Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[CH:10][N:11]=[C:5]2[CH:4]=1.C([O-])(=O)C.[Na+].[Br:17]Br.C(=O)([O-])O.[Na+]>[Br-].[K+].CO>[Br:17][C:9]1[N:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]2=[N:11][CH:10]=1
Reactant: BrBr
Reactant: COc1ccn2ccnc2c1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CO
Product: COc1ccn2c(Br)cnc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.9 %

Procedure:
7-Methoxyimidazo[1,2-α]pyridine (1.0 g, 6.8 mmol) and sodium acetate (0.67 g, 8.1 mmol) were dissolved in a saturated solution of potassium bromide in methanol (5 ml) and cooled to 0° C. before adding bromine (1.13 g, 7.1 mmol) dropwise over 5 min. The mixture was allowed to stir for 15 min before pouring onto saturated sodium hydrogencarbonate solution (50 ml). The resulting yellow solid was collected by filtration and dried. This solid was purified by flash column chromatography on silica eluting with 50% ethyl acetate in isohexane to afford 3-bromo-7-methoxyimidazo[1,2-α]pyridine (0.4 g, 26%) as a white solid. 1H NMR (360 MHz, CDCl3) δH 3.87 (3H, s), 6.64 (1H, dd, J 2 and 7), 6.88 (1H, d, J 2), 7.45 (1H, s), 7.92 (1H, d, J 7).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:23](=[O:39])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]2[NH:22][C:23](=[O:39])[CH2:24][C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH2:16][CH3:17]
Reactant: CCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-5-propoxy-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M195) (359 mg, 0.626 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (223 mg, 81%).
Reaction SMILES: Cl.[CH2:2]1[CH:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:6]2[CH2:5][CH2:4][NH:3]1.[Na].[C:16](Cl)(=[O:18])[CH3:17]>C(Cl)(Cl)Cl>[CH2:2]1[CH:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:6]2[CH2:5][CH2:4][N:3]1[C:16](=[O:18])[CH3:17]
Reactant: c1ccc2c(c1)OC1CNCCC21
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC2c3ccccc3OC2C1

Procedure:
To a mixture of 3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine hydrochloride (3.2 g, 15.1 mmol) and sodium hydrogenocarbonate (14 g) in chloroform (40 mL), was slowly added a solution of acetyl chloride (1.5 mL, 21 mmol) in chloroform (5 mL). After stirring for 2 h another portion of acetyl chloride was added. After 5 h the solvent was evaporated. Purification using silica gel chromatography (78 g SiO2) eluting with ethyl acetate yielded 1-(3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.C(N1C=CN=C1)(N1[CH:31]=[CH:30]N=C1)=O.N1C=CC=CC=1.CCO.C(O)(C(F)(F)F)=O>CC#N.CS(C)=O.CC#N.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH2:30][CH3:31])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A reaction mixture containing 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19), 1,1′-carbonyldiimidazole (17 mg, 0.106 mmol) and pyridine (9 μL, 0.113 mmol) in MeCN (0.75 mL) was stirred at 60° C. for 30 min, and then a second portion of pyridine (5 μL, 0.062 mmol) was added. After additional 30 min of stirring at 60° C., EtOH (6 μL, 0.100 mmol) was added. The reaction mixture was stirred at 50° C. over night, and then diluted with DMSO/MeCN/water. TFA (50 μL) was added and the crude product was purified by reversed phase chromatography (ACE C8, 5 μm, 21×50 mm, flow 25 ml/min, gradient: 0.1% TFA in water/MeCN over 6 minutes). The title compound was obtained in 54% yield (12.2 mg). 1H NMR (500 MHz, CDCl3) δ ppm 1.34 (t, J=7.08 Hz, 3 H) 2.45 (s, 3 H) 4.33 (q, J=7.08 Hz, 2 H) 6.92 (s, 1 H) 7.36 (dd, J=8.04, 7.66 Hz, 1 H) 7.42 (ddd, J=8.04, 2.32, 1.17 Hz, 1 H) 7.44 (dd, J=8.70, 1.95 Hz, 1 H) 7.71 (d, J=8.70 Hz, 1 H) 7.71 (d, J=1.95 Hz, 1 H) 7.71-7.72 (m, 1 H) 7.84 (ddd, J=7.66, 1.48, 1.17 Hz, 1 H). MS (ESI+) m/z 410 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31]I)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O.O1CCCC1>[CH2:1]([C:3]([CH2:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:25][CH:26]=1)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: ICCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)(CCc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 94.5 %

