Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[I:22]I.S(=O)(=O)(O)O.[N+]([O-])(O)=O>C(O)(=O)C>[I:22][C:3]1[CH:4]=[C:5]([C:19]([OH:21])=[O:20])[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C:2]=1[CH3:1]
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: II
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1c(I)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 85.7 %

Procedure:
To acetic acid (263.7 L, 6.8 rel vol) was charged 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (38.6 kg, 1 mol eq, limiting reagent), iodine (17.4 kg, 0.53 mol eq) and concentrated sulfuric acid (3.7 L, 0.1 rel vol). The temperature was adjusted to 50° C.-55° C. and 90% nitric acid (4.1 kg, 0.6 mol eq) charged over 15 minutes. The reaction was stirred until deemed to be complete as judged by HPLC analysis. The reaction was cooled, stirred and the product collected by filtration. The solid was washed twice with water (2×77.0 L, 2×2 rel vol) and acetone (2×38.6 kg, 2×1 rel vol). The solid was dried under vacuum to constant weight to yield the title compound (47.0 kg, 111.0 mol, 85.7%).
Reaction SMILES: N1C=NN=N1.C(N(CC)[P:9]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])C.[OH:22][C:23]1[CH:24]=[CH:25][C:26]2[N:48]([CH:49]=1)[C:29]1[N:30]([C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)[C:31](=[O:38])[C:32]3[C:37]([C:28]=1[N:27]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3.C([O:54]O)(C)(C)C.O>C(#N)C>[N+:45]([C:42]1[CH:43]=[CH:44][C:39]([N:30]2[C:29]3[N:48]4[CH:49]=[C:23]([O:22][P:9](=[O:54])([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:24]=[CH:25][C:26]4=[N:27][C:28]=3[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:38])=[CH:40][CH:41]=1)([O-:47])=[O:46]
Reactant: CC(C)(C)OO
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Reactant: O=c1c2ccccc2c2nc3ccc(O)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Agent: c1nnn[nH]1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OP(=O)(Oc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetrazole (2.0 equiv., 5.37 mmol, 0.38 g) and di-(tert-butyl) diethylphosphoramidite (1.6 equiv., 4.30 mmol, 1.07 g) were added to a solution of 10 (1.0 equiv., 2.69 mmol, 1.00 g) in anhydrous acetonitrile under Ar atmosphere. The reaction mixture was stirred at room temperature for 1 h. A 70% tert-butyl hydroperoxide solution in water (5.0 equiv., 13.45 mmol, 1.73 g) was added slowly and stirring was continued for 1 h. The reaction mixture was filtered through a glass filter and the filtrate was evaporated under reduced pressure. Purification by column chromatography (dichloromethane/methanol 97.2:2.5) afforded phosphoric acid di-tert-butyl ester 6-(4-nitrophenyl)-5-oxo-5,6-dihydro-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-9-yl ester (I21). A suspension of I21 in a 4 M HCl solution in isopropanol was stirred at room temperature overnight. The solvent was removed under reduced pressure to give phosphoric acid 5,6-dihydro-6-(4-nitrophenyl)-5-oxo-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-9-yl ester (76) as a hydrochloride salt (0.47 g, yield=36%, purity (LC)>95%).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]2[C:5]([C:6](=[O:15])[C:7](=[O:14])[NH:8]2)=[CH:4][CH:3]=1.[CH3:16][O-:17].[Na+].Cl>CO>[CH3:16][O:17][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]2[C:5]([C:6](=[O:15])[C:7](=[O:14])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2c(ccc(Cl)c2[N+](=O)[O-])C1=O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1[N+](=O)[O-])NC(=O)C2=O
Temperature: 60 °C
Reaction time: 14 h
Yield: 69 %

