Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[C:12](Cl)=[N:13][CH:14]=[N:15][C:16]=3Cl)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[C:12]([NH:32][S:29]([C:26]4[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:20])[CH3:21])=[CH:24][CH:25]=4)(=[O:30])=[O:31])=[N:13][CH:14]=[N:15][C:16]=3[O:1][CH2:5][CH2:4][OH:3])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: Clc1ncnc(Cl)c1Oc1ccc2c(c1)OCO2
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ncnc(OCCO)c2Oc2ccc3c(c2)OCO3)cc1

Procedure:
By reacting 5-(1,3-benzodioxol-5-yloxy)-4,6-dichloropyrimidine with p-tert-butylphenylsulfonamide and thereafter with ethylene glycol Na, there was obtained N-[5-(1,3-benzodioxol-5-yloxy)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-p-tert-butylbenzenesulfonamide as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.I[CH2:19][CH2:20][CH2:21][CH3:22]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:17][CH2:19][CH2:20][CH2:21][CH3:22])[C:6]([CH3:15])([CH3:16])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Reactant: CCCCI
Product: CCCCOc1cc2c(cc1Br)C(C(C)C)=CCC2(C)C
Yield: 66 %

Procedure:
Following General Procedure O, 3-bromo-5-isopropyl-8,8-dimethyl-7,8-dihydronaphthalen-2-ol (Compound 97, 0.36 g, 1.2 mmol) was reacted with 1-iodobutane to afford 0.28 g (66%) of the title compound as a clear oil.
Reaction SMILES: [CH3:1][N:2]([CH3:57])[C:3]1[S:4][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([C@H:17]([CH2:23][C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][C:33]=3[O:34][CH3:35])[C:30]([NH:36]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:29][CH:28]=[CH:27]4)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]2=[O:56])(=[O:10])=[O:9])=[CH:6][N:7]=1.[Cl:58]CCl>O1CCOCC1.Cl>[ClH:58].[CH2:21]([O:20][C:18](=[O:19])[C@H:17]([N:14]1[CH2:15][CH2:16][C@H:12]([NH:11][S:8]([C:5]2[S:4][C:3]([N:2]([CH3:1])[CH3:57])=[N:7][CH:6]=2)(=[O:9])=[O:10])[C:13]1=[O:56])[CH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[C:30]([NH2:36])=[N:29][CH:28]=[CH:27]2)[CH3:22]
Reactant: CCOC(=O)[C@@H](Cc1cc2ccnc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1OC)N1CC[C@H](NS(=O)(=O)c2cnc(N(C)C)s2)C1=O
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](Cc1cc2ccnc(N)c2cc1OC)N1CC[C@H](NS(=O)(=O)c2cnc(N(C)C)s2)C1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The ethyl (2R)-2-[(3S)-3-(2-(dimethylamino)thiazol-5-ylsulphonylamino)-2-oxopyrrolidin-1-yl]-3-(7-methoxy-1-(tritylamino)isoquinolin-6-yl)propanoate obtained above (0.35 g, 0.44 mmol) is dissolved in 5 ml of dichloromethane. The medium is cooled to 0° C. and 0.5 ml of a 4N solution of hydrochloric acid in dioxane is added. The medium is stirred at 20° C. for 18 h. It is concentrated to dryness and the residue is triturated from ether and filtered off. It is purified on a column of silica (40 g, gradient CH2Cl2/MeOH/NH4OH; 100:0 to 90:10:0.5). The product thus obtained is dissolved in 5 ml of dichloromethane and salified with 0.5 ml of a 4N solution of hydrochloric acid in dioxane. The medium is concentrated and the residue is triturated from ether and dried over P2O5. 230 mg of a solid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C1C(=O)N([Cl:21])C(=O)C1.CCOC(C)=O>CN(C=O)C>[Cl:21][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:13]
Reactant: COc1ccc2cc(O)ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cl)c(O)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To a solution of 6-methoxynaphthalen-2-ol (1.00 g, 5.74 mmol) in DMF (15 mL) was added NCS (843 mg, 6.31 mmol). The reaction mixture was stirred at 25° C. for 16 hours. Diluted the reaction with EtOAc, washed with H2O and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by silica gel column (PE/EtOAc=100/1) gave the product (940 mg, yield 87%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[N:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH3:24])[CH:17]=1)([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:6][C:5]=1[C:16]1[N:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[CH:26]=2)[CH3:24])[CH:17]=1
Reactant: CC(Nc1cc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])ncn1)c1cccc(C(F)(F)F)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(Nc1cc(-c2cc(N3CCCCC3)ccc2N)ncn1)c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 6-(2-nitro-5-(piperidin-1-yl)phenyl)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrimidin-4-amine (400 mg, 0.85 mmol, 1.00 equiv) in acetic acid (5 mL). To this was added zinc (552 mg, 8.62 mmol, 10.00 equiv) in several batches at 70° C. The resulting solution was stirred for 1 h at 70° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The solution was adjusted to pH 8 with ammonia (1 mol/L). The resulting solution was extracted with 4×50 ml of ethyl acetate and the organic layers combined, dried over sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with methanol:dichloromethane (1:50). The product was obtained as 200 mg (53%) of a black solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([Br:8])[Br:7])[C@H:3]1[C:9]([OH:11])=[O:10].Cl[CH2:14][C:15]1[N:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCCOCCOCCOCCOCC1.C(C(C)=O)C>[CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([Br:8])[Br:7])[C@H:3]1[C:9]([O:11][CH2:14][C:15]1[N:19]=[C:18]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[S:17][N:16]=1)=[O:10]
Reactant: ClCc1nsc(Oc2ccccc2)n1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C=C(Br)Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1(C)[C@H](C(=O)OCc2nsc(Oc3ccccc3)n2)[C@@H]1C=C(Br)Br
Reaction time: 24 h
Yield: 59.9 %

