Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:19])=[CH:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:7][CH:6]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26](Cl)=[O:27]>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26]([NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH3:19])=[CH:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:10]=1)=[O:27]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)CC=C(C)c1ccc(CCN)cc1
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(C(C)=CCC(=O)O)cc1

Procedure:
By the reaction of ethyl γ-[4-(2-aminoethyl)-phenyl]-but-2-ene-carboxylate hydrochloride with 5-chloro-2-methoxybenzoyl chloride, there is obtained γ-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-but-2-ene-carboxylic acid; m.p. 180°-183° C., after reprecipitation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][C:13](=[O:15])[O:12][C:10](=[O:11])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([OH:24])=[C:21]([CH:23]=1)[NH2:22]>ClCCl>[OH:24][C:20]1[CH:19]=[CH:18][C:17]([Cl:16])=[CH:23][C:21]=1[NH:22][C:13](=[O:15])[CH2:14][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: Nc1cc(Cl)ccc1O
Solvent: ClCCl
Product: O=C(O)CC(CC(=O)Nc1cc(Cl)ccc1O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
Prepared by dissolving an equimolar mixture of 3-(4-chlorophenyl)glutaric anhydride and commercial 5-chloro-2-hydroxyaniline in boiling dichloromethane. Upon cooling to rt product precipitates and yields after isolation 87% of N-(2-hydroxy-5-chlorophenyl)-3-(4-chlorophenyl)glutaramic acid as colourless crystals.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[F:7][CH:8]([F:28])[O:9][C:10]1[CH:18]=[CH:17][C:16]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13]>C(#N)C.O>[F:28][CH:8]([F:7])[O:9][C:10]1[CH:18]=[CH:17][C:16]([B:19]2[O:23][C:22]([CH3:24])([CH3:25])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:15][C:11]=1[C:12]([NH:14][CH3:1])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2ccc(OC(F)F)c(C(N)=O)c2)OC1(C)C
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC(F)F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), 2-difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (1.1 equiv) and tetrakis(triphenylphosphine) palladium0 (0.05 equiv) in acetonitrile/water (0.1 M of chloro-substrate) was stirred at 100° C. for 2 hours. Upon completion the reaction mixture was partitioned between water and CH2Cl2 and extracted with CH2Cl2. Combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the desired product.
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:5]=2[S:6][CH:7]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[OH-].[Na+]>C(OCC)C.C1COCC1>[NH2:2][CH2:1][C:3]1[C:4]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:5]=2[S:6][CH:7]=1
Reactant: Cc1cccc2scc(C#N)c12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc2scc(CN)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dropping a diethyl ether (20 ml) and THF (20 ml) solution containing 9.10 g (52.6 mmol) of the 3-cyano-4-methylbenzo[b]thiophene obtained in Step 4 into 50 ml of a diethyl ether suspension of 2.0 g (53 mmol) of lithium aluminum hydride over the course of 15 minutes at 0° C., the solution was stirred for 30 minutes at room temperature. Following completion of the reaction, excess LAH in the reaction solution was treated with hydrochloric acid followed by the addition of aqueous sodium hydroxide solution to make alkaline. After saturating the aqueous phase with potassium carbonate, extracting with dichloromethane and washing the organic phase with water, it was dried with magnesium sulfate. The solvent was then concentrated under reduced pressure to obtain 3-aminomethyl-4-methylbenzo[b]thiophene. 11.5 (250 mmol) of formic acid and 10.0 g (123 mmol) of 37% aqueous formaldehyde solution were sequentially added to this followed by stirring for 5 hours at 80° C. Following completion of the reaction, after adding aqueous hydrochloric acid solution to the reaction solution, it was concentrated under reduced pressure to remove the formic acid and formaldehyde. Aqueous sodium hydroxide solution was then added to make the solution alkaline followed by extraction with dichloromethane. After washing the organic phase with water, it was dried with magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 2.61 g (12.8 mmol) of the target compound (yield of the two steps: 24%). Confirmation of the compound was carried out by identifying from 1H-NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].[CH3:40][C:41]([NH:44][CH2:45][CH2:46][CH2:47][NH2:48])([CH3:43])[CH3:42]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:48][CH2:47][CH2:46][CH2:45][NH:44][C:41]([CH3:43])([CH3:42])[CH3:40])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39]
Reactant: CC(C)(C)NCCCN
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCCNC(C)(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 81 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (20 mg, 0.036 mmol) in THF(3 mL) was added N-(1,1-dimethylethyl)-1,3-propanediamine (0.028 mL, 0.177 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (18 mg, 80%). LC-MS m/z 618 (M+H)+; 1H-NMR (MeOD) δ 1.11 (s, 9H), 1.58 (m, 2H), 2.34 (s, 3H), 2.48 (m, 2H), 3.15 (m, 2H), 4.13 (s, 2H), 7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2 H), 7.82 (s, 1H), 7.98 (d, 1H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][S:9][CH2:10][CH2:11][NH:12][C:13]([NH:15][CH2:16][CH2:17][S:18][CH2:19][C:20]1[N:21]=[CH:22][NH:23][C:24]=1[CH3:25])=[S:14].[CH3:26]O>>[ClH:1].[ClH:1].[ClH:1].[CH3:26][S:14][C:13](=[N:12][CH2:11][CH2:10][S:9][CH2:8][C:4]1[N:5]=[CH:6][NH:7][C:3]=1[CH3:2])[NH:15][CH2:16][CH2:17][S:18][CH2:19][C:20]1[N:21]=[CH:22][NH:23][C:24]=1[CH3:25]
Reactant: CO
Reactant: Cc1[nH]cnc1CSCCNC(=S)NCCSCc1nc[nH]c1C
Agent: Cl
Product: CSC(=NCCSCc1nc[nH]c1C)NCCSCc1nc[nH]c1C