Procedure:
Diethyl ethylmalonate (50 g) was added to a suspension of sodium hydride (11 g) in dimethylformamide (200 ml) and tetrahydrofuran (50 ml), at 0° C., and the mixture was stirred at room temperature for 35 minutes. A solution of 2-(4-benzyloxyphenyl)ethyl iodide (90 g) was added to the reaction mixture at 0° C. and the whole mixture was stirred at 0° C. for 20 minutes and allowed to stand at room temperature overnight. The resultant mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:9) to give the subject compound (100 g).
Reaction SMILES: [CH3:1][C@H:2]1[C@:6]23[CH2:11][C@H:10]([C:12]([CH3:14])([CH3:13])[C@@H:5]2[CH2:4][CH2:3]1)[C@@:9]([OH:16])([CH3:15])[CH2:8][CH2:7]3.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].[OH2:29]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C@H:2]1[C@:6]23[CH2:11][C@H:10]([C:12]([CH3:14])([CH3:13])[C@@H:5]2[CH2:4][CH2:3]1)[C@@:9]([OH:16])([CH3:15])[CH2:8][CH2:7]3.[C:24]([O-:27])(=[O:29])[CH:25]=[CH2:26]
Reactant: C=CC(=O)Cl
Reactant: O
Agent: C[C@@H]1CC[C@H]2C(C)(C)[C@H]3C[C@@]12CC[C@@]3(C)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CC(=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In 200 ml of tetrahydrofuran, 25 g of (+)-Cedrol (manufactured by Lancaster) was dissolved, and to the solution were added 22.8 g of triethylamine and 1 g of N,N-dimethylaminopyridine. To the solution was dropwise added 15.2 g of acrylic chloride under cooling with ice over a period of 30 minutes and the mixture was stirred at room temperature for 2 days. To the reaction solution was added 100 ml of distilled water under cooling with ice, and the mixture was stirred for 30 minutes and 300 ml of ethyl acetate was added thereto. The water layer was removed by separation and the organic layer was washed with water, dried and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain 18.2 g of the desired compound which is a raw material monomer for repeating unit (b5).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([NH:13][C:14]([C:16]1[C:17]([CH3:29])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[N:20][CH:21]=1)=[O:15])[CH:8]=[CH:7]2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([NH:13][C:14]([C:16]1[C:17]([CH3:29])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[N:20][CH:21]=1)=[O:15])[CH:8]=[CH:7]2
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(N)ccc21
Yield: 92 %

Procedure:
A solution of 4-methyl-2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-nitro-indol-1-yl)-amide (1.64 mmol) in MeOH (45 mL) and 10% Pd/C (0.16 mmol) is hydrogenated in a 500 mL Parr bottle under 50 psi at rt overnight. Pd/C is filtered off. The filtrate is concentrated to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-amino-indol-1-yl)-amide (545 mg, 92%) as a solid. MS: 362 (M+H); 1H NMR (300 MHz, CD3OD): δ 3.84(s, H), 6.37(d, H), 6.81(dd, H), 7.01(d, H), 7.16-7.36(m, 3H), 7.55(m, H), 8.23(d, H), 8.36(d, H), 9.50(s, H).
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:15][C:11]1[C:10]([CH3:16])=[CH:9][C:8]([NH2:7])=[C:13]([CH3:14])[CH:12]=1
Reactant: Cc1cc(O)c(C)cc1N
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60 wt %, 0.36 g) was added to dimethyl sulfoxide (10 ml), and the mixture was stirred at 50° C. for 30 min and was then cooled to room temperature. 4-Amino-2,5-dimethylphenol (1.23 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/acetone (1/1) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
To a 0° C. solution of 2,6-dimethylpyridine (1.0 g, 0.009 mol) in CHCl3 (25 mL) was added mCPBA (3.17 g, 0.01 mol). The reaction mixture was then stirred for 12 h at RT, quenched with a saturated Na2CO3 solution. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford 2,6-dimethylpyridine 1-oxide (980 mg, 85%) as a solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][CH:8]1[C:17](O)=O.[OH-].[Na+].[N-:22]=[N+]=[N-].[Na+]>C1COCC1.CN(C=O)C.O>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][CH:8]1[CH2:17][NH2:22]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)C1CCc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: NCC1CCc2ccccc2O1
Reaction time: 18 h