Procedure:
A mixture of 3.3 g of (1R,3R) 2,2-dimethyl-3-(2,2-dibromoethenyl)-cyclopropane-1-carboxylic acid, 2.2 g of the product of Step A, 1.5 g of potassium carbonate, 100 mg of 1,4,7,10,13,16-hexaoxacyclooctadecane and 50 ml of methyl ethyl ketone wasrefluxed for 24 hours and was evaporated to dryness under reduced pressure.The residue was added to water and the aqueous mixture was extracted with ethyl acetate. The organic phase was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution withbenzene yielded 2.84 g of [5-phenoxy-(1,2,4)-thiadiazol-3-yl]-methyl (1R,3R) 2,2-dimethyl-3-(2,2-dibromoethenyl)-cyclopropane-1-carboxylate.
Reaction SMILES: [OH:1][C:2]1[C:3](=O)[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH-].[Na+].Cl.[CH3:17][O:18][NH2:19]>C(O)C>[CH3:17][O:18][N:19]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:12])[CH:11]=[C:2]1[OH:1]
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C1C(O)=CC(=O)c2ccccc21
Yield: 94.4 %

Procedure:
2-Hydroxy-1,4-naphthoquinone (3 g, 17 mmol) was dissolved in ethanol (30 mL) and aqueous sodium hydroxide (1N, 51 mL, 51 mmol) and treated with methoxyamine hydrochloride (2.86 g, 34 mmol) at 80° C. for 5 h. The mixture was cooled, the solvents were evaporated, and the crude mixture was acidified using 10% HCl (20 mL). The solids were filtered, rinsed with water, and dried in the vacuum to give the title compound (3.26 g, 93%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:20]#[C:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][CH2:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(C#Cc3nccs3)c2CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCc3nccs3)c2CC1
Yield: 9.9 %

Procedure:
Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-(thiazol-2-ylethynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (160 mg, 0.41 mmol) in ethanol (10 mL) to a suspension of 10% Pd/C (Degussa type E101, 160 mg), then acetic acid (0.5 mL). Hydrogenate for 7 h (68-70 psi) then filter the catalyst through Celite® and concentrate in vacuo. Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 4:1 gradient over 40 min) to obtain the desired intermediate (16 mg, 10%). MS (ES+) m/z: 393 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[N:10]([CH3:15])[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O>CO.ClCCl.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[N:10]([CH3:15])[C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: CN1C(=O)c2cc([N+](=O)[O-])ccc2C(C)(C)C1=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CN1C(=O)c2cc(N)ccc2C(C)(C)C1=O
Yield: 100.8 %

Procedure:
7-Nitro-2,4,4-trimethyl-4H-isoquinoline-1,3-dione (45 g, 20 mmol) was dissolved in a methanol (500 ml)/dichloromethane (100 ml) mixture and treated with 10% Pd/C (0.5 g). The reaction mixture was hydrogenated for 2 h before removal of the palladium catalyst by filtration through Celite. The filtrate was evaporated to dryness in vacuo to give the title compound (4.4 g, quant).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>>[O-:35][N+:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:6]2[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:4]([CH2:1][CH2:2][CH3:3])=[N:16][C:7]=2[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCCC(=O)OCC

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate ethyl 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (6.30 g, 17.8 mmol, available from Step 3 of Example 15) by reaction with m-CPBA (13.1 g) to provide ethyl 6-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate followed by reaction with p-toluenesulfonyl chloride (4.58 g, 24.0 mmol) and ammonium hydroxide solution (60 mL) to provide ethyl 6-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate as a tan solid after recrystallization from aqueous methanol, mp 112-113° C.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].F[C:8]1[C:25]([F:26])=[C:24]2[C:11]([CH2:12][C:13]3([C@H:22]4[C@H:30]([CH3:31])[O:29][C@H:28]([CH3:32])[CH2:27][N:23]42)[C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15][C:14]3=[O:21])=[CH:10][C:9]=1/[C:33](=[N:40]/[OH:41])/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[F:26][C:25]1[C:8]2[O:41][N:40]=[C:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:9]=2[CH:10]=[C:11]2[C:24]=1[N:23]1[CH2:27][C@@H:28]([CH3:32])[O:29][C@@H:30]([CH3:31])[C@@H:22]1[C:13]1([C:14](=[O:21])[NH:15][C:16](=[O:20])[NH:17][C:18]1=[O:19])[CH2:12]2
Reactant: C[C@@H]1CN2c3c(cc(/C(=N/O)c4ccccc4)c(F)c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN2c3c(cc4c(-c5ccccc5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 100 °C