Procedure:
Dry hydrogen chloride was passed into a solution of N,N'-bis-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea (7.7 g) in methanol at 80° for 5 hours. Concentration and re-evaporation with isopropyl alcohol afforded S-methyl-N,N'-bis-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-isothiourea trihydrochloride (9.0 g), m.p. 212°-215° (isopropyl alcohol).
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]([NH2:33])[NH:31][N:32]=2)=[CH:24][CH:23]=1)[CH3:20]>O1CCCC1>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]([NH:33][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[NH:31][N:32]=2)=[CH:24][CH:23]=1)[CH3:20]
Reactant: CCOc1ccc(-c2cc(N)[nH]n2)cc1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: CCOc1ccc(-c2cc(NC=C3C(=O)Nc4ccccc43)[nH]n2)cc1

Procedure:
The named compound is prepared by substituting 5-(4-ethoxy-phenyl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2635 gms. 5-(4-ethoxy-phenyl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.0 mL) overnight.
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].[CH2:12]([Mg]Cl)[C:13]([CH3:16])([CH3:15])[CH3:14].C(OCC)C>C(OCC)C.C1COCC1>[OH:3][C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([CH3:2])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: CC(C)(C)C[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)CC(C)(O)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
Dissolve 4-acetylbenzonitrile (1 g, 6.88 mmol) in diethyl ether/THF (1:1, 60 mL) and cool the solution to 0° C. Add 1 M neopentylmagnesium chloride in diethyl ether (8.3 mL, 8.3 mmol) under nitrogen and stir the mixture at room temperature overnight. Add saturated aqueous NH4Cl and extract the mixture twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1, 9:1) to give the desired intermediate (364 mg, 24%).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH2:19][C:20]#[CH:21])[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[F:30])=[O:9])=C.Cl.O1CCOCC1>CO.C1COCC1>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH2:19][C:20]#[CH:21])[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[F:30])=[O:9]
Reactant: C#CCn1c(C(=O)NOCCOC=C)c(Nc2ccc(I)cc2F)c2cnccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: C#CCn1c(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c2cnccc21
Temperature: 25 °C
Yield: 98.7 %

