Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[C:19]([NH2:22])[CH:18]=2)=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH:18]=2)=[CH:15][CH:16]=1
Reactant: O=C(Cl)CCCCBr
Reactant: COc1ccc(-c2cc(N)n[nH]2)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(NC(=O)CCCCBr)n[nH]2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 5-bromovaleryl chloride (2.1 mL, 15.7 mmol) in dry dimethylacetamide (DMA) (35 mL) was cooled to −10° C. (ice water bath) under N2; a solution of 5-(4-methoxy-phenyl)-1H-pyrazol-3-ylamine (3.0 g, 15.7 mmol) and diisopropylethylamine (2.74 mL, 15.7 mmol) in dry DMA (15 mL) was added over 30 min. After two hours at −10° C., LCMS shows completion of the reaction (acylation on the pyrazole ring was also detected). The reaction was quenched by addition of H2O (ca. 50 mL), and the thick white precipitate formed upon addition of water is recovered by filtration. When the reaction was allowed to reach room temperature before quenching, a putative exchange of Br with Cl caused reactivity problems in subsequent steps. Washing with Et2O (3×10 mL) efficiently removed the byproduct (acylation on pyrazole ring). 4.68 g of the title compound was obtained as a white powder (13.3 mmol, 85% yield). Mp=149.5-151.5° C.
Reaction SMILES: [CH:1]([P:3](=[O:17])([CH:15]=[CH2:16])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[CH2:2].Cl.[CH2:19]([NH2:21])[CH3:20].[OH-].[Na+].C(N)C1C=CC=CC=1>C1COCC1>[CH2:19]([N:21]1[CH2:16][CH2:15][P:3](=[O:17])([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=2)[CH2:1][CH2:2]1)[CH3:20]
Reactant: CCN
Reactant: C=CP(=O)(C=C)c1ccc([N+](=O)[O-])c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: NCc1ccccc1
Solvent: C1CCOC1
Product: CCN1CCP(=O)(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g, 1.94 mmol), ethylamine hydrochloride (0.174 g, 2.12 mmol), and 1 N NaOH (2 mL) were dissolved in 50% aqueous THF (5 mL) and heated to 105° C. under nitrogen. After one hour, another portion of benzylamine was added to the reaction mixture. The reaction mixture was refluxed for an additional 2 h, and then cooled to rt. The reaction mixture was partitioned between saturated aqueous NaHCO3 and CH2Cl2. The aqueous phase was washed once with CH2Cl2 and the organic layers were combined. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the compound (0.267 g, 46% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[C:15](=[O:17])[C:14]1[C:13]([O:18]C(=O)C)=[CH:12][C:11]([CH2:22][O:23]C(=O)C)=[CH:10][C:9]=1[C:8]2=[O:27].Cl.O>CO>[OH:18][C:13]1[C:14]2[C:15](=[O:17])[C:16]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[C:8](=[O:27])[C:9]=2[CH:10]=[C:11]([CH2:22][OH:23])[CH:12]=1
Reactant: COc1cccc2c1C(=O)c1c(OC(C)=O)cc(COC(C)=O)cc1C2=O
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1cccc2c1C(=O)c1c(O)cc(CO)cc1C2=O
Yield: 70.2 %

Procedure:
The 8-methoxy-3-acetoxymethyl-1-acetoxy anthraquinone (120 mg) of Example 22 was refluxed in methanol (30 ml) with concentrated hydrochloric acid (10 ml) and water (10 ml) for three hours. The solvents and acid were evaporated off in vacuum and the residue crystallized from chloroform to obtain reddish yellow crystals (65 mg) of 1-hydroxy-3-hydroxymethyl-8-methoxy anthraquinone (formula 19). m.p. 215°-216°, ir (KBr) 3520-3460, 1670, 1635, 1585 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH3:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](Cl)=[O:31].BrC1C=C(C=C(C(F)(F)F)C=1)C(O)=O>C1COCC1.S(Cl)(Cl)=O>[Br:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30]([N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:15])=[O:31]
Reactant: O=C(Cl)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CN(C(=O)c1cc(Br)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine (300 mg, 1.37 mmol, prepared according to DE10008042) in THF (3 mL) was added dropwise lithium bis(trimethylsilyl)amide (1M solution in THF, 1.44 mL, 1.44 mmol) at −78° C. The reaction mixture was stirred for 10 minutes at −78° C. A solution of 3-bromo-5-trifluoromethyl-benzoyl chloride (prepared by stirring 3-bromo-5-(trifluoromethyl)benzoic acid (406 mg, 1.51 mmol, CAS RN 328-67-6) in thionylchloride (3 mL) at 100° C. for 1 hour. The reaction mixture was evaporated and the residue was dissolved in 5 mL toluene and concentrated under vacuum. This procedure was repeated three times to completely remove remainder of thionylchloride) in THF (3 mL) was added at −78° C. The reaction mixture was stirred for 1 hour at this temperature and then poured on 30 mL H2O and 30 mL EtOAc. The layers were separated and the aqueous layer extracted a second time with 30 mL EtOAc. The combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Yellow solid (265 mg, 41%). MS (TurboSpray): m/z=470.991 [M+H]+.