Procedure:
LAH pellets (3.2 g, 84.3 mmole) were added slowly to a stirred solution of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (15 g, 84.3 mmole) in THF (150 ml). After the vigorous reaction subsided, the mixture was refluxed for 1 hr and then cooled. To the hot mixture were added sequentially, H2O (3.2 ml), 15% NaOH (3.2 ml), and then H2O (12.8 ml). The mixture was filtered and the filter cake washed with THF. The THF filtrate was concentrated in vacuo, and Ku/ gelrohr distilled to a clear oil (13.85 g, 100%). This alcohol intermediate was stirred in SOCl2 for 18 hr. The excess SOCl2 was removed in vacuo and the resulting dark oil was Ku/ gelrohr distilled to a clear oil (8.65 g, 56.2%). This alkyl chloride intermediate was heated to 100° in DMF with NaN3 (4.32 g, 66 mmole) and KI (0.2 g) for 72 hr. The mixture was diluted with H2O (250 ml) and extracted with CH2Cl2 three times. The CH2Cl2 extracts were concentrated in vacuo. The residue was hydrogenated at 60 psi over 10% Pd/C (1 g) in ethanol and 37% HCl (10 ml) for 3 hr. H2O (20 ml) was added and the mixture was filtered. The ethanol was removed in vacuo and the aqueous residue was made basic with 10N NaOH. The mixture was extracted three times with ethyl acetate (50 ml portions). The extracts were concentrated in vacuo and the tan oil was Ku/ gelrohr distilled to a dear oil (6.35 g, 82.2%). The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.[C@@H:10]12[O:17][C@@H:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH:14]12[O:17][CH:10]([CH2:16][CH2:15]1)[CH2:11][N:12]([C:7]([C:4]1[S:5][CH:6]=[C:2]([Br:1])[N:3]=1)=[O:9])[CH2:13]2
Reactant: O=C(O)c1nc(Br)cs1
Reactant: C1C[C@H]2CNC[C@@H]1O2
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(c1nc(Br)cs1)N1CC2CCC(C1)O2
Temperature: 0 °C
Reaction time: 15 h
Yield: 30.8 %

