Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[CH:35]=[N:36][N:37]([CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.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>[CH3:42][N:41]([CH3:43])[CH2:40][CH2:39][N:37]1[CH:38]=[C:34]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]2)[CH:35]=[N:36]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Reactant: CN(C)CCn1cc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCN(C)C)c4)cc23)CC1
Yield: 15.1 %

Procedure:
A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (40 mg, 0.084 mmol), [2-(4-bromo-1H-pyrazol-1-yl)ethyl]dimethylamine (27 mg, 0.126 mmol) and sodium carbonate (53 mg, 0.5 mmol) was suspended in dioxane (750 μL) and water (250 μL). This was flushed with argon for 10 min before the addition of tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol). The resulting mixture was reacted in a microwave for 20 min at 120° C. then diluted with EtOAc (10 mL). The mixture was filtered through Celite and an aqueous wash was performed. It was then purified by Gilson Preparatory HPLC to give 6 mg of the title compound (15%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[C:8]([OH:10])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:8]([C:3]5[N:2]([CH3:1])[CH:6]=[C:5]([CH3:7])[CH:4]=5)=[O:10])[CH:44]=[CH:43][CH:42]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1cc(C(=O)O)n(C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n(C)c1
Yield: 82 %

Procedure:
In the same manner as in Example 18-4 and using 1,4-dimethyl-1H-pyrrole-2-carboxylic acid (225 mg, 1.62 mmol), tetrahydrofuran (7 mL), oxalyl chloride (212 μL, 1.67 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (228 mg, 82%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[B:12]1[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]1.I[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[CH3:22][N:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([B:12]3[O:13][C:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[O:16]3)=[C:2]([CH3:1])[C:11]1=2
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1NCCO2
Reactant: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1N(C)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
An ice cold mixture of 5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (65.0 mg, 0.236 mmol) in N,N-dimethylformamide (DMF) (0.5 mL) was treated with iodomethane (0.044 mL, 0.709 mmol) and the mixture was stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (hexanes/ethyl acetate) to afford a pale yellow residue (40 mg, 59%): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.39 (d, J=8.2 Hz, 1 H), 6.69 (d, J=8.2 Hz, 1 H), 4.20-4.14 (m, 2 H), 3.12-3.03 (m, 2 H), 2.66 (s, 3 H), 2.49 (s, 3 H), 1.31 (s, 12 H); LC/MS (m/z) ES+=290 (M+1).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]=1.Cl>C(O)C.O.[Fe]>[F:13][CH:2]([F:1])[O:3][C:4]1[N:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(OC(F)F)nc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(OC(F)F)nc1
Yield: 103.9 %

Procedure:
2-Difluoromethoxy-5-nitro-pyridine obtained in Step A (1.6 g) was treated with iron (5 g) and concentrated hydrochloric acid (0.23 ml) in ethanol (15 ml) and water (2.5 ml) at 80° C. for 20 minutes. Filtration over Celite® and evaporation of the solvent afforded 6-difluoromethoxy-pyridin-3-yl-amine (1.4 g) as an orange solid. 1H NMR (400 MHz, CDCl3) 3.51 (br s, 2H), 6.89 (d, 1H), 7.23 (d, 1H), 7.44 (dd, 1H), 7.80 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.Cl[C:16](OC1C=CC=CC=1)=[O:17].C([O-])([O-])=O.[K+].[K+].[F:31][C:32]1([F:48])[O:36][C:35]2[CH:37]=[CH:38][C:39]([CH2:41][N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[CH:40][C:34]=2[O:33]1>O.C1(C)C=CC=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:16]([N:45]1[CH2:44][CH2:43][N:42]([CH2:41][C:39]2[CH:38]=[CH:37][C:35]3[O:36][C:32]([F:31])([F:48])[O:33][C:34]=3[CH:40]=2)[CH2:47][CH2:46]1)=[O:17]
Reactant: Nc1cnccc1Cl
Reactant: O=C(Cl)Oc1ccccc1
Reactant: FC1(F)Oc2ccc(CN3CCNCC3)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cnccc1Cl)N1CCN(Cc2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 2 °C
Reaction time: 7 h
Yield: 68.6 %

