Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][C:7]([C@@H:10]([NH:13]S(C(C)(C)C)=O)[CH2:11][CH3:12])=[CH:8][N:9]=1)(=[O:4])=[O:3].[ClH:20]>CO.O1CCOCC1>[ClH:20].[CH3:1][S:2]([C:5]1[S:6][C:7]([C@@H:10]([NH2:13])[CH2:11][CH3:12])=[CH:8][N:9]=1)(=[O:3])=[O:4]
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1cnc(S(C)(=O)=O)s1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@H](N)c1cnc(S(C)(=O)=O)s1
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(2-methanesulfonyl-thiazol-5-yl)-propyl]amide (80 mg, 0.3 mmol) in methanol (5 mL) was added a 4 N solution of hydrochloric acid (1 mL, 4 mmol) in dioxane. After 1 hour, the mixture was concentrated and diluted with dichloromethane (2 mL) followed by hexanes (10 mL), and concentrated to afford (S)-1-(2-methanesulfonyl-thiazol-5-yl)-propylamine hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C@H:4]1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1.C(N(CC)CC)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:34].O>C1COCC1>[Cl:24][C:19]1[CH:18]=[C:17]([C@H:4]2[C@@H:3]([CH2:2][NH:1][C:33]([O:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:34])[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN)[C@H](c2ccc(Cl)c(Cl)c2)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@H](CNC(=O)Oc2ccc([N+](=O)[O-])cc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.4 %

Procedure:
To a solution of tert-butyl (6R,7S)-7-(aminomethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (200 mg) and triethylamine (0.149 mL) in THF (4.0 mL) was added 4-nitrophenyl chloroformate (129 mg) under ice-cooling, and the mixture was stirred at room temperature for 5 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (99 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][O:29]2)=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: C1=COCCC1
Reactant: CCc1cc(Br)ccc1CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: CCc1cc(Br)ccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a solution of (4-bromo-2-ethylphenyl)methanol (CAS 877131-21-0) (2.8 g, 13 mmol) in methylene chloride (45 mL) were added pyridinium p-toluenesulfonate (327 mg, 1.3 mmol) and 3,4-dihydro-2H-pyran (2.4 mL, 26 mmol) and stirred at RT for 16 h. The reaction mixture was diluted with water, extracted with methylene chloride, dried with magnesium sulfate and concentrated. Purification by MPLC (30% ethyl acetate in hexanes) afforded 2.9 g of Intermediate 1 as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[C:15]1([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:22]2[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][N:4]3[C:8](=[O:9])[C:7]4=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]4[C:5]3=[O:14])[CH2:26][CH2:27]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Yield: 88 %

Procedure:
The title compound was prepared in a yield of 88% in a similar manner to that described in Preparation 1' by reacting N-(2-bromoethyl)phthalimide and 4-diphenylmethylenepiperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: Fc1ccc(I)c(Br)c1
Product: Fc1ccc(Sc2ccc(Cl)cc2Cl)c(Br)c1