Procedure:
To a solution of 6-chloro-7-nitro-1H-indole-2,3-dione (2.0 g, 8.83 mmol) in methanol (20 mL) was added a solution of sodium methoxide in methanol (28%, 3.8 mL) at room temperature. The mixture was stirred at 60° C. for 14 hr. 1N Hydrogen chloride (10 mL) was added to the reaction mixture at 0° C. and the mixture was extracted with ethyl acetate. The organic layer was washed with brine (×3), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture to give the title compound (1.349 g, 6.07 mmol, 69%) as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:7][C@H:8]([C@@H:30]([NH:38][C:39](=[O:49])[C@H:40]([CH:46]([CH3:48])[CH3:47])[NH:41][C:42]([O:44][CH3:45])=[O:43])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][N:10]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[NH:11][C:12](=[O:22])[C@H:13]([CH:19]([CH3:21])[CH3:20])[NH:14][C:15]([O:17][CH3:18])=[O:16]>CN(C1C=CN=CC=1)C.O1CCOCC1.N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:7][C@H:8]([C@@H:30]([NH:38][C:39](=[O:49])[C@H:40]([CH:46]([CH3:48])[CH3:47])[NH:41][C:42]([O:44][CH3:45])=[O:43])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:9][N:10]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[NH:11][C:12](=[O:22])[C@H:13]([CH:19]([CH3:20])[CH3:21])[NH:14][C:15]([O:17][CH3:18])=[O:16])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCC(=O)O[C@@H](CN(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OC)C(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
50 μ(0.495 mmol) of butyric acid chloride and 2 mg (0.017 mmol) of DMAP are added to an ice-cooled mixture of 200 mg (0.33 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(methoxy-carbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[N-methoxycarbonyl-(L)-valyl]-hydrazine (Example 73a) in 2.6 ml of dioxane and 0.4 ml of pyridine. After 18 h at RT, according to HPLC there is still 1-[2(S)-hydroxy-3(S)-(N-(methoxycarbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[N-methoxycarbonyl-(L)-valyl]-hydrazine present in the reaction mixture, and therefore a further 0.75 equivalents of butyric acid chloride and a few granules of DMAP are added. After a further 18 h, a 3rd portion of 1.5 equivalents of butyric acid chloride is added and the mixture is further stirred for one night at RT (→HPLC: fully reacted). The reaction mixture is diluted with ethyl acetate and washed with 2 portions of saturated NaHCO3 solution, water and brine, the aqueous phases are extracted twice with ethyl acetate, and the organic phases are dried with Na2SO4 and concentrated by evaporation. Digestion of the oily residue from hexane in an ultrasound bath yields the pure title compound: TLC Rf (O)=0.67; tRet (V)=17.2 min; FAB-MS (M+H)+ =676.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:12].Br[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:12])[CH3:20]
Reactant: Nc1ccc2ccccc2c1N
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCNc1c(N)ccc2ccccc12

Procedure:
A solution of VII (11.4 g, 58 mmol) and ethyl 3-bromopropionate (7.5 mL, 58 mmol) in DMF (120 mL) was heated to 50° C. for 8 h. The reaction mixture was poured into water and neutralized with NaHCO3. The products were extracted into CH2Cl2 (2×200 mL). The combined organics were washed with water (4×200 mL) and dried over Na2SO4. The solvent was evaporated in vacuo and the products separated by flash chromatography using 27% EtOAc in hexane as the eluant to give the product VIII, 2.60 g (17%) as a brown solid: MS m/z 259 (MH+); 1H NMR (DMSO-d6) δ 1.22 (t, 3H), 2.64 (t, 2H), 3.09 (br t, 2H), 4.05 (br s, 1H), 4.09 (q, 2H), 5.19 (br s, 2H), 7.04 (d, 1H), 7.13 (dd, 1H), 7.33 (dd, 1H), 7.40 (d, 1H), 7.66 (d, 1H) and 7.97 (d, 1H); and the product XII, 2.06 g (13%) as a brown solid: MS m/z 259 (MH+); H NMR (DMSO-d6) d 1.21 (t, 3H), 2.63 (t, 2H), 3.43 (br m, 2H), 4.10 (q, 2H), 4.65 (br s, 1H), 4.97 (br s, 2H), 7.04 (d, 1H), 7.11-7.18 (m, 2H), 7.27 (dd, 1H), 7.62 (d, 1H), and 7.94 (d, 1H)
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[Cl:13][C:14]([Cl:25])([Cl:24])[CH:15]1[N:19]2[CH2:20][CH2:21][CH2:22][CH:18]2[C:17](=[O:23])[O:16]1.C(Br)C=C.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([C:18]12[CH2:22][CH2:21][CH2:20][N:19]1[CH:15]([C:14]([Cl:13])([Cl:24])[Cl:25])[O:16][C:17]2=[O:23])[CH:1]=[CH2:2]
Reactant: O=C1OC(C(Cl)(Cl)Cl)N2CCCC12
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC12CCCN1C(C(Cl)(Cl)Cl)OC2=O
Temperature: -68 °C
Reaction time: 0.67 h