Procedure:
A 2 L, three-neck Morton flask equipped with a mechanical stirrer, thermocouple, and addition funnel under a nitrogen atmosphere was charged with 3-amino-4-chloropyridine (35.0 g, 272 mmol) and toluene (740 mL). The brown solution was cooled to 2° C. Pyridine (25.3 mL, 310 mmol) was added in one portion, followed by the dropwise addition of phenyl chloroformate (32.6 mL, 259 mmol) over 30 min. The maximum internal temperature was 5° C. After stirring at 2-5° C. for 7 h the reaction mixture became a thick yellow suspension. A cooled solution of K2CO3 (53.6 g, 388 mmol) in water (216 mL) was added over 3 min, during which the maximum internal temperature was 6° C. 1-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine (66.3 g, 259 mmol) was then added as a solid over 1 min. The mixture was allowed to warm slowly to room temperature and stirred for 15 h. Water (200 mL) was added and the toluene layer was separated and extracted with aqueous HCl (1.8 M, 600 mL). The aqueous extract was washed with toluene (2×300 mL). MeOH (500 mL) was added to the aqueous layer and the solution was cooled to 5° C. The pH was adjusted to pH 8-9 with the addition of NaOH solution (50 wt %, ca. 50 mL). The addition was at such a rate that the internal temperature did not exceed 17° C. The resulting suspension was stirred at 5° C. for 2 h. The product was collected by filtration and rinsed with MeOH/H2O (1:1, 70 mL). The solid was dried in vacuum oven at 50° C. for 24 h to afford the title compound as a yellow/green solid (73 g, 69%).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C:4](=[O:30])[CH2:3]1)[C@:16]1([CH3:17])[C:11](=[C:12]([CH2:22]SC2C=CC=CC=2)[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3>[Ni]>[OH:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C:4](=[O:30])[CH2:3]1)[C@:16]1([CH3:17])[C:11](=[C:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3
Reactant: C[C@]12CCC(=O)C(CSc3ccccc3)=C1CC[C@H]1[C@@H]3[C@@H](O)CC(=O)[C@@]3(C)CC[C@@H]12
Agent: [Ni]
Product: CC1=C2CC[C@H]3[C@@H]4[C@@H](O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Yield: 64.4 %

Procedure:
Analogously to Example 6(b), 10.0 g of 15α-hydroxy-4-(phenylthiomethyl)androst-4-ene-3,17-dione is treated with Raney nickel, thus isolating 4.8 g of 15α-hydroxy-4-methylandrost-4-ene-3,17-dione as a foam.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:16]=[C:17]([C:25]#[N:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>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.O>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:16]=[C:17]([C:25]#[N:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)cc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(C#N)c3ccccc3c2)cc1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 40.4 %

Procedure:
4-Methoxycarbonylphenylboronic acid (0.039 g), 3-bromonaphthalene-1-carbonitrile (0.05 g), tetrakis(triphenylphosphine)palladium (0.012 g) and cesium carbonate (0.11 g) were suspended in a mixed solvent of N,N-dimethylformamide (3 mL) and water (1 mL), and the resulting mixture was stirred at 150° C. for 40 minutes using microwave reactor (Biotage). The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/0-66/34) to give 4-(4-cyanonaphthalene-2-yl)benzoic acid methyl ester (0.025 g).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][OH:9])=[O:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:22][S:23]([O:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:2]=1[F:1])(=[O:25])=[O:24]
Reactant: O=C(NCCO)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCNC(=O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of 2,4-difluoro-N-(2-hydroxyethyl)benzamide (299 mg, 1.49 mmol) and triethylamine (302 mg, 2.98 mmol) in CH2Cl2 under nitrogen at 0° C. was added methanesulfonyl chloride (335 mg, 2.98 mmol) The reaction mixture was stirred for 1 h at 0° C. 1 N HCl (5 mL) was added to quench the reaction and the solution was diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 (100 mL) and saturated NaCl (100 mL), dried over MgSO4, filtered and concentrated in vacuo. Purification by column chromatography (hexanes:EtOAc 4:1) yielded 2-[(2,4-difluorobenzoyl)amino]ethyl methanesulfonate (300 mg, 72%) as a clear liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][N:5]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)[C:6]#[N:7].[OH-:15].[Na+]>Cl>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][N:5]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)[C:6]([NH2:7])=[O:15]
Reactant: CN(C)CCN(C#N)c1cnccn1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CN(C)CCN(C(N)=O)c1cnccn1
Reaction time: 1 h