Procedure:
To a stirred solution of 3-(2-fluoro-4-iodo-phenylamino)-1-prop-2-ynyl-1-H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide (35.0 mg, 0.067 mmol) in anhydrous MeOH (6.7 mL) and anhydrous THF (3.4 mL) under N2 was added 4 M HCl in dioxane (50 μL, 0.20 mmol, 3.0 eq), and the reaction mixture was stirred at room temperature. After 3 h the solvent was removed in vacuo and the residue was redissolved in acetonitrile (2.0 mL) and loaded onto Phenomenex Strata-X cartridge (5 g). The cartridge was washed with water (10 mL) and MeOH (15 ml). The desired product was then eluted using 2M ammonia in MeOH. Trituration from DCM-hexane afforded the title compound as a yellow solid (32.7 mg, 98.5%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.58 (d, J=0.82 Hz, 1H), 8.36 (d, J=5.93 Hz, 1H), 7.79-7.62 (m, 2H), 7.60-7.47 (m, 1H), 7.30-7.15 (m, 1H), 6.34-6.15 (m, 1H), 5.33 (s, 2H), 4.77 (broad s, 1H), 3.84 (t, J=4.54 Hz, 2H), 3.61-3.50 (m, 2H), 3.42-3.34 (m, 2H); LC-MS (method E): [M+H]+=495.1, RT=3.54 min.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccccn1
Reactant: CS(=O)c1ncc2cc(Br)c(=O)n(C3CCCC3)c2n1
Product: O=c1c(Br)cc2cnc(Nc3ccccn3)nc2n1C1CCCC1
Yield: 37 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one and 2-aminopyridine were reacted according to the procedure outlined in Example 37 to provide 6-bromo-8-cyclopentyl-2-(pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one in 37% yield. mp: 273˜275° C. Anal. Calc'd for C17H16BrN5O.0.1H2O: C, 52.62; H, 4.21; N, 18.05. Found C, 52.23; H, 4.10; N, 17.91. M++1: Calc'd: 386.05, Found 385.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl:12][CH:13](Br)[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][CH2:13][CH2:14][CH2:15][O:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CCC(Cl)Br
Reactant: COc1cc(O)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)cc(OCCCCl)c1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
A mixture of 3,5-dimethoxyphenol, 100.0 g (0.6486 mole), chlorobromopropane, 148.0 g (0.96 mole) and potassium carbonate, 89.6 g (0.96 mole) was heated overnight at gentle reflux in 600 ml of acetone. The reaction mixture was cooled at room temperature, filtered, and stripped to dryness via a rotary evaporator. The resulting oil was dissolved in chloroform and the solution extracted with 5% aqueous sodium hydroxide; removal of chloroform gave a dark brown oil. A 5 g sample of the oil was pumped in vacuo overnight at 80° C. This produced 3.23 g (53.2% yield based on the aliquot taken) of dark brown oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:46])[C:3]([C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=2)[CH:32]=[CH:33][CH:34]=1)([C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)[OH:4].Cl.N1C=CC=CC=1>>[NH:8]1[CH:9]=[C:5]([C:3]([C:29]2[CH:30]=[C:31]([C:35]3[CH:36]=[CH:37][C:38]([O:41][C:42]([F:43])([F:44])[F:45])=[CH:39][CH:40]=3)[CH:32]=[CH:33][CH:34]=2)([OH:4])[CH:2]([CH3:1])[CH3:46])[N:6]=[CH:7]1
Reactant: CC(C)C(O)(c1cccc(-c2ccc(OC(F)(F)F)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(O)(c1cccc(-c2ccc(OC(F)(F)F)cc2)c1)c1c[nH]cn1
Yield: 170.3 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 2-methyl-1-[4′-(trifluoromethoxy)[1,1′-biphenyl]-3-yl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (3.63 g) and pyridine hydrochloride (1.22 g), the title compound (3.76 g) was obtained as colorless needle crystals.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)=[CH:24][CH:23]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][N:38]1[CH2:39][CH2:40][CH:35]([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)=[CH:30][CH:31]=2)[CH2:36][CH2:37]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2ccc(C3CCNCC3)cc2)cc1
Reactant: O=C(CCCBr)Nc1ccccc1Cc1ccccc1
Product: O=C(CCCN1CCC(c2ccc(Cc3ccc(F)cc3)cc2)CC1)Nc1ccccc1Cc1ccccc1

Procedure:
The compound (11) synthesized in Reference Example 11 and the compound (7) synthesized in Reference Example 7 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][CH:27]([NH:33][CH3:34])[CH2:28]2>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:33]([CH3:34])[CH:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[CH:32][C:23]=4[O:22][CH3:21])[CH2:28]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNC1CCc2c(cccc2OC)C1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3c(cccc3OC)C1)CC2