Procedure:
To a solution of diisopropylamine (60 ml) in tetrahydrofuran (160 ml) was added dropwise n-butyllithium (2.64M hexane solution, 161 ml) over 20 minutes under ice-cooling, and the mixture was directly stirred for 40 minutes. To the mixture cooled to −68° C. was added dropwise a solution of 3-trichloromethyltetrahydropyrrolo[1,2-c]oxazol-1-one (80.0 g) in tetrahydrofuran (640 ml) over 30 minutes, and the mixture was directly stirred for 20 minutes. To the mixture was added allyl bromide (57 ml), and the mixture was directly stirred for 1 hour. To the reaction mixture was added saturated aqueous ammonium chloride solution (1000 ml), and the mixture was extracted with ethyl acetate (800 ml). The separated organic layer was washed with water (800 ml) and saturated aqueous sodium chloride solution (500 ml). The separated aqueous layer was extracted with ethyl acetate (400 ml, 500 ml) twice. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the titled compound (86.1 g).
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([N:25]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)[CH:22]=[CH:23][CH:24]=4)[CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[N:6]1.Cl.CCOCC>CO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]5)[CH:20]=4)[CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[N:6]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3cnc4[nH]cc(-c5cnn(Cc6cc(F)ccc6F)c5)c4c3)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Fc1ccc(F)c(Cn2cc(-c3c[nH]c4ncc(-c5cccc(N6CCNCC6)c5)cc34)cn2)c1
Reaction time: 4 h
Yield: 9.7 %

Procedure:
To a stirred solution of tert-butyl 4-(3-(3-(1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (Example-31) (200 mg, 0.351 mmol) in methanol (5 ml) added saturated HCl in methanol at 0° C. This gradually brought to RT and stirred for four hours. Reaction mass was cooled and added ether to get solids. Solvents decanted and solids washed by ethyl acetate and dried. This residue was made free base using saturated sodium carbonate. This afforded 16.0 mg (9.75% yield) of titled compound after purification by preparative TLC (SiO2 using 3% methanol in chloroform as eluent). 1H NMR (CD3OD, 300 MHz): δ 8.557-8.550 (d, 1H), 8.192-8.184 (d, 1H), 7.866 (s, 1H), 7.762 (s, 1H), 7.446-7.360 (m, 2H), 7.160-7.10 (m, 2H), 7.05-6.85 (m, 3H), 5.420 (s, 2H), 3.276-3.242 (m, 4H), 3.119-3.086 (m, 4H). MS: m/z=470.9 (M+1); HPLC: 97.41% in method A.
Reaction SMILES: [H-].[Na+].[C:3]([SH:6])(=[O:5])[CH3:4].CS(O[C@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C@H:14]([CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][N:33]3[N:37]=[CH:38][CH:39]=[C:32]23)[CH2:13]1)(=O)=O>CN(C)C=O>[C:3]([S:6][C@@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[C@H:14]([CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][N:33]3[N:37]=[CH:38][CH:39]=[C:32]23)[CH2:13]1)(=[O:5])[CH3:4]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CN2CCCn3nccc32)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(=O)S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](CN2CCCn3nccc32)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C

