Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1SC(C([O-])=S)=CC=1.[NH2:10][C:11](=[S:22])[C:12]1[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=1[CH3:17].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=O>CC(C)=O>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[N:10]=[C:11]([C:12]3[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=3[CH3:17])[S:22][CH:24]=2)=[CH:28][CH:29]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: Cc1ccc(C([O-])=S)s1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccc(OC)cc3)cs2)c(C)s1
Yield: 104.3 %

Procedure:
Methyl 4-]4-(4-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate: 30 mg (0.122 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 1.2 mL of reagent grade acetone. 2-bromo-4′-methoxy acetophenone (0.146 mmol; 28 mg; Aldrich Chemical Co.) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and a solid was filtered and washed with methanol and dried in vacuo to afford 46 mg (90% yield) of methyl 4-[4-(4-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH2:35][C:36]1[CH:37]=[C:38]([CH:51]=[CH:52][C:53]=1[N:54]1[CH2:59][CH2:58][N:57]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[CH3:66])[CH2:56][CH2:55]1)[C:39]([NH:41][CH2:42][CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][C:46]1=[O:50])=[O:40].Br[C:68]1[N:73]=[CH:72][CH:71]=[CH:70][N:69]=1>CC(O)(C)C.C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:50]=[C:46]1[CH2:47][CH2:48][CH2:49][N:45]1[CH2:44][CH2:43][CH2:42][NH:41][C:39](=[O:40])[C:38]1[CH:51]=[CH:52][C:53]([N:54]2[CH2:59][CH2:58][N:57]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[CH3:66])[CH2:56][CH2:55]2)=[C:36]([NH:35][C:68]2[N:73]=[CH:72][CH:71]=[CH:70][N:69]=2)[CH:37]=1
Reactant: Brc1ncccn1
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2Nc2ncccn2)CC1