Procedure:
N-(2-Dimethylaminoethyl)-N-(2-pyrazinyl)cyanamide (2.83 g., 0.015 mole) is dissolved in 20 ml of 6N hydrochloric acid. After one hour, the mixture is made alkaline with concentrated sodium hydroxide and concentrated. The residue is extracted with ether which is concentrated. The residue is crystallized from butyl chloride and N-(2-dimethylaminoethyl)-N-(2-pyrazinyl)urea melting at 105°-108° C. is obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([NH2:18])=[CH:8][CH:7]=1.[N:19]([O-])=O.[Na+].Cl.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:34]2[CH2:35][C:36](=[O:39])[NH:37][N:38]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].C([O-])(=O)C.[Na+]>O.C(O)C>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([NH:18][N:19]=[C:35]2[C:34]([C:28]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=3)=[N:38][NH:37][C:36]2=[O:39])=[CH:8][CH:7]=1
Reactant: COc1ccc(C2=NNC(=O)C2)cc1OC
Reactant: O=N[O-]
Reactant: Nc1ccc(OCCCBr)c(-c2ccccc2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C2=NNC(=O)C2=NNc2ccc(OCCCBr)c(-c3ccccc3)c2)cc1OC
Reaction time: 1 h
Yield: 27.2 %

Procedure:
6-(3-Bromo-propoxy)-biphenyl-3-ylamine (r, 250 mg, 0.82 mmol) was diazotized with sodium nitrite (67 mg, 0.98 mmol) in 1:1 water/ethanol and 0.5 mL concentrated HCl at 0° C. After approximately 1 hour, the diazonium solution was added dropwise to a suspension of 5-(3,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one (200 mg, 0.9 mmol) and sodium acetate (1.1 g) in 10 mL 1:1 water/ethanol. The orange solid which precipitated was filtered and washed with water and dried. The crude product was purified by silica gel chromatography (eluent: 5% methanol/DCM) to afford 120 mg of 4-{[6-(3-bromo-propoxy)-biphenyl-3-yl]-hydrazono}-5-(3,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one (s): HPLC (Rt) 5.02 min; m/e 536.1, MS (ES+): 538.9; 1H NMR (500 MHz, CDCl3): 13.9 (bs, 1H), 9.0 (bs, 1H), 7.7-6.9 (m, 11H), 4.1 (m, 2H), 3.9 (s, 3H), 3.7 (s, 3H), 3.5 (m, 2H), 3.3 (m, 2H), 2.2 (m, 2H) and 2.1 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]([CH3:24])[C@:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:6]=1.C(N(CC)CC)C.[CH2:32]([O:34][CH:35]([O:38][CH2:39][CH3:40])[CH2:36]Br)[CH3:33]>CN(C)C=O>[CH2:32]([O:34][CH:35]([O:38][CH2:39][CH3:40])[CH2:36][NH:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]([CH3:24])[C@:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:6]=1)[CH3:33]
Reactant: CCOC(CBr)OCC
Reactant: C[C@@H](n1cc(N)cn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(CNc1cnn([C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
(2R,3R)-3-(4-amino-1H-pyrazol-1-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol obtained in Step 2 (0.12 g, 0.35 mmol) was dissolved in N,N-dimethylformamide (2 mL) and triethylamine (0.058 g, 0.42 mmol) was slowly added thereto. The mixture was stirred at room temperature for 30 minutes, and bromoacetaldehyde diethyl acetal (0.065 mL, 0.42 mmol) was added thereto, followed by stirring at 80° C. for 4 hours. The reaction was terminated by adding ice water (0.1 mL) thereto. The resulting residue was extracted with ethyl acetate (20 mL), and the extract was washed successively with saturated ammonium chloride (20 mL) and brine (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under a reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the title compound (0.071 g, yield 44%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(OCCCCC)(=O)C>O>[ClH:13].[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCCN1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCOC(C)=O
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 97 °C
Reaction time: 8 h