Procedure:
Prepared from 2,4-dichloro-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: N.O1CCOCC1.C([N:10](CC)CC)C.[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C@@H:27]2[C:32]([C:33]#[N:34])=[C:31]([CH3:35])[N:30]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:29](=[O:46])[NH:28]2)=[C:21]([S:23](Cl)(=[O:25])=[O:24])[CH:22]=1)#[N:16]>C(#N)C>[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C@@H:27]2[C:32]([C:33]#[N:34])=[C:31]([CH3:35])[N:30]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:29](=[O:46])[NH:28]2)=[C:21]([S:23]([NH2:10])(=[O:25])=[O:24])[CH:22]=1)#[N:16]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CCN(CC)CC
Agent: N
Solvent: CC#N
Solvent: C1COCCO1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(N)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
At room temperature, a 0.5 M solution of ammonia in dioxane (25.79 ml, 12.9 mmol; 10 eq.) and triethylamine (130 mg, 1.3 mmol; 1 eq.) were added to 5-cyano-2-{(4S)-5-cyano-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (3.10 g, content 20%, 1.29 mmol), and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure, water/acetonitrile (˜10:1) was added to the residue and the solution was lyophilized. The substance obtained was dissolved in acetonitrile and then purified by preparative HPLC (column: Waters Sunfire C18, 5 μm; column dimensions: 250 mm×20 mm; detection: 240 nm; temperature: 28° C.; flow rate: 25 ml/min; injection volume: 500 μl; mobile phase: acetonitrile/0.2% trifluoroacetic acid 45:55). The title compound was obtained as a solid (0.155 g, 26% of theory).
Reaction SMILES: N[CH:2]([CH2:15][O:16][CH3:17])[CH2:3][O:4][C:5]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[O:7][N:6]=1.[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1.C=O.[C:31]([BH3-])#[N:32].[Na+].[OH-].[Na+]>C(OCC)(=O)C.O>[ClH:14].[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[O:7][N:6]=[C:5]([O:4][CH2:3][CH:2]([N:32]([CH3:31])[CH3:18])[CH2:15][O:16][CH3:17])[C:9]=2[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COCC(N)COc1noc2ccc(Cl)cc12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COCC(COc1noc2ccc(Cl)cc12)N(C)C
Product: Cl

Procedure:
To a solution of 0.50 g of 3-(2-amino-3-methoxypropoxy)-5-chloro-1,2-benzoisoxazole are added 0.41 g of p-toluenesulfonic acid and 0.34 ml of 37% formalin, and 0.26 g of sodium cyanoborohydride is then added at 15°-20° C., after which they are subjected to reaction at the same temperature for one hour. Water and ethyl acetate are added to the reaction mixture, and the pH is adjusted to 10 with a 10% (w/w) aqueous sodium hydroxide solution and the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which 0.89 ml of a dioxane solution (2.2N) of hydrogen chloride is added. The crystals precipitated are collected by filtration and recrystallized from a mixed solvent of acetone and methanol, to obtain 0.35 g of colorless, crystalline 5-chloro-3-(2-dimethylamino-3-methoxypropoxy)-1,2-benzoisoxazole hydrochloride having a melting point of 163°-164° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:16])[C:11](OCC)=[O:12].CO.[CH3:19][NH2:20]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:16])[C:11]([NH:20][CH3:19])=[O:12]
Reactant: CCOC(=O)C(=O)c1ccccc1COC
Reactant: CN
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CNC(=O)C(=O)c1ccccc1COC
Reaction time: 2 h

