Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([CH:22]=C1CCP(C2C=CC=CC=2)C1(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18].C(O)(=O)C1C=CC=CC=1.C1C=CC=CC=1>CCCCCC>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=[CH:22][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=C1CCP(c2ccccc2)C1(c1ccccc1)c1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)C=CC=C(c1ccccc1)c1ccccc1
Reaction time: 3.5 h
Yield: 82.4 %

Procedure:
β-Phenylcinnamaldehyde (3.36 g), (carbethoxymethylene)triphenylphospholane (5.68 g), and benzoic acid (0.2 g) were added to anhydrous benzene (80 mL), and the mixture was refluxed under stirring for 3.5 hours. Subsequently, the resultant mixture was cooled to room temperature and condensed under reduced pressure. n-Hexane was added to the residue, and the insoluble matter was collected through filtration and washed several times with n-hexane. The filtrate and the resulting wash liquid were combined and condensed under reduced pressure. The product was purified through silica gel column chromatography (silica gel 40 g, eluent; n-hexane:ethyl acetate=50:1), to thereby yield 3.70 g of the product of interest (yield 82.4%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[O:16]1[C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1>CCOCC>[CH2:9]([O:8][C:5]1[N:6]=[CH:7][C:2]([C:23]2([OH:26])[CH2:24][CH2:25][C:20]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:21][CH2:22]2)=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc(OCc2ccccc2)nc1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CCOCC
Product: OC1(c2ccc(OCc3ccccc3)nc2)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from 5-bromo-2-benzyloxy-pyridine (Alfa Aesar) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]([CH3:21])([CH3:20])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]#[N:26].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]([CH3:21])([CH3:20])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([O:19][CH2:24][C:25]#[N:26])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(Cc1c[nH]c2c(O)cccc12)NC(=O)OC(C)(C)C
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(Cc1c[nH]c2c(OCC#N)cccc12)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A mixture of [2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (15.55 g, 51.1 mmol), bromoacetonitrile (10.7 mL, 153 mmol), K2CO3 (17.78 g, 128.6 mmol) and 2-butanone is heated to reflux. After 1 hour the mixture is allowed to cool and is filtered through celite. The filtrate is concentrated to an oil which is purified by flash chromatography with CH2Cl2 followed by 5% ethyl acetate/CH2Cl2 to give 15.18 g of [2-(7-cyanomethoxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (86%). MS (ES−) m/z 342.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[C:15]([N:34]1[CH:38]=[C:37]([CH:39]=[O:40])[N:36]=[CH:35]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[OH:40][CH:39]([C:37]1[N:36]=[CH:35][N:34]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:38]=1)[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 14.80 mmol of 4-iodobenzonitrile [3058-39-7] in 20 ml of tetrahydrofuran is cooled to −30° C., and 14.80 mmol of i-propylmagnesium chloride (2M in tetrahydrofuran) are added. The mixture is stirred at −30° C. for 60 minutes and a solution, precooled to −30° C., of 11.84 mmol of 1-trityl-1H-imidazole-4-carbaldehyde [33016-47-6] in 30 ml of tetrahydrofuran is added. The mixture is stirred at −30° C. for 30 minutes, and then the reaction mixture is warmed to room temperature and quenched with saturated aqueous ammonium chloride solution. The phases are separated, and the aqueous phase is extracted with ethyl acetate (3×). The combined organic phases are washed with brine, dried with magnesium sulphate and evaporated. The title compound is obtained as a white solid from the residue by recrystallization from ethyl acetate. Rf=0.23 (CH2Cl2-2M NH3 in EtOH 97:3); Rt=7.32.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18](O)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[NH2:31][C:32]1[C:33](=[O:41])[N:34]([CH2:39][CH3:40])[CH:35]=[CH:36][C:37]=1[NH2:38].CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]2[NH:31][C:32]3[C:33](=[O:41])[N:34]([CH2:39][CH3:40])[CH:35]=[CH:36][C:37]=3[N:38]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCn1ccc(N)c(N)c1=O
Reactant: O=C(NC1CCCC(C(=O)O)C1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ccc2nc(C3CCCC(NC(=O)OCc4ccccc4)C3)[nH]c2c1=O
Temperature: 0 °C
Yield: 88 %

Procedure:
In a 100 mL round bottom flask, 3-benzyloxycarbonylamino-cyclohexanecarboxylic acid (0.53 g, 1.96 mmol), TEA (0.44 g, 4.31 mmol), and HOBt (0.53 g, 3.92 mmol) were added sequentially to a solution of 3,4-diamino-1-ethyl-1H-pyridin-2-one (0.30 g, 1.96 mmol) in DMF (15 mL) at room temperature. The solution was then cooled to 0° C., EDCI (0.75 g, 3.92 mmol) was added, and the reaction mixture was allowed to stir, with warming to room temperature. After stirring for 17 h, the reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2. The combined extracts were dried with MgSO4, and concentrated. The solid was rinsed with Et2O to give [3-(5-ethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (0.68 g, 84% yield). The intermediate amide (0.43 g, 1.04 mmol) was dissolved in glacial acetic acid (6.26 g, 104.2 mmol) and heated at 120° C. for 2 days. After cooling to room temperature, the solvent was removed in vacuo and the crude product was purified by flash chromatography eluting with 3% MeOH in CH2Cl2 to give [3-(5-ethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (0.22 g, 54% yield). 1H-NMR (DMSO): δ 7.35 (m, 6H), 6.53 (m, 1H), 5.01 (s, 2H), 3.99 (m, 2H), 3.43 (m, 1H), 2.86 (m, 1H), 2.07 (m, 1H), 1.83 (m, 3H), 1.42 (m, 3H), 1.20 (m, 3H), 1.17 (m, 1H). MS: calculated for C22H26N4O3+H 395.2; found: 395.4.