Procedure:
To a 125 mL 3 neck flask with mechanical stirring, condensers, and a heating apparatus consisting of an RTD probe in the flask hooked via a temperature controller to a heating mantle, the following were added: 7.61 g methyl 4-hydroxybenzoate, 11.05 g -chloroethylpiperidine hydrochloride, 16.59 g powdered potassium carbonate, and 60 mL amyl acetate. The mixture was slowly heated under nitrogen in an oil bath to 97° C. The reaction was allowed to proceed overnight. The mixture was cooled to ambient temperature and 40 mL deionized water was added to dissolve the solids. The aqueous layer was separated and discarded and the water wash repeated. 25 mL of 8N hydrochloric acid were added in a single aliquot to extract the intermediate. The layers were separated and the acidic aqueous layer returned to the reaction flask. The aqueous layer was heated to 95° C. and the reaction was allowed to proceed for 24 hours as a stress test. After 6 hours, 0.3% of ester remained. The mixture was cooled to 40° C. and 25 mL acetone was added. The mixture was cooled to 0° C.-5° C. for 1 hour. The filter cakes were rinsed with approx. 25 mL acetone and dried. HPLC revealed 0.2 g of product in filtrate. Yield (crystalline) 13.38 g (95.1% of theoretical).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@@:12]([CH2:16][OH:17])([CH2:13][O:14]2)[C@@H:11]([OH:18])[C@H:10]([OH:19])[C@H:9]3[OH:20])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][O:38]CC1C=CC=CC=1.O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@@:12]([CH2:16][OH:17])([CH2:13][O:14]2)[C@@H:11]([OH:18])[C@H:10]([OH:19])[C@H:9]3[OH:20])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:36][CH2:37][OH:38])=[CH:26][CH:27]=1
Reactant: BrCCOCc1ccccc1
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: OCCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-5-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol (14 mg, 0.034 mmol) in acetonitrile (0.5 mL) was added potassium carbonate (14 mg, 0.1 mmol) followed by the addition of (2-bromo-ethoxymethyl)-benzene (0.010 mL, 0.063 mmol) and the reaction mixture was heated to 50 degrees Celsius for 24 hours. The reaction showed some product formation but the majority of starting material remained. An additional 3 equivalents of potassium carbonate was added, the temperature was increased to 83 degrees Celsius and the reaction mixture stirred for an additional 5 hours. The reaction mixture was cooled to room temperature, water (20 mL) and ethyl acetate were added, the organic phase separated and the aqueous phase was extracted 3 times with ethyl acetate (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel using the ISCO automated chromatography unit (4 g silica gel column) and eluting with a gradient of 0 to 23% methanol in dichloromethane. 4 mg of the desired compound (1S,2S,3S,4R,5S)-5-(3-(4-(2-(Benzyloxy)ethoxy)benzyl)-4-chlorophenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol was obtained. LCMS 587 (M+HCO2−, negative mode). 1H NMR (500 MHz, METHANOL-d4) delta ppm 3.56 (d, J=8.1 Hz, 1 H), 3.60 (d, J=7.6 Hz, 1 H), 3.63-3.67 (m, 1 H), 3.69 (d, J=12.7 Hz, 2 H), 3.79 (d, J=8.3 Hz, 1 H), 3.82 (d, J=4.6 Hz, 1 H), 3.83-3.87 (m, 1 H), 4.05 (s, 2 H), 4.11-4.14 (m, 2 H), 4.16 (d, J=7.3 Hz, 1 H), 4.62 (s, 2 H), 6.86 (d, J=8.5 Hz, 2 H), 7.12 (d, J=8.5 Hz, 2 H), 7.29 (d, J=7.1 Hz, 1 H), 7.31-7.43 (m, 6 H), 7.47 (s, 1 H).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+]>C(O)CCC>[F:13][C:12]([F:15])([F:14])[C:4]1[N:3]=[C:2]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1