Procedure:
28.3 g of the ethyl 2-(2-methoxymethyl-phenyl)-2-oxoacetate obtained in (1), 109 g of toluene, and 54.4 g of methanol were mixed, 28.6 g of a 40% aqueous methylamine solution was added while retaining at 25° C., and the mixture was retained at 25° C. for 2 hours. Thereafter, 54.4 g of water was added, 80 g of toluene were further added, this was allowed to stand still, and an organic layer was recovered. The organic layer was washed with 178 g of 5% hydrochloric acid, 54.4 g of an aqueous saturated sodium bicarbonate solution, and 54.4 g of water, respectively, and concentrated with an evaporator to obtain 12.0 g of 2-(2-methoxymethyl-phenyl)-N-methyl-2-oxo-acetamide.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=1.CI>C1COCC1.C([Li])CCC.[Cl-].[NH4+]>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)([CH3:1])[C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=1
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C(c1ccc(Cl)cc1)C1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(c1ccc(Cl)cc1)C1CCCC1
Temperature: -35 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (0.15 ml) in THF (2 ml), n-butyl lithium (1.5 M hexane solution, 0.6 ml) was added at −78° C., stirred for 10 minutes and another solution of methyl 2-(4-chlorophenyl)-2-cyclopentylacetate (200 mg) in THF (1.5 ml) was added dropwise. After 15 minutes' stirring, the system temperature was raised to −35° C., and methyl iodide (0.15 ml) was added. The reaction liquid temperature was raised to 0° C., and the liquid was stirred for 1.5 hours, diluted with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and condensed under reduced pressure. The resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate 60/1) to provide methyl 2-(4-chlorophenyl)-2-cyclopentylpropionate (180 mg) as yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of 0.97 mmol 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (CAS: 286961-14-6) in 6 ml dimethylformamide, 2.91 mmol potassium carbonate, 1.02 mmol p-bromobenzotrifluoride, and 0.06 mmol dichlor(1,1′ bis(diphenylphosphino)ferrocene) palladium(II)dichloromethane complex were successively added. The reaction was then stirred at 80° C. for 6 hours, concentrated in vacuo and purified by column chromatography (SiO2, 20 g, heptane), to give the title compound. MS (m/e): 271.1 (M-isobuthylene)
Reaction SMILES: Cl[C:2](=[N:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]([C:16]1[N:17]([CH2:44][CH2:45][CH3:46])[N:18]=[C:19]2[C:28]=1[C:27]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:21]=[C:20]2[N:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][CH2:13][C:14]#[CH:15].C(N(CC)CC)C>ClCCl>[C:3]1([C:2]2[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][C:16]3[N:17]([CH2:44][CH2:45][CH3:46])[N:18]=[C:19]4[C:28]=3[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]4[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[O:10][N:9]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ON=C(Cl)c1ccccc1
Reactant: C#CCCCc1c2c(nn1CCC)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCc1cc(-c2ccccc2)no1
Yield: 80 %

Procedure:
α-Chlorobenzaldoxime (0.64 g, 4.1 mmol) was added to a solution of di(tert-butyl) 1-pent-4-ynyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (prepared as described in Parts A-E of Example 57, 1.36 g, 2.76 mmol) and triethylamine (0.60 mL, 4.14 mmol) in dichloromethane (10 mL). The solution was heated at 40° C. for 19 hours, during which time additional α-chlorobenzaldoxime (0.65 g) was added. The reaction was worked up as described in Part B of Example 595. The crude product was purified by chromatography (silica gel, sequential elution with 20% then 40% ethyl acetate in hexanes) to provide 1.35 g of di(tert-butyl) 1-[3-(3-phenylisoxazol-5-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:6]([CH3:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(C(C)C)C(C)C>C1COCC1>[C:8]([C:7]1[C:6]([CH3:13])=[C:5]([C:3](=[O:4])[CH2:2][N:24]2[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:22][C@@H:23]2[CH2:27][OH:28])[CH:12]=[CH:11][CH:10]=1)#[N:9]
Reactant: Cc1c(C#N)cccc1C(=O)CCl
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c(C#N)cccc1C(=O)CN1CCN(C(=O)OC(C)(C)C)C[C@@H]1CO
Temperature: 25 °C

Procedure:
To a solution of 3-(chloroacetyl)-2-methylbenzonitrile (1.7 g, 8.8 mmol) in THF (17.6 mL) was added (R)-4-N-boc-2-hydroxymethyl-piperazine (2.279 g, 10.54 mmol) and DIPEA (3.07 mL, 17.56 mmol) at rt. The reaction mixture was stirred at rt over the weekend. After concentration, the residue was partitioned between EtOAc and aqueous NaHCO3 (saturated). The aqueous layer was extracted with EtOAc (2×). The combined organic phase was washed with brine, dried over anhydrous MgSO4, and filtered. Concentration was followed by purification by prep TLC (silica gel; 10% MeOH/DCM) to give the title compound: LC/MS (M+1)+=374.14
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][C@@H:9]1[CH3:21])([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:28][O:27][C:25](=[O:26])[CH2:24][N:13]1[C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][C@H:9]([CH3:21])[C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])[C:14]1=[O:15]
Reactant: COC(=O)CBr
Reactant: C[C@H]1Oc2ccc(F)cc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)Oc2ccc(F)cc21
Yield: 99.8 %