Reaction SMILES: C(O[C@@H]1O[C@H](COC(=O)C)[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@H]1[NH:24][C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26])(=O)C.C1(C)C(S)=CC=CC=1.B(F)(F)F.CCOCC.C(O[C@H:54]1[C@@H:67]([O:68][C:69](=[O:71])[CH3:70])[C@H:66]([O:72][C:73](=[O:75])[CH3:74])[C@@H:65]([CH2:76][O:77][C:78](=[O:80])[CH3:79])[O:64][C@@H:55]1[S:56][C:57]1[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=1)(=O)C>C(Cl)Cl>[C:69]([O:68][C@H:67]1[C@H:66]([O:72][C:73](=[O:75])[CH3:74])[C@@H:65]([CH2:76][O:77][C:78](=[O:80])[CH3:79])[O:64][C@@H:55]([S:56][C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)[C@@H:54]1[NH:24][C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26])(=[O:71])[CH3:70]
Reactant: CC(=O)OC[C@H]1O[C@H](Sc2ccc(C)cc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=O)OCC(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cc1ccccc1S
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(C)cc2)[C@H](NC(=O)OCC(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 89 %

Procedure:
The tittle compound was prepared from 1,3,4,6-tetra-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxylcarbonylamino)-β-D-glucopyranose (Boullanger, P. et al Carbohydr. Res. 1990, 202, 151) (11.8 g, 22.5 mmol), thiocresol (3.07 g, 24.75 mmol) and BF3-Et2O (10 mL) in dry CH2Cl2 (60 mL) by the procedure described above (see compound 1) The crude product was crystallization from ether to give 21 (11.8 g, 89%) as white crystals: m.p. 175–176° C.; [α]D22 +3° (c, 0.5, CHCl3); 1H-NMR (400 MHz, CDCl3) δ 2.00 (s, 3H), 2.01 (s, 3H), 2.09 (s, 3H), 2.35 (s, 3H), 3.71–3.73 (m, 1H), 4.11–4.25 (m, 2H), 4.73 (d, 1H, J=12.0 Hz), 4.79 (d, 1H, J=10.8 Hz), 5.01 (t, 1H, J=9.8 Hz), 5.26 (d, 1H, J=9.8 Hz), 5.31 (d, 1H, J=9.1 Hz), 7.11 (d, 2H, J=8.0 Hz), 7.41 (d, 2H, J=8.0 Hz); 13C-NMR (400 MHz, CDCl3); δ 20.56, 20.61, 20.73, 21.15, 54.93, 62.25, 68.44, 73.14, 74.47, 75.70, 86.65, 95.36, 127.84, 129.71, 133.62, 138.70, 153.85, 169.45, 170.61; HRMS for C22H26NO9SCl3Na (M+Na) calcd 610.0266. found 610.0286. Anal. Calcd for C22H26NO9SCl3: C, 45.03; H, 4.47; N, 2.39. Found: C, 45.46; H, 4.26; N, 2.30.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.C([O-])([O-])=O.[K+].[K+].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].C(OCC)(=O)C>CN1CCCC1=O.[Cu]I>[C:19]1([CH3:24])[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12
Reactant: Cc1ccccc1Br
Reactant: O=C1CN2C(=O)CCC2N1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccccc1N1C(=O)CN2C(=O)CCC21
Yield: 15.4 %

Procedure:
To a solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (1.3 g, 9.28 mmol, prepared as described in J. Med. Chem. 36,4214, 1994) in N-methylpyrrolidone (NMP, 12 cc), CuI (0.5 g, 2.62 mmol), K2CO3 (1.3 g, 9.28 mmol) and 2-bromotoluene (6 g, 35 mmol) were added under stirring. The suspension was heated in a microwave apparatus (250 Watt) for 1 h. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2Cl2. The organic phases were gathered and dried over Na2SO4, filtered and concentrated to dryness. The residue was triturated with Et2O. The solid was filtered, and crystallized the first time with iPrOH and then with AcOEt to yield 0.33 g of the title compound, mp=138-139° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH4+].[Cl-]>C1COCC1.CCCCCC>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)([OH:28])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
A solution of 44.8 g of 1-bromo-4-methoxybenzene in 700 ml of THF is cooled to −78° C., 168 ml of a 1.6M solution of n-butyllithium in hexane are added dropwise and the mixture is then stirred at −78° C. for 30 minutes. The solution of 45.3 g of 1-benzyl-4-piperidinone in 100 ml of THF is then added dropwise and the mixture is stirred at −78° C. for 2 hours. The reaction mixture is poured into 400 ml of saturated NH4Cl solution and extracted with ether, the organic phase is washed with water, with saturated NaCl solution and dried over MgSO4, and the solvent is evaporated off under vacuum. 48.6 g of the expected product are obtained after crystallization from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH:8]=[CH:9][N:10](C)C)[S:5][CH:6]=1.O.[NH2:15]N>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:8]=[CH:9][NH:10][N:15]=2)[S:5][CH:6]=1
Reactant: CN(C)C=CC(=O)c1cc(Cl)cs1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Clc1csc(-c2cc[nH]n2)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 1-(4-chloro-2-thienyl)-3-(dimethylamino)prop-2-en-1-one (24.6 mmol) and hydrazine hydrate (49.2 mmol) in 25 mL ethanol was refluxed for 15 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and dried in vacuum to afford 4.5 g (99% yield) 3-(4-chloro-2-thienyl)-1H-pyrazole which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=1)([F:7])[F:6])C.FC(F)(CCC1C=CC=CC=1)CO>>[Br:14][C:10]1[CH:9]=[C:8]([C:5]([F:6])([F:7])[CH2:4][OH:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(F)(F)c1cccc(Br)c1
Agent: OCC(F)(F)CCc1ccccc1
Product: OCC(F)(F)c1cccc(Br)c1

Procedure:
Obtained from Intermediate 48 (21.1 g, 75.8 mmol) by the procedure described in Intermediate 2. The title compound was obtained (17.2 g, 96%) as oil.