Reaction SMILES: [CH:1]([C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:2].C1COCC1.[C:21]1([CH3:29])[CH:26]=[CH:25][CH:24]=[C:23]([Mg]Cl)[CH:22]=1.[NH4+].[Cl-]>O>[OH:2][C@H:1]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:29])[CH:22]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc([Mg]Cl)c1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc([C@@H](O)[C@H]2[C@@H](c3ccccc3)CC(=O)N2C)c1
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a 0° C. solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 74 mg, 0.4 mmol) in anhyd. THF (5 mL) was added a solution of m-tolyl magnesium chloride (1M in THF, 0.5 mL, 0.5 mmol, 1.25 equiv). The reaction mixture was stirred for 1 h, then treated with a saturated NH4Cl solution and water. The resulting mixture was extracted with EtOAc, dried (Na2SO4) and concentrated under reduced pressure. The residue was triturated (Et2O/hex) to give (±)-(4R*,5R*)-5-[(1R*)hydroxy(3-methylphenyl)methyl]-1-methyl-4-phenylpyrrolidin-2-one (82 mg, 77%): mp 163-165° C.; TLC (EtOAc) Rf 0.45.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[OH:11])=[O:3].[CH3:12][C:13]([CH3:15])=O.N1CCCC1>CO>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]2[C:2](=[O:3])[CH2:1][C:13]([CH3:15])([CH3:12])[O:11][C:5]=2[CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1O
Reactant: CC(C)=O
Solvent: C1CCNC1
Solvent: CO
Product: CC1(C)CC(=O)c2ccc(Cl)cc2O1

Procedure:
A solution of 4-chloro-2-hydroxyacetophenone (20 g, 0.1176 mol), acetone (13.3 mL, 0.1811 mol) and pyrrolidine (15 mL, 0.18 mol) in methanol (475 mL) was stirred at 25° C. overnight. The mixture was then concentrated to a red oil. Water was added and the solution was adjusted to pH 1 with concentrated hydrochloric acid. The product was extracted with diethylether. The organic layer was dried over magnesium sulfate and diethylether was evaporated under reduced pressure. The residue was dissolved in a small volume of methanol. The solution was treated with charcoal, filtered and water was added to the filtrate. The resulting precipitate was collected by filtration, washed with water and dried (79%). mp: 63-66° C., IR (KBr): υ: 3086 (C—H aromatic), 2976, 2931 (C—H aliphatic), 1693 (C=0) cm−1, Anal. (C11H11O2Cl) C, H.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH2:10][C@H:9]1[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:7].[N:39]1([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([N:48]2[CH2:49][CH2:50][CH:45]([N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:46][CH2:47]2)=[O:19])[CH2:10][C@H:9]1[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:7]
Reactant: O=C(O)CCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reactant: C1CCN(C2CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(CCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)N1CCC(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-carboxypropyl)-2-(1H-indol-3-yl-methyl)piperazine (180 mg), 4-piperidinopiperidine (56 mg) and 1-hydroxybenzotriazole hydrate (45 mg) in dichloromethane (4 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (64 mg) at ice-bath temperature. After stirring for 30 minutes, the reaction mixture was allowed to warm to room temperature and was stirred for 2 hours and 40 minutes. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous saturated sodium bicarbonate and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (10:1) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[3-(4,1'-bipiperidin-1-yl-carbonyl)propyl]-2-(1H-indol-3-yl-methyl)piperazine, which was converted to the corresponding dihydrochloride salt (0.18 g) by treatment with 4N hydrogen chloride in dioxane solution.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[CH3:21].Cl[C:36]1[N:41]=[CH:40][C:39]([CH2:42][CH3:43])=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:42]([C:39]1[CH:38]=[N:37][C:36]([C:9]2[CH:10]=[CH:11][C:6]([CH:5]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=3)[CH2:4][CH2:3][C:2]([F:33])([F:34])[F:1])=[C:7]([CH3:21])[CH:8]=2)=[N:41][CH:40]=1)[CH3:43]
Reactant: CCc1cnc(Cl)nc1