Procedure:
0.30 g (0.97 mmol) ((6R,7S)-2-Fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester in 8 ml dimethylformamide were stirred with 0.14 ml (1.45 mmol) methyl bromoacetate and 0.48 g (1.45 mmol) cesium carbonate overnight. Extraction with water/ethylacetate and chromatography on silicagel with ethylacetate/heptane 1:4 yielded 0.37 g (quant.) ((6R,7S)-7-tert-butoxycarbonylamino-2-fluoro-6-methyl-8-oxo-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-acetic acid methyl ester, MS m/e (%): 383.1 (M+H+, 14), 327.3 (24), 283.4 (199).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].Cl>CO.O>[CH:6]1([CH2:5][CH:4]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([N:18]([CH3:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:3]([OH:26])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(N(C)c2ccccc2)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(c1ccccc1)c1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.5 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(methyl-phenyl-amino)-6-oxo-6H-pyridazin-1-yl]-propionic acid methyl ester (66.3 mg, 0.18 mmol) in methanol (0.5 mL, 0.37M) was treated with a 4N aqueous sodium hydroxide solution (0.05 mL, 0.2 mmol) and was stirred at 25° C. overnight. After this time, the reaction was diluted with water (10 mL), acidified with a 1N aqueous hydrochloric acid solution and then was extracted into methylene chloride (3×25 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(methyl-phenyl-amino)-6-oxo-6H-pyridazin-1-yl]-propionic acid (67.3 mg) as a viscous, yellow oil. This material was used without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11](=[O:19])[N:12]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:8]=2[CH:7]=1)[CH3:4].C1COCC1.[CH3:27][O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[C:33]([O:41][CH3:42])[CH:32]=1)=[O:30]>O.CN(C=O)C>[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[N:10]([S:37]([C:34]3[CH:35]=[CH:36][C:31]([C:29]([O:28][CH3:27])=[O:30])=[CH:32][C:33]=3[O:41][CH3:42])(=[O:39])=[O:38])[C:11](=[O:19])[N:12]([CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:8]=2[CH:7]=1)[CH3:4]
Reactant: CCOc1ccc2[nH]c(=O)n(C3CCOCC3)c2c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)n(C1CCOCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
0.18 g of sodium hydride as a 60% dispersion in oil is added in portions to a mixture of 1 g of 5- ethoxy-1,3-dihydro-3-(tetrahydropyran-4-yl)-2H-benzimidazol-2-one, 30 ml of THF and 20 ml of DMF and the mixture is stirred for 30 minutes at RT. 1.2 g of 4- methoxycarbonyl-2-methoxybenzenesulfonyl chloride are then added and the mixture is stirred for 3 hours at RT. The reaction mixture is poured into 200 ml of water and the precipitate formed is filtered off and washed with iso ether to give 1.13 g of the expected product after drying. M.p.=165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:9])=[C:6]([CH:8]=1)[NH2:7].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[O:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:9])=[C:6]([NH:7][C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([F:10])([F:21])[F:22])=[O:20])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(Cl)ccc1O)Nc1ccccc1C(F)(F)F
Reaction time: 8 h

Procedure:
5-Chloro-2-hydroxyaniline (1 g) was suspended in toluene (50 ml) and treated with 2-trifluoromethylphenylisocyanate (1.2 ml). The reaction was stirred overnight and then filtered. The filter-cake was slurried and filtered twice with 15 ml toluene and washed once more with petrol. Drying at 55° C. gave 1-(5-Chloro-2-hydroxy-phenyl)-3-(2-trifluoromethyl-phenyl)-urea (2.06 g). Mp.=183-184° C. 1-(2-Hydroxy-6-methoxy-pyridin-3-yl)-3-(3-trifluoromethyl-phenyl)-urea (Compound 4):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2=[CH:7][CH:8]=[C:9]3[C:13]([N:12]([CH2:14][C@H:15]([NH:17]C(=O)C(F)(F)F)[CH3:16])[CH:11]=[CH:10]3)=[C:5]2[CH:4]=1.[OH-:26].[K+].[OH2:28].[OH-:29].[Na+]>CO>[C:3]([OH:2])(=[O:29])/[CH:25]=[CH:24]/[C:6]([OH:28])=[O:26].[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2=[CH:7][CH:8]=[C:9]3[C:13]([N:12]([CH2:14][C@H:15]([NH2:17])[CH3:16])[CH:11]=[CH:10]3)=[C:5]2[CH:4]=1
Reactant: [OH-]
Reactant: O
Reactant: COc1ccc2ccc3ccn(C[C@@H](C)NC(=O)C(F)(F)F)c3c2c1
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ccc3ccn(C[C@@H](C)N)c3c2c1
Product: O=C(O)/C=C/C(=O)O
Yield: 69 %