Reactant: NCc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CCCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=C(O)c1ccccc1-c1ccc(CNc2nc(C(F)(F)F)nc3c2CCCC3)cc1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
To 10 mL of n-butanol were added 0.526 g of 4-chloro-5,6,7,8-tetrahydro-2-trifluoromethylquinazoline, 0.408 g of 4' aminomethyl-(1,1'-biphenyl)-2-carboxylic acid and 1.1 g of sodium acetate. The resulting mixture was refluxed for 3 days, cooled to room temperature and all solvents were removed by evaporation. The residue was taken up in ethyl acetate and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to yield an off-white solid which was purified by silica chromatography to yield the desired product (0.39 g, 59%). The compound was characterized as its sodium salt: 1H NMR (DMSO-d6, 400 MHz) δ 7.88 (t, J=6.0 Hz, 1H), 7.39 (m, 2H), 7.28 (m, 3H), 7.17 (m, 3H), 4.60 (d, J=5.9 Hz, 2H), 2.61 (m, 2H), 2.38 (m, 2H), 1.74 (m, 4H); negative FAB-MS m/e 448(M-H), 426(M-Na). Anal. calcd for C23H19F3N3NaO2.1.0H2O: C, 59.10; H, 4.53; N, 8.99. Found: C, 59.03; H, 4.48; N, 9.09.
Reaction SMILES: [CH3:1][C:2]([C:21]1[N:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].ClC1N=NC(C2C=CC(C(C)(C3C=CC(OCC4C=CC=CN=4)=CN=3)C(C)C)=CC=2)=CC=1.Cl[C:61]1[N:62]=[N:63][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:65][CH:66]=1.CC(C1C=CC(OCC2C=CC=CN=2)=CN=1)(C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)C(C)C.ClC1N=NC(Cl)=CC=1>>[CH3:1][C:2]([C:21]1[N:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([C:6]1[CH:7]=[CH:8][C:9]([C:61]2[N:62]=[N:63][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:65][CH:66]=2)=[CH:10][CH:11]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)C(C)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(O)cn1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Agent: CC(C)C(C)(c1ccc(-c2ccc(Cl)nn2)cc1)c1ccc(OCc2ccccn2)cn1
Agent: CC(C)C(C)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(OCc2ccccn2)cn1
Agent: Clc1ccc(Cl)nn1
Product: CC(C)C(C)(c1ccc(-c2ccc(C(F)(F)F)nn2)cc1)c1ccc(O)cn1

Procedure:
Compound 8b was prepared from 8a following procedures similar to those described for preparing compound 5b substituting compound 8a and 3-chloro-6-trifluoromethylpyridazine for compound 5a and 3,6-dichloropyridazine, respectively. m/z (ES) 402 (MH)+
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnn(Cc2ccccc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)cnn1Cc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 40.3 %

Procedure:
A mixture of methyl 1-benzyl-5-methyl-1H-pyrazole-4-carboxylate (200 mg, 0.86 mmol), lithium hydroxide monohydrate (111 mg, 2.62 mmol), tetrahydrofuran (10 mL), methanol (2 mL) and water (2 mL) was stirred at 20° C. for 4 hours. The mixture was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and separated by chiral HPLC (condition: column AD-H (20 mm*250 mm*5 μm), hexane: ethanol (0.2% DEA)=50:50, flow rate: 13 mL/min) to give 1-benzyl-5-methyl-1H-pyrazole-4-carboxylic acid (75 mg, 40%). LRMS (M+H+) m/z: calcd. 216.09. found 216.