Procedure:
N-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-3-(pyrimidin-2-ylamino)-4-(4-o-tolyl-piperazin-1-yl)-benzamide (compound no. 242) was prepared as follows: In a microwavable glass tube, Pd(OAc)2 (0.0025 g, 0.0115 mmol) and X—PHOS (5.4 mg, 0.0115 mmol) were taken in a mixture of t-BuOH:toluene (1:5) (2.0 mL) and stirred. This solution was evacuated for 5 min and purged with nitrogen. 3-Amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide (0.05 g, 0.115 mmol) and 2-bromo-pyrimidine (2.7 mg, 0.172 mmol) were added to this, evacuated and nitrogen purged. This mixture was stirred at 140° C. under MW for 30 min. LC-MS indicated the product formation along with some other by-products. The reaction mixture was concentrated, dissolved in methanol and purified on preparative HPLC using water/methanol as eluent to give desire product (10.0 mg, 17%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:18]=[O:19])=[CH:8][C:9]=1[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[BH4-].[Na+].C(OCC)(=O)C.O>C(O)C.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:18][OH:19])=[CH:8][C:9]=1[NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C=O)cc1NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1sc(CO)cc1NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a suspension of 3-tert-butoxycarbonylamino-5-formyl-thiophene-2-carboxylic acid methyl ester (1.49 g) in ethanol/water (95 mL/95 mL) sodiumborohydride (105.8 mg) was added at 0° C. The mixture was stirred for 1 h at this temperature. Then ethyl acetate and water were added. The aqueous phase was extracted several times with ethyl acetate, the combined organic phases dried over sodium sulfate and the solvent removed in vacuo. The product with the molecular weight of 287.33 (C12H17NO5S) was obtained in this way; MS (ESI): 288 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[NH:5][CH3:6].C(NC(C)C)(C)C.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([N:5]([CH3:6])[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CNc1cccc(Br)c1F
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CN(C(=O)c1ccc(F)cc1)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
Step 3 A solution of 3-bromo-2-fluoro-N-methylaniline (32 mg, 0.157 mmol) and diisopropylamine (0.055 mL, 0.314 mmol) in DCM (2 mL) was treated with 4-fluorobenzoyl chloride (0.028 mL, 0.235 mmol) and the mixture was stirred at rt for 2 h. The mixture was partitioned between DCM and NaHCO3 (aq). The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 90:10 to 80:20 hexane-EtOAc) to provide N-(3-bromo-2-fluorophenyl)-4-fluoro-N-methylbenzamide as a white solid (35 mg, 68%). Mass spectrum m/z 326, 328 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([I:17])[C:5]([CH3:16])=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([I:17])[C:5]([CH3:16])=[C:6]([CH:7]=1)[NH2:8]
Reactant: Cc1c(I)cc(Cl)cc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(N)cc(Cl)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of 1,1-dimethylethyl (5-chloro-3-iodo-2-methylphenyl)carbamate (5 g, 13.6 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (10 mL). The solution was stirred at ambient temperature for 2 hours, then concentrated in-vacuo. The resultant residue was partitioned between saturated sodium bicarbonate and ethyl acetate. The aqueous portion was extracted twice with ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford an orange residue which was purified by column chromatography (silica gel, 5% ethyl acetate in hexane). The product was isolated to afford 3.05 g, 11.4 mmol (84%) of 5-chloro-3-iodo-2-methylaniline as a yellow solid. 1H NMR (400 MHz, CDCl3): 7.26 (d, 1H), 6.64 (d, 1H), 3.78 (br s, 2H), 2.28 (s, 3H); MS (EI) for C7H7ClIN: 268 (MH+).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[C:10](=[O:16])[NH:11][C:12](=[S:15])[NH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].[CH3:17]I>CN(C=O)C>[CH3:4][C:2]([NH:5][S:6]([C:9]1[C:10]([OH:16])=[N:11][C:12]([S:15][CH3:17])=[N:13][CH:14]=1)(=[O:7])=[O:8])([CH3:1])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)NS(=O)(=O)c1c[nH]c(=S)[nH]c1=O
Solvent: CN(C)C=O
Product: CSc1ncc(S(=O)(=O)NC(C)(C)C)c(O)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
N-(1,1-Dimethylethyl)-1,2,3,4-tetrahydro-4-oxo-2-thioxo-5-pyrimidinesulfonamide (30.69 g, 116.7 mmol) was dissolved in DMF (300 mL) and methyliodide was added (8.72 mL, 140 mmoles) and the mixture was stirred at ambient temperature for 24 hours. An additional quantity of methyliodide (2.5 mL) was added and the reaction stirred an additional 24 hours. A final addition of methyliodide (2.0 mL) was made followed by another 24 hours of stirring to complete the reaction. The DMF was removed under reduced pressure, the residue was suspended in water (300 mL), sodium carbonate was added until the solution was neutralized, then the pH was adjusted to 8 with sodium hydroxide pellets. The aqueous solution was filtered, extracted with three 150 mL portions of ethyl acetate. The pH of the aqueous portion was adjusted to 3 with 37% HCl, the white solid that precipitated out was filtered, washed with water, and dried in a vacuum oven to yield 20.16 gm (72.78 mmol, 62%) of product which was used as is in the next step. An analytical sample crystallized from ethanol/water, had a m.p. 225.5° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12](F)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:29][C:30]1[CH:31]=[CH:32][C:33]([C@@H:36]([NH2:38])[CH3:37])=[N:34][CH:35]=1>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:38][C@H:36]([C:33]4[CH:32]=[CH:31][C:30]([F:29])=[CH:35][N:34]=4)[CH3:37])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1F
Reactant: C[C@H](N)c1ccc(F)cn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cn1
Temperature: 130 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
A suspension of 6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2,5-difluoronicotinonitrile (Method 32, 5.75 g, 22.0 mmol), in n-BuOH (28.75 ml) was prepared at room temperature in a 48 ml sealed tube. DIEA (4.98 ml, 28.6 mmol) was then added, followed by the addition of (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 33; 4.0 g, 28.6 mmol). The tube was then sealed, and the suspension was heated to 130° C. over 45 minutes. The reaction was then allowed to stir at 130° C. for 18 hours. The reaction was then cooled to room temperature and concentrated by rotary evaporation at 60° C. to remove n-BuOH. The remaining oil was then taken up in DCM (100 ml) and washed with water (2×100 ml). The combined aqueous fractions were then extracted with DCM (100 ml), and the combined organic fractions were dried over Na2SO4, filtered and concentrated. The resulting oil was then purified by column chromatography (DCM, then DCM-MeOH=100:1) to give the title compound (5.2 g, 62%). 1H NMR (400 MHz, CD3OD) δ 8.43 (d, J=2.5 Hz, 1H), 7.60-7.34 (m, 3H), 6.09-5.63 (m, 1H), 5.24 (q, J=7.0 Hz, 1H), 1.91 (septet, 1H), 1.58 (d, J=6.6 Hz, 3H), 1.08-0.90 (m, 2H), 0.79-0.70 (m, 2H). MS: Calcd.: 381. Found: [M+H]+ 382.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1B(O)O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:20]2[CH:19]=[CH:18][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: COc1ccc(Br)c(OC)c1-c1ccccn1
Product: COc1ccc(-c2ccc3ccccc3c2)c(OC)c1-c1ccccn1