Procedure:
To a solution of sodium hydride (60% suspension in oil, 0.27 g) in N,N-dimethylformamide (15 ml) was added dropwise thioacetic S-acid (0.51 ml) with stirring under ice-cooling. The mixture was stirred at the same temperature for 30 minutes. A solution of (2S,4R)-4-methanesulfonyloxy -1-(4-nitrobenzyloxycarbonyl)-2-{4,5,6,7-tetrahydropyrazolo [1,5-a]pyrimidin-4-yl)methylpyrrolidine (2.65 g) in N,N-dimethylformamide (15 ml) was added to the mixture obtained above with stirring at the same temperature and the mixture was stirred at 80°~90° C. for 2 hours. The reaction mixture was poured into ice-water (100 ml) and extracted twice with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl) -2-{4,5,6,7-tetrahydropyrazolo-[1,5-a]pyrimidin-4-yl}methylpyrrolidine (2.23 g).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].O.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH:2]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][CH:6]=1)#[N:9]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
4-Acetylbenzonitrile (44al, 1.00 g, 6.9 mmol), sodium hydroxide (0.40 g, 10.0 mmol) and water (20 ml) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. Benzaldehyde (1b, 0.70 ml, 6.9 mmol) was added and the mixture stirred for 2 hr at room temperature. The resulting mixture was filtered and recrystallized from ethanol to give 1.46 g (91%) of a yellow solid: mp 120° C. [expected mp 119-120° C.]; 1H NMR: δ 7.34 (m, 3H), 7.62 (m, 2H), 7.80 (m, 4H), 8.06 (d, 2H, J=8.1 Hz); 13C NMR: δ 115.9, 117.9, 121.1, 128.6, 128.8, 129.0, 131.0, 132.4, 134.3, 141.4, 146.4, 188.9.
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2].[C:14]([O:18][C:19]([NH:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24]Cl)=[O:20])([CH3:17])([CH3:16])[CH3:15].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[C:14]([O:18][C:19]([NH:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24][O:12][C:11]1[C:6]2[N:7]([C:3]([CH:1]=[O:2])=[C:4]([CH3:13])[N:5]=2)[CH:8]=[CH:9][CH:10]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1nc2c(O)cccn2c1C=O
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)OC(C)(C)C)c1COc1cccn2c(C=O)c(C)nc12

Procedure:
Starting from 3-formyl-8-hydroxy-2-methylimidazo[1,2-a]pyridine (2.4 g), 2-tert-butoxycarbonylamino-6-methylbenzyl chloride (4.2 g), sodium iodide (2.5 g) and sodium carbonate (3.7 g) in acetone (400 ml) analogously using the process of Example B1 gives, after recrystallization from diisopropyl ether/ethyl acetate, 4.4 g (80%) of the title compound of m.p. 189-191° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:22])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[CH:4]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>CN(C)C=O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:4]=1)=[O:22]
Reactant: CCCCCBr
Reactant: COc1ccccc1CC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCn1cc(C(=O)Cc2ccccc2OC)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 49 %