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCc1cnc(-c2ccc(C(CCC(F)(F)F)Nc3ccc(C(=O)OC)cc3)c(C)c2)nc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A reaction mixture of methyl 4-((4,4,4-trifluoro-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)amino)benzoate (0.600 g) obtained in Example 10, step A, 2-chloro-5-ethylpyrimidine (0.215 g), tetrakistriphenylphosphinepalladium (0.145 g), sodium carbonate (0.400 g), DME (3 mL) and water (1 ml) was stirred at 130° C. for 1 hr under microwave irradiation under a nitrogen atmosphere. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.507 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([OH:10])[CH:9]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F>CN(C=O)C.O>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O:10][C:8]1[CH:9]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=1[O:11][CH3:12]
Reactant: COc1ccc(F)cc1O
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1Oc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. oil, 0.281 g) was added to a solution of 5-fluoro-2-methoxyphenol (1.0 g) in DMF (20 ml) and stirred at RT for 30 min. 2-Chloro-1-fluoro-4-nitrobenzene (1.23 g) was added and the mixture stirred at RT for 16 h then diluted with water and extracted with diethylether. The organics were dried and evaporated under reduced pressure, yield 1.95 g.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]2[N:11]3[CH2:25][CH2:24][N:23]([CH3:26])[C:22](=[O:27])[C:12]3=[C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[C:8](=[O:28])[N:7]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Cl:37])[CH:31]=2)[N:6]=1)=[O:4].Cl.[NH2:39][NH:40][C:41]([NH2:43])=[O:42].C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:15]([O:14][C:13]1[C:9]2[C:8](=[O:28])[N:7]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Cl:37])[CH:31]=3)[N:6]=[C:5]([C:3](=[O:4])[CH2:2][NH:39][NH:40][C:41]([NH2:43])=[O:42])[C:10]=2[N:11]2[CH2:25][CH2:24][N:23]([CH3:26])[C:22](=[O:27])[C:12]=12)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)CBr)c32)C1=O
Reactant: NNC(N)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)CNNC(N)=O)c32)C1=O

Procedure:
A solution of crude 4-bromoacetyl-10-(benzyloxy)-2-(3-chloro-4-fluorobenzyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (1.25 g, 2.13 mmol) in anhydrous THF, semicarbazide hydrochloride (0.35 g, 3.14 mmol), and diisopropylethylamine (0.66 mL, 3.77 mmol) was heated in a sealed tube at 100° C. for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was dissolved in DMSO and subject to reverse phase preparative HPLC purification. Collection and lyophilization of appropriate fraction provided the intermediate 2-{2-[10-(benzyloxy)-2-(3-chloro-4-fluorobenzyl)-8-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazin-4-yl]-2-oxoethyl}hydrazinecarboxamide as white solid.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1>C(OCC)(=O)C>[CH3:10][C:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)=[O:11]
Reactant: Nc1ccc(I)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
4-Iodoaniline (11.0 g, 50.4 mmol) was dissolved in 60 mL of ethyl acetate and the solution was added with 10 mL of acetic anhydride (10.8 g, 106 mmol) and 7.8 mL of pyridine (7.65 g, 99.4 mmol), and the mixture was stirred at room temperature for 2 hours with an equipment of a CaCl2 tube. A solvent was evaporated under reduced pressure to obtain 4-iodoacetanilide (yield: 13.0 g, percent yield: 99.0%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:33][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:15]([S:18]([CH:21]([CH3:22])[CH3:23])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: NC1CCCC1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)C(C)C
Product: CC(C)S(=O)(=O)C(C#N)=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCCC1
Yield: 99 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-methylsulfanyl-2-propenenitrile (0.500 g, 1.16 mmol) was stirred in cyclopentylamine (2 ml) for 24 h at 80° C. under nitrogen in a sealed flask. Work up as described in Example 40, 2) gave 540 mg (99%) of the title compound as white crystals. Mp 172-173 ° C. 1H NMR (200 MHz, CDCl3): δ=1.41 (d, 6H), 1.40-1.57 (m, 4H), 1.74-1.93 (m, 4H), 3.25 (heptet, 1H), 3.56 (m, 1H), 7.54 (s, 2H), 7.67 (s, 1H), 7.94 (br s, 1H), 9.22 (br s, 1H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[O:27]=[C:28]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:31][C:30](=[O:39])[N:29]1[CH2:40][CH2:41][CH2:42][CH2:43][NH2:44]>ClCCl>[O:27]=[C:28]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:31][C:30](=[O:39])[N:29]1[CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: NCCCCN1C(=O)C=C(c2ccccc2)C1=O