Procedure:
A mixture of 0.97 g of (R)-N-[2-(8-methoxy-1H-benz[g]indol-1-yl)-1-methyl-ethyl]-trifluoroacetamide, 1 g of potassium hydroxide, 2 ml of water and 40 ml of methanol was boiled under reflux for 15 hours. The reaction mixture was subsequently poured into 80 ml of 1N sodium hydroxide solution, extracted twice with 80 ml of diethyl ether each time and once with 80 ml of ethyl acetate and the combined organic phases were washed once with 120 ml and dried over magnesium sulfate. After concentration in a vacuum, the residue was dissolved in 100 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 322 mg of fumaric acid in 30 ml of methanol. The mixture was stirred at room temperature for 3 hours and the white crystals were subsequently filtered off. 600 mg (69%) of (R)-2-(8-methoxy-1H-benz[g]indol-1-yl)-1-methyl-ethylamine fumarate (1:0.5) with m.p. 209° were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[CH3:2].[C:33]([O-:36])(=[O:35])[CH3:34].[K+]>[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC.C(#N)C>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:35][C:33](=[O:36])[CH3:34])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:32][C:4](=[O:3])[CH3:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCCCCCCBr)c(C(=O)OCC)cc1OCCCCCCBr
Reactant: CC(=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OCCCCCCOC(C)=O)c(C(=O)OCC)cc1OCCCCCCOC(C)=O

Procedure:
50.0 g (86.0 mmol) diethyl-2,5-bis-(6-bromohexoxy)terephthalate, 84.5 g (861 mmol) potassium acetate and 4.4 g (11 mmol) methyl trioctyl ammonium chloride (Aliquat 336®, tricaprylyl methyl ammonium chloride, Fluka, CAS 5137.55.3) in 500 ml absolute acetonitrile are heated under reflux in a nitrogen atmosphere for 48 hours. After distilling off the solvent, the reaction mixture is taken up in 1200 ml ethyl acetate and washed three times with water (3×300 ml). The organic phase is dried over MgSO4 and the solvent is then distilled off. 1000 ml petroleum ether is added to the residual, oily residue and the product crystallizing out after 16 hours at -20° C. is recrystallized from petroleum ether/ethyl acetate.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:18](=NO)[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:24]>CC#N.O>[C:1]([C:3]1[N:4]=[C:5]2[C:18](=[O:24])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2]
Reactant: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=NO
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A suspension of 33 (522 mg, 1.97 mmol) and [bis(trifluoroacetoxy)iodo]benzene (1.69 g, 3.9 mmol) in CH3CN/H2O (9:1, 20 ml) was stirred 24 h at room temperature. The solid was collected by filtration and washed with CH3CN. The residue was dissolved in DMSO (2 ml) and precipitated by addition of H2O. The obtained solid was filtered and dried under vacuum, affording 36 (286 mg, 58%) as light brown solid. 1H NMR (300 MHz, DMSO d6): δ 8.65 (bs, 1H), 8.31 (bs, 1H), 8.09 (dd, 1H), 7.93 (m, 2H), 7.77 (ddd, 1H). ESI+MS: calcd for C13H6N4O2: 250.22; found: 251.1 (MH+).