Procedure:
This compound was prepared by the same procedure as used in EXAMPLE 3 using 1,3-dimethoxy-2-(pyrid-2-yl)-4-bromobenzene 38 and naphth-2-yl boronic acid to yield 39.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH:22]=[CH2:23])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CC(O)=O>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH:22]=[CH2:23])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: C=Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a solution (S)-ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-vinylnaphthalen-2-yl)acetate (7.4 mg, 0.0175 mmol) in THF/MeOH (1/1, 1 mL), was added NaOH (2 N, 280 L). The reaction mixture was stirred at room temperature overnight. Then the temperature was raised to 40° C. and the reaction mixture was stirred for 4 h. The reaction was then cooled down and neutralized by adding HOAc. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to provide 5.3 mg of the desired product. 1H-NMR: 400 MHz, (CD3OD) δ: 8.07 (s, 1H), 7.89 (d, J=4.0 Hz, 1H), 7.60-7.54 (m, 4H), 7.48-7.44 (m, 1H), 7.35-7.31 (m, 2H), 7.25-7.22 (m, 1H), 5.76-5.71 (m, 1H), 5.29-5.26 (m, 1H), 5.21 (s, 1H), 0.98 (s, 9H). LCMS-ESI− (m/z): [M−H]− calcd for C24H23ClO3: 393.1. Found: 393.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[C:10](=[N:16][OH:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC1CN(Cc2ccccc2)CC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1CN(Cc2ccccc2)CC1=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
A solution of 31.7 g (0.168 mole) of 1-benzyl-4-methyl-3-pyrrolidone [prepared as described in Step (4) above] dissolved in 200 ml of ethanol was added dropwise to a solution of 59.4 g (0.79 mole) of hydroxylamine hydrochloride dissolved in 200 ml of water over a period of 1 hour, whilst keeping the temperature at 20° to 25° C. 62.1 g (0.45 mole) of potassium carbonate were then added, and the mixture was stirred at room temperature overnight, after which it was diluted with 100 ml of water. The aqueous solution was extracted with chloroform, and the chloroform extract was washed with water, dried and concentrated by evaporation under reduced pressure, to give 36.9 g of 1-benzyl-3-(hydroxyimino)-4-methylpyrrolidine as brown crystals.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([CH:13]([OH:17])[CH:14]([CH3:16])[CH3:15])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:26])=[CH:28][CH:29]=2)[C:8]2[CH:12]=[C:11]([CH:13]([OH:17])[CH:14]([CH3:16])[CH3:15])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1sc(C(O)C(C)C)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1sc(C(O)C(C)C)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a mixture of 4-({cyclohexyl[2-ethyl-5-(1-hydroxy-2-methylpropyl)thiophen-3-yl]methyl}amino)benzoic acid (150 mg) synthesized in Example 293 (1), ethyl 3-(methylamino)propanoate (71.1 mg), 1-hydroxybenzotriazole monohydrate (83.0 mg) and triethylamine (76 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (104 mg), and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (132 mg, 73%) as a white solid. The obtained resultant product was a mixture of two diastereomers (about 2:3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[CH:13][CH:12]=2)[N:3]=1.[Cl:22][C:23]1[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][N:24]=1>>[Cl:22][C:23]1[C:28]([O:29][C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[CH:20][N:19]=[CH:18]4)=[CH:13][CH:12]=3)[N:3]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3ccnc3)cc2)n1
Reactant: Oc1cccnc1Cl
Product: COc1nc(Nc2ccc(-n3ccnc3)cc2)nc(Oc2cccnc2Cl)n1
Yield: 37 %

Procedure:
This compound was prepared in analogy to example 3 from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-(4-imidazol-1-yl-phenyl)-amine and 2-chloro-3-hydroxypyridine. The title compound was isolated as a colorless solid in 37% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>Cl>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][C:14]3[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:15]=3[C:16]([OH:18])=[O:17])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(I)cc1C(=O)O
Agent: Cl
Product: O=C(O)c1cc(I)ccc1Nc1ccnc2cc(Cl)ccc12