Procedure:
Cs2CO3 (130 mg, 0.0004 mmol) was added to a solution of (2R,4S,4aS)-rel-9,10-difluoro-8-[(E)-(hydroxyimino)(phenyl)methyl]-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione (Intermediate 29, 100 mg, 0.0002 mmol) in DMF (1.5 mL), and the mixture was heated to 100° C. for 14 h. The reaction mixture was cooled to room temperature and filtered through a Celite bed. The solvent was removed, and the residue was subjected to reverse phase prep-HPLC purification (10 mM ammonium acetate in water, CH3CN) providing the title compound as a racemic mixture. Yield: 9.97 g (9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:5].[C:18](=O)([O-])[O-:19].[K+].[K+].C(Cl)(Cl)=O.C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]=[C:18]=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc(OCCc2ccccc2)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(OCCc2ccccc2)c(Cl)c1
Temperature: 85 °C

Procedure:
A mixture of 3-chloro-4-(phenethyloxy)aniline (16.06 g; 0.0648 mol), toluene (500 ml) and potassium carbonate (4.5 g; 0.035 mol) is prepared and maintained under nitrogen atmosphere. A. 12.5% solution of phosgene in benzene (65 ml; 0.072 mol) is added to the above mixture. A precipitate forms immediately. The mixture is heated at 85° C. for 45 minutes. By the end of this period the precipitate has dissolved. The reaction mixture is cooled down and filtered. The product is not isolated but rather it is used immediately.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.[Cl:12][C:13]1[CH:26]=[CH:25][C:16]([CH:17]([NH2:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:14]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:24][CH:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:16]1[CH:25]=[CH:26][C:13]([Cl:12])=[CH:14][CH:15]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: Clc1ccc(C(Nc2nc3ccccc3[nH]2)c2ccccc2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-chlorobenzhydrylamine HCl by Procedure A. The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 180-184° C.). MS(ES+)m/z 334 ([M+1]+, 100). 1NMR (DMSO-d6) δ 6.18 (d, 1H), 6.80-6.90 (m, 2H), 7.08-7.14 (m, 2H), 7.20-7.40 (m, 9H), 7.66 (d, 1 H), 10.6 (s, 1 H).
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: O
Solvent: CN(C)C=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: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)O)=[CH:2]1.S(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:20][CH:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1csc2ccccc12)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: ClC(c1csc2ccccc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of 1-benzothiophen-3-yl(cyclohexyl)methanol (2.32 g) synthesized above in toluene (25 mL) was added dropwise thionyl chloride (824 μL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (2.42 g, 97%) as an orange oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1.[C:16]([O:20][C:21]([NH:23][C:24]1([CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([OH:48])[CH:43]=3)=[CH:37][CH:36]=2)[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[O:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([O:20][C:21]([NH:23][C:24]1([CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH2:12][C:11]4[CH:14]=[CH:15][C:8]([Cl:7])=[CH:9][CH:10]=4)[CH:43]=3)=[CH:39][CH:40]=2)[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[O:26][CH2:25]1)=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)NC1(CCCc2ccc(Oc3cccc(O)c3)cc2)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(CCCc2ccc(Oc3cccc(OCc4ccc(Cl)cc4)c3)cc2)COC(C)(C)OC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Potassium carbonate (150 mg) and p-chlorobenzyl bromide (103 mg) were added to a DMF solution (5 mL) of the compound of Example 105 (150 mg) and the mixture was stirred for 1 hour at 70° C. Subsequently, the mixture was decanted into water and was extracted with ethyl acetate. The organic phase was sequentially washed with water and a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the desired product (170 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(CO)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccc(CO)o2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[5-(hydroxymethyl)-2-furyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (223 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=2:3→ethyl acetate) to give the title compound as a free base (basic TLC:Rf=0.03 (hexane:ethyl acetate=1:1)) (yield 142 mg). A solution of the obtained free base (141 mg) in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (43 mg) in ethanol (2 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 107 mg, 42%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:16][C:15]2=[O:30])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:31]>C(OCC)(=O)C>[ClH:31].[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:16][C:15]2=[O:30])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)OC(c3ccccc3)c3ccccc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1OC(c2ccccc2)c2ccccc2N1C1CCNCC1

Procedure:
1-(1-Boc-4-piperidyl)-4-phenyl-3,1-benzoxazin-2-one from Step 3 above (1.97 g, 4.67 mmol) was stirred in ethyl acetate in an ice bath, then saturated with HCl gas and stirred another 15 min in the cold. The mixture was evaporated in vacuo. Three portions of ethyl acetate were successively added and evaporated in vacuo to give 1-(4-piperidyl)-4-phenyl-3,1-benzoxazin-2-one hydrochloride.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:33]([NH2:36])[CH2:34][CH3:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH2:33]([NH:36][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])[CH2:34][CH3:35]
Reactant: CCCN
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with propylamine (0.019 ml, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with a 4:1 ethyl acetate-hexanes mixture. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 47 mg of the title compound.