiv.). The mixture was purged with H2, and allowed to stir under H2 overnight at RT. The reaction was filtered through a pad of celite and the cake was washed with MeOH. The organics were concentrated and purified by ISCO SiO2 chromatography to yield (+/−)-tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl)ethoxy)cyclohexylcarbamate in 55% yield. LC/MS (m/z)=428.2 (MH+), Rt=0.59 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07 (d, J=6.85 Hz, 3H), 1.46 (s, 9H), 1.72-1.88 (m, 2H), 2.62 (tt, J=12.23, 3.30 Hz, 1H), 3.08 (s, 3H), 3.21 (d, J=14.62 Hz, 1H), 3.35-3.47 (m, 1H), 3.58 (br. s., 1H), 3.64 (br. s., 2H), 3.70-3.86 (m, 1H), 3.94-4.10 (m, 1H), 4.10-4.22 (m, 1H), 5.43 (d, J=9.00 Hz, 1H), 6.89 (d, J=5.04 Hz, 1H), 7.98 (d, J=4.99 Hz, 1H), 8.03 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1.C(N(CC)CC)C.[O:23]1C[CH2:26][CH2:25][CH2:24]1.C(Cl)(=O)C=C>O>[C:24]([O:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:10][CH2:11]1)(=[O:23])[CH:25]=[CH2:26]
Reactant: C1CCOC1
Reactant: O[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)O[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Reaction time: 3 h

Procedure:
First, 4.24 g of trans-4-(2,3-difluorophenyl)cyclohexanol, 2 g of triethylamine, and 60 ml of tetrahydrofuran were placed in a 100 ml flask. Then, 2.3 g of acryloyl chloride was added dropwise to the mixture under ice water cooling. The mixture was stirred at the same temperature for 3 hours. Water was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene/hexane=1/1) and recrystallized from hexane to obtain 2.8 g of trans-4-(2,3-difluorophenyl)cyclohexyl acrylate (Y: 52.6%). The compound thus obtained had a purity of 99.9% by GC and 99.5% by HPLC. Furthermore, the compound had an m.p. of 72.9° C. to 73.6° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[C:18]([CH2:20][CH3:21])[CH:19]=[C:13]4[NH:12][C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[C:22](Br)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[C:18]([CH2:20][CH3:21])[CH:19]=[C:13]4[N:12]([C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1cc2[nH]c3c(cnc4c3cnn4CC)c(=O)n2n1
Reactant: O=C(Br)c1ccccc1
Product: CCc1cc2n(C(=O)c3ccccc3)c3c(cnc4c3cnn4CC)c(=O)n2n1

Procedure:
By treating the product of Example 25 with benzoyl bromide according to the procedure of Example 2, 3,9-diethyl-3,11dihydro-11-benzoyl-6H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one is obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[N:15][CH:16]=2)=[N:8][C:7]([CH:28](O)[CH2:29][CH2:30][CH3:31])=[N:6]1)[CH2:2][CH2:3][CH3:4].C(N(S(F)(F)[F:39])CC)C>>[CH2:1]([N:5]1[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[N:15][CH:16]=2)=[N:8][C:7]([CH:28]([F:39])[CH2:29][CH2:30][CH3:31])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C(O)CCC)nc1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reactant: CCN(CC)S(F)(F)F
Product: CCCCn1nc(C(F)CCC)nc1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1

Procedure:
Reaction of the compound of Example 10 with DAST (diethylaminosulfur trifluoride) gave 5-[2-[5-[[1-butyl-3-(1-fluorobutyl)-1H-1,2,4-triazol-5-yl]methyl]-2-pyridinyl]phenyl]-1H-tetrazole: NMR (CDCL3) δ 0.91 (t, J=7 Hz, 3H), 0.99 (t, J=7 Hz, 3H), 1.22-1.63 (m, 4H), 1.71-2.28 (m, 4H), 4.03 (t, J=7 Hz, 2H), 4.14 (s, 2H), 5.52 (ddd, J=48, 9, and 6 Hz, 1H), 7.23 (d, J=9 Hz, 1H), 7.38-7.50 (m, 3H), 7.69 (dd, J=9 and 2 Hz, 1H), 7.80-7.88 (m, 1H), 8.53 (d, J=2 Hz, 1H); MS(EC) m/e (rel intensity) 435(100); HRMS. Calc'd. for M+H: 435.2421. Found: 435.2459.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH:20]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:32]([CH3:49])[C:33]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])=[C:38]([C:47]#[N:48])[CH:37]=4)=[O:34])=[CH:26][CH:25]=3)[C:21]([OH:23])=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[NH2:48][CH2:47][C:38]1[CH:37]=[C:36]([NH:35][C:33](=[O:34])[N:32]([CH2:31][CH2:30][C:27]2[CH:28]=[CH:29][C:24]([CH:20]([NH:19][C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])=[N:10][CH:11]=[CH:12]4)[C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)[CH3:49])[CH:41]=[CH:40][C:39]=1[S:42]([CH2:45][CH3:46])(=[O:44])=[O:43]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2)cc1C#N
Agent: [Ni]
Solvent: CO
Product: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2)cc1CN
Yield: 72.9 %

Procedure:
A solution of 25D (460 mg, 0.59 mmol) in MeOH (50 mL) with catalytic Raney Ni was stirred under an atmosphere of H2 (70 psi) for 20 h. The reaction mixture was filtered through Celite and concentrated to give 25E (340 mg, 73%) as a yellow oil. MS (ESI) m/z 790.95 (M+H)+.