Procedure:
4,7-Dichloroquinoline and 2-amino-5-iodo benzoic acid are refluxed in dilute hydrochloric acid for 1 hour to give 2-(7-chloro-4-quinolylamino)-5-iodo benzoic acid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]([Cu])#[N:35]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:34]#[N:35])[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: N#C[Cu]
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1C#N
Temperature: 100 °C
Reaction time: 14 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (500 mg, 0.837 mmol) in DMF (7.5 mL) was added CuCN (150 mg, 1.67 mmol). The reaction was heated to 100° C. and stirred at that temperature for 14 hours. The reaction was then cooled to room temperature, diluted with EtOAc (200 mL), and washed with 100 mL of 2.5 M aqueous ammonia. The organic layer was washed with brine (75 mL) and then filtered through a plug of silica gel. The filtrate was concentrated, and the residue was purified by flash chromatography on silica gel (5 to 50% EtOAc/hexanes) to afford 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzonitrile. Rf=0.29 (25% EtOAc/hexanes). LCMS=497.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.91 (s, 1H), 7.88 (s, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.79 (s, 2H), 7.74 (d, J=8.2 Hz, 1H), 5.78 (d, J=7.8 Hz, 1H), 4.93 (d, J=16.1 Hz, 1H), 4.53 (d, J=15.8 Hz, 1H), 4.23 (m, 1H), 0.86 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25](=O)[C:26](OC)=[O:27].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25]1[C:26](=[O:27])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(C)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]cc(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c2c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 64.3 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (260 mg, 1.4 mmol) and methyl 2-(5-methyl-1H-indol-3-yl)oxoacetate (300 mg, 1.4 mmol) in DMF (5.4 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (1.4 mL, 1.4 mmol) at 4° C. under N2. The reaction was stirred for 20 min, and additional potassium tert-butoxide (1.0 M, 2.8 mL, 2.8 mmol) was added. The resulting dark purple solution was heated to 50° C. and stirred over night. The mixture was cooled to 4° C. and quenched with 1.0 N hydrochloric acid (9 mL), and extracted with EtOAc (300 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (150 mL), brine (150 mL), and dried (MgSO4). The mixture was filtered, and concentrated to a red solid. Flash chromatography (SiO2, 40% EtOAc/hexanes) gave the title compound (320 mg, 65%) as a red solid, mp 174–176° C. 1H NMR (DMSO-d6) δ 8.02 (s, 1H), 7.61 (m, 1H), 7.24 (s, 1H), 7.16 (m, 1H), 6.95 (m, 1H), 6.85 (m, 1H), 6.75 (m, 1H), 6.46 (s, 1H), 5.71 (s, 1H) 3.62 (s, 3H), 1.71 (s, 3H). MS (ESI): m/z=356 [C22H17N3O2+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)=[O:5].[Br:18]Br>C(O)(=O)C>[Br:18][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[CH3:1])=[CH:8][C:9]=1[CH3:13]
Reactant: BrBr
Reactant: Cc1cccc(NC(=O)c2ccccc2C)c1
Solvent: CC(=O)O
Product: Cc1cc(NC(=O)c2ccccc2C)ccc1Br
Temperature: 12.5 °C
Reaction time: 1 h

Procedure:
3-(2-methylbenzoylamino)toluene (80 g) is dissolved in acetic acid (500 mL), and thereto is added a solution of bromine (19.0 ml) in acetic acid (40 mL) with stirring under ice cooling over a period of about one hour. During which the mixture is cooled at an inner temperature of below 20° C. (mean inner temperature: 10-15° C.) since the temperature raises. The reaction mixture is continuously stirred overnight. The resulting suspension is added to ice-water, and the resulting crystals are taken by filtration, washed with water, and dried at 60° C. The resultant is recrystallized from methanol-water to give 2-bromo-5-(2-methylbenzoylamino)toluene (105.0 g), white needles (yield 97%, Mp 144.5-146.0° C.)
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>>[CH:1]1([C:4]2[N:5]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:2][CH2:3]1
Reactant: BrCC1CC1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2CC2CC2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and (bromomethyl)cyclopropane: 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 2H), 6.37 (d, J=1.7 Hz, 1H), 4.19 (d, J=6.6 Hz, 2H), 1.92 (m, 1H), 1.24 (m, 1H), 1.11 (m, 2H), 0.86 (m, 2H), 0.61 (m, 2H), 0.39 (m, 2H); MS (ES) m/z 305 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:14])=[CH:10][C:11](Cl)=[O:12]>C(Cl)(Cl)Cl>[CH3:8][C:9]([CH3:14])=[CH:10][C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: Nc1ccccc1
Reactant: CC(C)=CC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)=CC(=O)Nc1ccccc1
Yield: 91 %

Procedure:
To a stirred solution of 4.1 g (0.44 mol) of aniline in 200 ml of chloroform, at 25° C., was added slowly a solution of 25 g (0.21 mol) of 3-methylcrotonoyl chloride in 100 ml of chloroform. The reaction mixture was refluxed for 1.5 hours, and then the precipitate was removed by filtration. The chloroform solution was washed successively with 1N hydrochloric acid and saturated sodium bicarbonate solution, and then it was dried (MgSO4) and evaporated in vacuo. This gave 33.5 g (91% yield) of the title compound as a solid, mp 122°-125° C.