Procedure:
60% Sodium hydride in mineral oil (1.8 g, 45.23 mmol) was suspended in dimethylformamide (100 ml) and 1-(1H-indol-3-yl)-2-(2-methoxyphenyl)ethanone 3 (10 g, 37.70 mmol) was added portionwise at room temperature, allowing to stir further 45 min at room temperature after the addition was finished. 1-Bromopentane (7.02 ml, 56.55 mmol) was added dropwise at room temperature and the reaction mixture was stirred at room temperature overnight. Water (200 ml) was added and the mixture was extracted three times with ethyl acetate (3×200 ml). The organic fractions were combined, washed with water (200 ml) and brine (200 ml) and dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (Biotage Isolera 4, SNAP-100 g, 5%-20% ethyl acetate hexane containing 5% dichloromethane) to give 6.2 g (41%) of 2-(2-methoxyphenyl)-1-(1-pentyl-1H-indol-3-yl)ethanone (JWH-250) 4 as an orange/tan solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][O:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1.[CH:27]([N:30](CC)C(C)C)(C)C.N#CBr>C(#N)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][N:22]([C:27]#[N:30])[CH2:21][CH2:20]2)=[CH:25][CH:26]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Brc1ccc(COC[C@@H]2C[C@@H]2C2CCNCC2)cc1
Agent: N#CBr
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: N#CN1CCC([C@H]2C[C@H]2COCc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from step B (1.00 g, 3.08 mmol) and N,N-diisopropylethylamine (1.61 mL, 9.25 mmol) were dissolved in acetonitrile (20 mL). Cyanogen bromide (5M in acetonitrile, 0.746 mL, 3.7 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned between CH2Cl2 and water. The organic layer was saved and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered and evaporated to yield a crude material, which was purified by silica gel column chromatography (gradient elution 0% to 100% EtOAc in hexanes) to yield the title compound as a viscous oil.
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]([CH3:19])[C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[C:4]([CH3:20])[CH:3]=1.[Li]CCCC.[CH3:26][S:27]SC>C1COCC1>[CH3:19][C:17]1[CH:18]=[C:2]([S:27][CH3:26])[CH:3]=[C:4]([CH3:20])[C:5]=1[O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9]
Reactant: Cc1cc(Br)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cc(C)c(O[Si](C(C)C)(C(C)C)C(C)C)c(C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To a stirring solution of (4-bromo-2,6-dimethylphenoxy)-triisopropylsilane (0.5 g, 1.4 mmol) in THF (15 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 0.56 mL), the reaction mixture was stirred at −78° C. for 1 hr, then dimethyldisulfide (0.16 mL, 1.82 mmol) was added at −78° C. The reaction mixture was stirred at room temperature for 1 h and quenched with saturated NH4Cl and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude (2,6-dimethyl-4-methylsulfanylphenoxy)triisopropyl-silane as an oil (0.46 g, 100%): 1H NMR (300 MHz, DMSO-d6): δ 6.92 (s, 2 H), 2.41 (s, 3 H), 2.20 (s, 6 H), 1.29 (m, 3 H), 1.10 (d, J=7.2 Hz, 18 H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (2:98); Rf=0.57.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=3)=[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1.O.[O:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH:33]1([C:36]([N:23]([C:19]2[CH:18]=[C:17]([C:16]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9][N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[C:44]([CH:43]2[CH2:41][CH2:42]2)=[O:40])=[O:37])[CH2:35][CH2:34]1
Reactant: C1CCOC1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2CCCC3)ccn1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CC1)N(C(=O)C1CC1)c1cc(-c2c(-c3ccc(F)cc3)nn3c2CCCC3)ccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
154 mg (0.5 mmol) of 4-[2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl]pyridin-2-amine and 193 mg (1.5 mmol, 3 eq) of Huenigs base are dissolved in 4 mL tetrahydrofuran. To this are added 156 mg of cyclopropanecarbonyl chloride (1.5 mmol, 3 eq) and the reaction mixture is stirred for 20 hrs at room temperature. Then the reaction mixture is treated with water and extracted with ethyl acetate. The organic phases are dried over Na2SO4 and the solvents are removed under vacuum. The crude material is purified by column chromatography on silica (eluent cyclohexane/ethyl acetate). 180 mg (75%) of N-(cyclopropylcarbonyl)-N-{4-[2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl}cyclopropanecarboxamide are obtained as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]#[CH:21])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:22]([C@@H:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH3:26])=[N+:23]=[N-:24].[Na].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.O>O1CCOCC1.C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:24]=[N:23][N:22]([C@@H:25]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)[CH3:26])[CH:21]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C#CC[C@@H]1C(=O)NC=CN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc([C@@H](C)N=[N+]=[N-])cc1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na]
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1ccc([C@@H](C)n2cc(C[C@@H]3C(=O)NC=CN3S(=O)(=O)c3ccc(Cl)c(Cl)c3)nn2)cc1
Reaction time: 0.08 h

Procedure:
To a solution of (R)-4-(3,4-dichlorobenzenesulfonyl)-3-(prop-2-ynyl)-3,4-dihydro-pyrazin-2(1H)-one (1.46 g, 4.24 mmol) and (R)-methyl 4-(1-azidoethyl)benzoate (0.870 g, 4.24 mmol) in dioxane (80 mL) and tert-butanol (120 mL) were added CuSO4.5H2O (1.11 g, 4.46 mmol in 8.0 mL H2O) and sodium-L-ascorbate (0.880 g, 4.44 mmol in 8.0 mL H2O). After 5 min, H2O (40 mL) was added and the reaction mixture was stirred for 16 h. The solvent was concentrated to approximately 40 mL under reduced pressure and diluted with 200 mL EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (1×100 mL). The extracts were washed with 5% NaHCO3 (200 mL×2), brine (200 mL×2), dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on silica (100% CH2Cl2 to 10% MeOH in CH2Cl2) to yield the title compound.