Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.[Mg].Br[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH3:12].[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15].C1C[O:22]CC1>BrC1C=C(C)C=CC=1C>[CH3:12][C:6]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[C:13](=[O:17])[C:14]([OH:22])=[O:15]
Reactant: Cc1ccc(C)c(Br)c1
Reactant: C1CCOC1
Reactant: O=C(Cl)C(=O)Cl
Agent: II
Agent: [Mg]
Product: Cc1ccc(C)c(C(=O)C(=O)O)c1
Temperature: -65 °C

Procedure:
Two drops of 2-bromo-1,4-dimethylbenzene and an iodine crystal were add to magnesium turnings (1.7 g, 70.8 mmol). After heating to initiate the reaction, tetrahydrofuran (50 mL) was added, and then 2-bromo-1,4-dimethylbenzene (10 g, 54.1 mmol) was added dropwise the reaction mixture. The reaction was heated at reflux for an additional 1.5 h after the addition was complete, and then cooled to −65° C. and a solution of oxalyl chloride (5.2 mL, 7.6 g, 60 mmol) in THF (60 mL) was added dropwise. After 1 h the reaction mixture was warmed to 0° C., quenched with saturated aqueous ammonium chloride, poured into water and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4) and concentrated under reduced pressure. The crude mixture was taken up in ethyl acetate and extracted two times with sodium hydroxide (1 N). The combined aqueous layers were adjusted to pH 3 with HCl (1 N) and extracted with ethyl acetate (3×). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to provide the title compound as a tan solid (4.49 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[S:7].CO[CH:11](OC)[CH2:12]Br.Cl>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:11]=[CH:12][N:8]=1
Reactant: NC(=S)c1cccs1
Reactant: COC(CBr)OC
Agent: Cl
Solvent: CCO
Product: c1csc(-c2nccs2)c1
Yield: 168.3 %

Procedure:
In a manner similar to Step B of Example 1, the reaction of 13.3 grams (0.027 mole) of (thien-2-yl)thiocarboxamide with 16.0 grams (0.0945 mole) of bromoacetaldehyde dimethyl acetal and 2 ml of concentrated hydrochloric acid in 250 ml of ethanol yielded 7.6 grams of 2-(thien-2-yl)thiazole as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH:14]([OH:15])[CH2:13][N:12]([CH3:16])[C:11]2=[O:17])=[C:4]([F:18])[CH:3]=1.[CH3:19][N:20]=[C:21]=[O:22]>C(#N)C.N12CCC(CC1)CN2>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH:14]([O:15][C:21](=[O:22])[NH:20][CH3:19])[CH2:13][N:12]([CH3:16])[C:11]2=[O:17])=[C:4]([F:18])[CH:3]=1
Reactant: CN=C=O
Reactant: COc1cc(N2C(=O)N(C)CC2O)c(F)cc1Cl
Agent: C1CN2CCC1CN2
Solvent: CC#N
Product: CNC(=O)OC1CN(C)C(=O)N1c1cc(OC)c(Cl)cc1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
27.5 g (0.10 mol) of 3-(4-chloro-2-fluoro-5-methoxyphenyl)-4-hydroxy-1-methylimidazolidin-2-one (Example 1) are dissolved in 200 ml of acetonitrile, 50 mg of diazabicyclo[2.2.2]octane are added, and 6.84 g (0.12 mol) of methyl isocyanate are added dropwise at 20° C. The mixture is stirred for 5 hours at 50° C. and the solvent is removed by distillation. The solid residue which remains is boiled up in 200 ml of ether and cooled in an ice-bath. The precipitate is filtered off under suction and dried. 31.0 g (93% of theory) of 3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-4-(N-methylcarbamoyloxy)imidazolidin2-one are obtained in the form of colorless crystals having the melting point 128°-131° C.
Reaction SMILES: N=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[NH:8][C:9]([N:11]1C=CN=C1)=[S:10].Cl[CH2:17][C:18]1[NH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][N:22]=1>CN(C=O)C>[C:23]1([C:20]2[N:19]=[C:18]([CH2:17][S:10][C:9]3[N:11]=[C:4]4[CH:5]=[CH:6][CH:7]=[CH:2][N:3]4[N:8]=3)[NH:22][CH:21]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCc1ncc(-c2ccccc2)[nH]1
Reactant: N=c1ccccn1NC(=S)n1ccnc1
Solvent: CN(C)C=O
Product: c1ccc(-c2c[nH]c(CSc3nc4ccccn4n3)n2)cc1
Temperature: 100 °C