Procedure:
The title compound is prepared analogously to Example 1 by reacting 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane, triethylamine and 5-methoxy-2-methylamino-1,2,3,4-tetrahydronaphthalene. Mp: 149°-150° C. (decomp.).
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][C:28]([O:30][CH2:31][CH3:32])=[O:29]>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][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:4]=1)=[O:22]
Reactant: CCOC(=O)CCCCBr
Reactant: COc1ccccc1CC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCn1cc(C(=O)Cc2ccccc2OC)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21.8 %

Procedure:
60% Sodium hydride in mineral oil (480 mg, 12 mmol) was suspended in dimethylformamide (50 ml) and 1-(1H-indol-3-yl)-2-(2-methoxyphenyl)ethanone 3 (2.66 g, 10 mmol) was added portionwise at room temperature, allowing to stir further 45 min at room temperature after the addition was finished. Ethyl 5-bromovalerate (2.37 ml, 15 mmol) was added dropwise at room temperature and the reaction mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the residue was taken into water (30 ml) and extracted three times with ethyl acetate (3×50 ml). The organic fractions were combined and dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20% ethyl acetate in hexane) to give 856 mg (22%) of ethyl 5-(3-(2-(2-methoxyphenyl)acetyl)-1H-indol-1-yl)pentanoate (Ethyl N-(carboxybutyrate) JWH-250) 7 as a semi solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[N:39]1[CH:44]=[CH:43][N:42]=[CH:41][C:40]=1[C:45](O)=[O:46]>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:45]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][N:39]=2)=[O:46])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:4])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(O)c1cnccn1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)c1cnccn1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure E using pyrazine-2-carboxylic acid. The final product was obtained in 64% yield.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13](Cl)[C:12]3[C@@H:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[O:23][C:24]4([CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:40]([B-](F)(F)F)([CH3:42])=[CH2:41].[K+].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([C:40]([CH3:42])=[CH2:41])[C:12]3[C@@H:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[O:23][C:24]4([CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Reactant: C=C(C)[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C(C)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: 100 °C
Reaction time: 72 h

Procedure:
500 mg (3R,9S)-9-(tert-butyldimethylsilyloxy)-4-chloro-7,7-dimethyl-3-(4-(trifluoromethyl)phenyl)-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran] and 254 mg potassium isopropenyltrifluoroborate are dissolved in 3 ml tetrahydrofurane, 0.5 ml toluene and 3 ml of a 2 M solution of caesium carbonate in water. The mixture is purged for 15 minutes with argon. Then 42 mg 1,1′-bis-(diphenylphosphino)-ferrocene-dichloro-palladium-(II) complex with dichloromethane are added and the mixture is stirred for 72 hours at 100° C. The mixture is partitioned between water and dichloromethane. The aqueous phase is twice extracted with dichloromethane. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 90:10).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(CC)CC.[Cl:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([S:31](Cl)(=[O:33])=[O:32])[CH:29]=2)[C:24]([Cl:35])=[CH:23][N:22]=1>C(Cl)Cl>[Cl:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([S:31]([NH:1][C@H:2]3[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]3)(=[O:33])=[O:32])[CH:29]=2)[C:24]([Cl:35])=[CH:23][N:22]=1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: CCOC(=O)[C@H]1CC[C@H](N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl trans-4-aminocyclohexanecarboxylate (168 mg, 0.81 mmol), NEt3 (0.22 mL, 1.6 mmol) and 1,4-dichloro-7-isoquinolinesulphonyl chloride (200 mg, 0.67 mmol) in CH2Cl2 (8 mL) was stirred at 0° C. for 1 h. The mixture was diluted with CH2Cl2 (100 mL), was washed with dilute HCl (50 mL, 1 M), water, dried (MgSO4) and evaporated in vacuo to give ethyl trans-4-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (232 mg, 0.54 mmol) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:19][CH3:20])=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH3:20][O:19][C:4]1[C:3]([CH2:1][NH:24][CH3:23])=[CH:18][CH:17]=[CH:16][C:5]=1[O:6][C:7]1[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: [BH3-]C#N
Reactant: COc1c(C=O)cccc1Oc1nc(C)ccc1C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2nc(C)ccc2C#N)c1OC
Yield: 41 %

Procedure:
2-(3-Formyl-2-methoxy-phenoxy)-6-methyl-nicotinonitrile (0.30 g, 1.1 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (50 mL) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.13 g, 1.1 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 2-(2-methoxy-3-methylaminomethyl-phenoxy)-6-methyl-nicotinonitrile fumarate (180 mg, 40%) as an off-white solid.