Reactant: O=C(O)C=Cc1cccnc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(C=Cc1cccnc1)NCCCCN1C(=O)C=C(c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
2.7 g (17.8 mmol) 3-(3-pyridyl)-acrylic acid and 1.8 g (17.8 mmol) TEA are suspended in 50 ml abs. dichloromethane and cooled to ca. 0° C. under moisture exclusion. 3.1 g (17.8 mmol) 88% HOBT and 3.4 g (17.8 mmol) EDC are added and the mixture is stirred for 30 min under ice cooling. 5.0 g (17.8 mmol) 4-(2,5-dioxo-3-phenyl-2,5-dihydropyrrol-1-yl)-butylamine hydrochloride are dissolved in 30 ml abs. dichloromethane and added dropwise under ice cooling. The mixture is stirred overnight at RT without further cooling. Subsequently, the batch is washed with 25 ml 1M NaOH and with 50 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The resinous residue is chromatography pre-purified over silica gel with CHCl3/CH3OH (95/5) and further purified by flash chromatography with CHCl3/CH3OH (95/5). After withdraw of the solvent, this is crystallized from acetic acid ethyl ester: Colorless crystals with MP. 141–143° C.; Yield 0.6 g (9%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)[O:3]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:16][CH2:15][CH2:14][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:17])([CH3:1])[O:3]2)[CH:10]=[N:11]1)(=[O:21])=[O:20]
Reactant: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC1(C)OB(c2cnn(CCOS(C)(=O)=O)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (0.150 g, 0.630 mmol) and TEA (0.132 mL, 0.945 mmol) in 5 mL of DCM was added methansulfonyl chloride (0.0536 mL, 0.693 mmol) with stirring at 0° C. The reaction was allowed to proceed at 0° C. for 30 minutes. The reaction was loaded directly onto a silica gel column pre-pre-wetted with and eluted with 50% ethyl acetate in hexanes to afford 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate (0.169 g, 0.513 mmol, 81.4% yield) MS (apci) m/z=317.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH:18](I)[CH3:19]>CC(C)=O>[CH3:17][CH:18]([O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)[CH3:19]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1cccc(OC(C)C)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
1-(3-Hydroxyphenyl)ethanone (1.36 g, 10 mmol) was dissolved in acetone (50 mL), and the resultant mixture was sequentially added with potassium carbonate (2.76 g, 20 mmol) and 1-methylethyl iodide (1.5 mL, 15 mmol), and stirred at 70° C. overnight. The reaction solution was filtered, washed with acetone, and concentrated in vacuo. The resultant residue was added with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with 1N aqueous solution of sodium hydroxide and brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. 1-(3-(1-methylethoxy)phenyl)ethanone (1.67 g, yield 94%) was obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:24][CH3:25])=[CH:4][C:5]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[CH2:12][CH:11]3[C:6]=2[C:7]=1[CH2:8][N:9]([CH3:23])[CH2:10]3.[OH-].[C:27]1([N+](C)(C)C)C=CC=CC=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:25][O:24][C:3]1[C:2]([O:1][CH3:27])=[C:7]2[CH2:8][N:9]([CH3:23])[CH2:10][CH:11]3[CH2:12][C:13]4[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[C:5](=[C:6]23)[CH:4]=1
Reactant: C[N+](C)(C)c1ccccc1
Reactant: COc1cc2c(cc1OC)-c1cc(OC)c(O)c3c1C(C2)CN(C)C3
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)-c1cc(OC)c(OC)c3c1C(C2)CN(C)C3

Procedure:
9.1 g. (±)-5,6,6a,7-Tetrahydro-3-hydroxy-2,9,10-trimethoxy-5-methyl-4H-dibenz(de,g)isoquinoline (see Example 2) are reacted with phenyltrimethylammonium hydroxide in toluene/dimethylformamide in a manner analogous to that described in Example 7. When the methylation is finished, the reaction mixture is worked up in the manner described in Example 7. By chromatography of the crude product on silica gel (elution with chloroform +1% triethylamine) and crystallisation from chloroform-diethyl ether, there is obtained (±)-5,6,6a,7-tetrahydro-2,3,9,10-tetramethoxy-5-methyl-4H-dibenz(de,g)isoquinoline in the form of beige crystals; m.p. 170°-177° C.