Reaction SMILES: Cl[C:2]1[C:3]([O:16][CH2:17][C:18]2(C(F)(F)F)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].ClC1C(OCC2CCCCC2)=C[C:32](F)=[C:33]([CH:41]=1)C(OC(C)(C)C)=O>>[CH:18]1([CH2:17][O:16][C:3]2[C:2]([CH:41]3[CH2:33][CH2:32]3)=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])=[C:5]([F:15])[CH:4]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCCCC2)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 3 and making variations as required to replace tert-butyl 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)-methoxy)benzoate with tert-butyl 5-chloro-4-(cyclohexylmethoxy)-2-fluorobenzoate, the title compound was obtained as colorless oil (13.73 g, 88%): MS (ES+) m/z 387.2 (M+39).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:9]=[C:8]([C:16](O)=[O:17])[C:7]1=[O:19].C(Cl)(=O)C([Cl:27])=O.CN(C)C=O>ClCCl>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:9]=[C:8]([C:16]([Cl:27])=[O:17])[C:7]1=[O:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccccc1Cn1c(=O)c(C(=O)O)cc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccccc1Cn1c(=O)c(C(=O)Cl)cc2cccnc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
3.83 g (12.3 mmol) of 1-(2-methoxybenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (100 mL), and 7.5 mL (89 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for one hour at 40° C. The reaction solution was concentrated under reduced pressure, and thus 1-(2-methoxybenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (100 mL), and this solution was added to a dichloromethane (100 mL) solution of 1.52 g (13.6 mmol) of 1,3-cyclohexanedione and 2.11 mL (14.8 mmol) of triethylamine under ice cooling. The mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated. The residue was washed with diisopropyl ether, and thus 4.82 g of the title compound was obtained as a light yellow solid (yield: 97%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.O1CCOCC1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: C1CCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc(N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
2 g (0.012 mol) of 2-amino-6-chloro-3-nitropyridine, 30 ml of dioxane and 20 ml of water, and 1.8 g of pyrrolidine are charged to a fully equipped round-bottomed flask. The mixture is brought to 70° C. for one hour with stirring and then the mixture is poured onto an ice/water mixture with stirring. The precipitate formed is filtered off and dried. 2.2 g of yellow powder are obtained, Yd=88%.
Reaction SMILES: [CH:1](=[O:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([Mg]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)C>[OH:7][CH:1]([C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccco1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: OC(c1ccccc1)c1ccco1
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
A solution of furfuraldehyde (288 g.) in diethyl ether (400 ml.) was added over 30 minutes to a stirred solution of phenyl magnesium bromide [prepared from bromobenzene (314 g.) and magnesium (48 g.)] in diethyl ether (1400 ml.) at -25° C. The cooling bath was removed and the mixture was allowed to attain 10° C. over 30 minutes. The mixture was recooled to 0° C. and saturated aqueous ammonium chloride solution was added at that temperature. The mixture was diluted with water (2 liters) and the organic phase was separated. The aqueous phase was filtered and extracted with diethyl ether (3 × 200 ml.) and the combined etheral solutions were dried over sodium sulphate, filtered and evaporated to dryness. The resulting pale red oil was distilled to give (±) 2-(α-hydroxybenzyl)furan (240 g.), b.p. 110°-130° C./0.05 mm.Hg.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[O:16]=[C:17]1[C:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][NH:20][C:19]([C:31]([OH:33])=O)=[CH:18]1.[C:34]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1)(=[O:37])[NH:35][NH2:36].O.ON1C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][O:38][C:34]([NH:35][NH:36][C:31]([C:19]2[NH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17](=[O:16])[CH:18]=2)=[O:33])=[O:37])=[CH:45][CH:44]=1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: COc1ccc(COC(=O)NN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COC(=O)NNC(=O)c2cc(=O)c(OCc3ccccc3)c[nH]2)cc1
Reaction time: 8 h
Yield: 17.7 %

Procedure:
A solution of 4.54 g (0.022 moles) dicyclohexylcarbodiimide in 25 ml dry of dimethylformamide was added to a stirred suspension of 4.90 g (0.020 moles) of 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid, 4.50 g (0.022 moles) of 4-methoxybenzyl carbazate, 0.12 g (1.0 mmol) of 4-dimethylamino-pyridine and 0.155 g (1.0 mmol) of 1-hydroxybenzotriazole hydrate in 25 ml of dry dimethylformamide at room temperature and stirring was continued overnight. The precipitate was filtered off and the filtrate was evaporated in vacuo. The residue solidified by stirring with ether and aqueous sodium bicarbonate and the solid was collected, washed with water and finally dried in vacuo. The crude material (8.14 g) was extracted in a soxhlet-apparatus with 800 ml CHCl3 (7 hours). 5.70 g (67%) of pure 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid, 2-[[(4-methoxyphenyl)methoxy]carbonyl]hydrazide crystallized directly from the cold CHCl3 -extract, and an additional impure amount (1.5 g, 18%) of the title compound could be obtained by evaporation of the CHCl3 -solution in vacuo; melting point 174.5°-178° C.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:28][C:29](=[O:31])[CH3:30].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>CN(C=O)C>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:28][C:29](=[O:31])[CH3:30])[CH2:12][CH2:13]1
Reactant: Oc1ccccc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1
Reactant: CC(=O)CCl
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1ccccc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-(1-((1S,2R,4R)-Bicyclo[2.2.1]heptan-2-yl)piperidin-4-yl)phenol (compound no. 229) (27.0 mg, 0.1 mmol) was dissolved in DMF (0.5 mL) and treated with K2CO3 (100 mg, 0.72 mmol) followed by the 1-chloropropan-2-one (19 mg, 0.4 mmol) and Nal (100 mg, 0.66 mmol) and the reaction was allowed to stir at room temperature for 48 h. The crude reaction mixture was filtered, diluted with DMSO to 1 mL and purified by LC/MS (10-99 CH3CN—H2O gradient with 0.03% TFA, 9 minute) to provide 1-(2-(1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)piperidin-4-yl)phenoxy)propan-2-one (compound no. 53) as the TFA salt. LC/MS (RP-C18, 10-99% CH3CN/0.05% TFA gradient over 5 min) m/z 327.0 [M+H]+, retention time 2.32 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]([CH3:9])[CH:3]=1.[C:10]([O:13]C(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:9][O:13][C:10](=[O:12])[CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)cc[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OCc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-methylpyridine-1-oxide (4.00 g, 21.40 mmol) in DCM (20 mL) is added acetic anhydride (6 mL). The mixture is stirred at room temperature for 1 hour and then heated at reflux overnight. The solvent is removed under vacuum and the crude product is filtered through a silica plug, eluting with DCM to afford the title compound as an orange oil (815 mg).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[C:22]([NH2:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>ClCCl>[CH2:9]([O:16][C:17]1[C:22]([NH2:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([Br:1])[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1c(OCc2ccccc2)ccc(F)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: Nc1c(OCc2ccccc2)cc(Br)c(F)c1F

Procedure:
A round bottom flask containing N-bromosuccinimide (0.52 mg, 2.93 mmol), and dichloromethane (5 mL) is stirred in an ice bath. A solution of the 6-benzyloxy-2,3-difluoro-phenylamine (0.69 mg, 2.93 mmol) in 10 mL of dichloromethane is added quickly in one portion. The resulting mixture is stirred for 20 min then water is added and the resulting mixture is extracted twice with DCM. The organic portion is dried over MgSO4, filtered and concentrated to afford the title compound, which is used directly in the next step without purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([NH2:19])=[N:15][NH:16]2)=[CH:12][CH:11]=1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([NH:19][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[N:15][NH:16]2)=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2cc(Cl)ccc12)c1cccs1
Temperature: 6 °C
Reaction time: 17 h

Procedure:
0.64 cm3 of 2-thiophenecarbonyl chloride is added to 1 g of 6-chloro-1H-indazole-3-amine in 15 cm3 of pyridine, after cooling to about 6° C. with an ice bath, the reaction medium is then allowed to return to room temperature over 17 hours and concentrated to dryness under reduced pressure (2 kPa; 45° C.), and the residue is then taken up in 20 cm3 of ethyl acetate, 20 cm3 of water and 20 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.), and the residue is then purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 15-40 μm; diameter 3 cm), eluting with a dichloromethane/methanol mixture (99/1 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); after drying (90 Pa; 50° C.), 660 mg of N-(6-chloro-1H-indazol-3-yl)-2-thiophenecarboxamide are obtained in the form of a pale yellow solid melting at 215° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 100 °C
Yield: 90 %

Procedure:
A stirred mixture of 2-chloro-5-nitropyridine (3.16 g, 20.0 mmol), 1-methyl-piperazine (2.00 g, 2.00 mmol) and potassium carbonate (2.76 g, 20.0 mmol) in DMF is heated at 100° C. for 24 h, cooled, poured into water and extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (SiO2, 2% ammonia in 10:90 ethanol:ethyl acetate as eluent) affords the title compound as an off-white solid, 4.0 g (90% yield), identified by NMR analysis.