Procedure:
To a solution of 4-bromothiazole-2-carboxylic acid (prepared according to the procedure given in WO 2008/57336, 1.00 g, 4.82 mmol) in DMF (15 ml) was added HOST (0.88 g, 5.78 mmol) at room temperature, followed by the addition of (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane (prepared according to the procedure given in WO 2004/31186, 0.60 gm, 5.30 mmol). The reaction mixture was cooled to 0° C. and to this were added EDC (1.38 g, 7.23 mmol) and triethylamine (1.46 g, 2.02 ml, 14.46 mmol). The reaction mixture was stirred at room temperature for 15 hr and the progress of reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue so obtained was taken in ethyl acetate (150 ml) and washed with saturated sodium bicarbonate solution (1×40 ml), brine (1×20 ml) and organic layers separated were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get a crude product. The crude product was purified by column chromatography over silica gel (100-200 mesh) using 25% ethyl acetate in hexanes as an eluent to obtain the title compound (0.45 g, 30.8%). MS: m/z 304 (M+1).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:19]=[C:18]([O:20][C@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C:15]([C:16]#[N:17])=[CH:14][N:13]=1.N1C=CC=CC=1>C1COCC1>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2[CH:19]=[C:18]([O:20][C@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC[C@@H](C)Oc1cc(N)ncc1C#N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC[C@@H](C)Oc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Phenyl chloroformate (1.53 ml, 12.2 mmol) was added drop wise to a mixture of (R)-6-amino-4-((1-methoxypropan-2-yl)oxy)nicotinonitrile (intermediate 146, 1.37 g, 5.55 mmol) and pyridine (0.99 ml, 12.2 mmol) in THF (60 ml) at 0° C. The reaction mixture was stirred for 12 h at room temperature and additional pyridine (0.98 ml, 12.2 mmol) and phenyl chloroformate (1.53 ml, 12.2 mmol) were added. After stirring for a further 36 h at room temperature the reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution, the organic layer washed with saturated brine, dried over MgSO4 and evaporated. The residue was triturated with Et2O and the product obtained by filtration as a white solid. (UPLC-MS 6) tR 1.04; ESI-MS 328.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].[OH-].[Na+].Cl>C(Cl)(Cl)Cl.C(O)(C)C.C(OCC)C>[CH3:12][N:11]([CH3:13])[CH2:10][CH:9]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[S:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)C=CC(=O)c1ccc(F)cc1
Reactant: Sc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CC=C(Sc1ccccc1)c1ccc(F)cc1

Procedure:
By using a method similar to that described in Example 35, but starting from 1-(4-fluorophenyl)-3-dimethylamino-2-propen-1-one (10 g), phosphorus oxychloride (4.76 cc), thiophenol (5.57 cc) and sodium cyanoborohydride (1.92 g), a residue is obtained which is taken up in chloroform. The solution is then adjusted to pH 10 by adding a concentrated aqueous solution of sodium hydroxide. The organic phase is separated and then the aqueous phase is extracted with methylene chloride. The organic phases are collected, dried over sodium sulphate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa) at 30° C. A residue is obtained which is dissolved in isopropanol (30 cc). A 3N solution (12 cc) of hydrochloric acid gas in ethyl ether is added to this solution. The solid which precipitates is separated off by filtration and recrystallised from isopropanol (30 cc). In this way 1-dimethylamino-3-(4-fluorophenyl)-3-phenylthio-2-propene (E) hydrochloride (3.3 g) is obtained in the form of a white solid melting at 160° C.
Reaction SMILES: O.NN.[N:4]1[C:13]2[CH:12]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[C:23]([N+:24]([O-])=O)=[CH:22][C:21]([CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:20][N:19]=3)[CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1>CO.[Ni]>[NH2:24][C:23]1[C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH:12]2[C:13]3[N:4]=[CH:5][CH:6]=[CH:7][C:8]=3[CH2:9][CH2:10][CH2:11]2)=[N:19][CH:20]=[C:21]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1
Reactant: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Reaction time: 0.42 h

Procedure:
Hydrazine hydrate (7 ml) in methanol (25 ml) was added with stirring over 25 minutes to a cooled (5-10° C.) solution of 2-[3-(5,6,7,8-tetrahydroquinol-8-yl)propylamino-3-nitro-5-(pyrid-3-ylmethyl)pyridine (6.1 g) in methanol (300 ml) containing Raney Nickel (ca. 12 g). The solution was stirred for a further hour at 5° C., the catalyst was removed by filtration and the filtrate was concentrated to dryness in vacuo giving the title compound as an orange oil (theoretical yield assumed) which was used unpurified in the next reaction.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:14](=[O:19])[C:15]=2[C:16](Cl)=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.O1CCCC1.[NH:41]1[CH2:46][CH2:45][CH:44]([O:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:43][CH2:42]1>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:14](=[O:19])[C:15]=2[C:16]([N:41]2[CH2:42][CH2:43][CH:44]([O:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:45][CH2:46]2)=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(-c2ccc(C(C)(C)C)cc2)c(C(=O)Cl)c(=O)n1-c1ccc(C#N)cc1
Reactant: CCOC(=O)COC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)COC1CCN(C(=O)c2c(-c3ccc(C(C)(C)C)cc3)n(C)n(-c3ccc(C#N)cc3)c2=O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 28.5 %

Procedure:
A mixture of 3.5 g of 3-(4-t-butylphenyl)-4-chlorocarbonyl-1-(4-cyanophenyl)-2-methyl-2H-pyrazol-5-one, 1.8 g of triethylamine, 50 ml of tetrahydrofuran, 20 ml of N,N-dimethylformamide and 2.38 g of ethyl 4-piperidinoxyacetate was stirred at room temperature for 20 hours. The reaction solution was evaporated under reduced pressure, and after addition of water, the resulting residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride successively and dried over sodium sulfate. The insolubles were filtered off, and then the solvent was removed by evaporation. The resulting residue was purified by silica gel chromatography (eluent; ethyl acetate/chloroform=1:1) to give 1.38 g of the title compound as a colorless amorphous solid.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[O:17]=[C:18]([NH:33][CH2:34][C:35](=O)[NH:36][C@@H:37]1[CH2:41]CNC1)[CH2:19][NH:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1>C(Cl)Cl.[OH-].[OH-].[Pd+2]>[OH:1][C:2]1([C:9]2[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:36]2[CH2:37][CH2:41][C@@H:34]([NH:33][C:18](=[O:17])[CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH2:35]2)[CH2:4][CH2:3]1
Reactant: CC(C)c1ncc(C2(O)CCC(=O)CC2)s1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC(=O)N[C@@H]1CCNC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)c1ncc(C2(O)CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Reaction time: 24 h
Yield: 46.4 %

Procedure:
To a Parr hydrogenation bottle was added 4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexanone (0.363 g, 1.52 mmol) and N-[2-oxo-2-({2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}amino)ethyl]-3-(trifluoromethyl)benzamide (0.435 g, 1.38 mmol), dissolved in CH2Cl2 (20 mL), followed by the addition of 10% Pd(OH)2 (0.8 g). This mixture was hydrogenated at 50 psi for 24 hour. After the catalyst was filtered and washed with methanol, the filtrate was concentrated in vacuo and chromatographed to give 0.345 g of title compound in 62% yield. MS (EI) calcd: (M+1)+=539.2; found: 539.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]2[CH3:25])=[C:4]([F:27])[CH:3]=1.[N:28]([C:31]1[C:32]([CH3:37])=[N:33][O:34][C:35]=1[CH3:36])=[C:29]=[O:30]>ClCCl>[CH3:37][C:32]1[C:31]([NH:28][C:29]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][N:10]3[C:14](=[O:15])[C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]3[CH3:25])=[C:4]([F:27])[CH:3]=2)=[O:30])=[C:35]([CH3:36])[O:34][N:33]=1
Reactant: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc(N)cc2F)C1=O
Reactant: Cc1noc(C)c1N=C=O
Solvent: ClCCl
Product: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc(NC(=O)Nc3c(C)noc3C)cc2F)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.8 %

Procedure:
A mixture of (+/−)-3-[2-(4-amino-2-fluoro-phenyl)-2-oxo-ethyl]-2-methyl-5-phenyl-5-propyl-3,5-dihydro-imidazol-4-one (116 mg, 0.25 mmol) and 4-isocyanato3,5-dimethyl-isoxazole (34.5 mg, 0.25 mmol) in 3 mL dichloromethane is stirred at room temperature for 18 hours. Subsequently the solvent is evaporated and the residue is dissolved in acetonitrile, the solution filtrated and subjected to preparative HPLC purification (Method 3) to yield (+/−)-1-(3,5-dimethyl-isoxazol-4-yl)-3-{3-fluoro-4-[2-(2-methyl-5-oxo-4-phenyl-4-propyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-urea (44 mg, 35%), LC/MS at 254 nm; [M+H] 506; Rt 2.754 min.