Procedure:
A solution of imidazole-1-carbothioic acid (2-imino-2H-pyridin-1-yl)-amide (18 mg, 0.080 mmol) in DMF (0.5 mL) was added to 2-chloromethyl-5-phenyl-1H-imidazole (23 mg, 0.12 mmol) and the mixture was heated at 100° C. overnight. Volatiles were evaporated and the residue was purified by preparative LC-MS to yield the title compound. LC-MS: m/z=308.2 (MH+), tR=0.67 min, method A.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31](=[O:36])[CH2:30][N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)C(C)(C)C)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1 g), 1-bromo-3,3-dimethylbutan-2-one (0.4 mL), potassium carbonate (0.75 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then 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 to give the title compound as a colorless solid (0.4 g, 32%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:32]1[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]1)=[O:20])=[N:5]2
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Product: COc1nc2cc(F)c(F)cc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 70 %

Procedure:
Ethyl N-(6,7-di fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethyl phenyl)piperazine were reacted by the same way with the example 169 to obtain the titled compound (yield, 70%). 1H NMR (300 MHz, CDCl3) δ 2.30 (s, 6H), 3.26-3.28 (m, 4H), 3.74-3.76 (m, 4H), 4.15 (s, 3H), 6.59 (s, 3H), 7.29 (s, 1H), 7.49-7.53 (m, 1H), 7.52-7.62 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:33]([C:32]3[CH:35]=[CH:36][C:29]([N:28]([CH3:37])[CH3:27])=[CH:30][CH:31]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-[4-(2-Amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.040 g, 0.10 mmol), ethanol (3 ml), and 4-dimethylamino-benzaldehyde (0.019 g, 0.13 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.4 ml, 0.4 mmol). The reaction mixture was heated at 70° C. for 3.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with ethyl acetate/dichloromethane (v/v; 1:1), 1.5% methanol in ethyl acetate/dichloromethane (v/v; 1:1) and finally 2% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained after trituration with diethyl ether as a pale yellow solid (0.005 g, 10%); 1H-NMR (250 Mz, DMSO-d6) 2.78 (m, 4H, piperazine N(CH2)2), 3.01 (s, 6H, N(CH3)2), 3.40 (s, 2H, NCH2CO), 3.72 (m, 4H, piperazine N(CH2)2), 6.83 (d, J=8.79 Hz, 2H, 3,5-ArH or 2,6-ArH), 7.25 (d, J=3.42 Hz, 1H) and 7.51 (d, J=3.53 Hz, 1H) (thiazole 4-H, 5-H), 8.03 (d, 3H, J=9.88 Hz, 3,5-ArH or 2,6-ArH, and imidazo[4,5-b]pyridine 5-H); 11.95 (s, 1H, CONH), 13.12 (s, 1H, imidazo[4,5-b]pyridine N—H); LC-MS (ESI, m/z) 6.17 min—497, 499 [(M+H)+, Cl isotopic pattern]; ESI-HRMS Found: 497.1652, calculated for C23H26N8ClOS (M+H)+: 497.1633.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:7][CH:6]=1.[C:18]([CH2:21][N:22]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29][N:28]([CH2:34][C:35]([OH:37])=[O:36])[CH2:27][CH2:26][N:25]([CH2:38][C:39]([OH:41])=[O:40])[CH2:24][CH2:23]1)([OH:20])=[O:19].[OH-].[K+]>O1CCOCC1.O>[OH:1][CH:2]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:7][CH:6]=1)[CH2:17][N:31]1[CH2:32][CH2:33][N:22]([CH2:21][C:18]([OH:20])=[O:19])[CH2:23][CH2:24][N:25]([CH2:38][C:39]([OH:41])=[O:40])[CH2:26][CH2:27][N:28]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29][CH2:30]1
Reactant: OCCCCCc1ccc(OCC2CO2)cc1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)COc2ccc(CCCCCO)cc2)CCN(CC(=O)O)CC1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
12.3 g (51.97 mmol) of 2,3-epoxy-1-[4-(5-hydroxypentyl)-phenoxy]-propane and 10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) are dissolved in a mixture of 50 ml of dioxane and 80 ml of water, and the pH is brought to pH 10 with 6N potassium hydroxide solution. It is stirred for 24 hours at 40° C. It is evaporated to dryness, the residue is taken up with 200 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 3 with 5N hydrochloric acid and evaporated to dryness. The residue is concentrated by evaporation in a vacuum and boiled out (extracted) with 200 ml of methanol/50 ml of methylene chloride. It is cooled in an ice bath and filtered off from precipitated potassium chloride. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 50 ml of water/20 ml of ethanol and then added to a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water. After concentration by evaporation in a vacuum, 8.92 g (53% of theory) of the title compound is obtained as strongly hygroscopic, vitreous solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:15][C:16]3[C:25]([C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][C:17]=3[CH3:32])=[O:14])=[CH:11][C:10]([C:33]([F:36])([F:35])[F:34])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:37]([Sn](CCCC)(CCCC)C(OCC)=C)CCC.O>CN(C=O)C.C1(P([Pd](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]([C:19]1[CH:24]=[C:25]([C:26]([NH:28][CH:29]([CH3:30])[CH3:31])=[O:27])[C:16]([NH:15][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:33]([F:34])([F:36])[F:35])[CH:11]=2)=[O:14])=[C:17]([CH3:32])[CH:18]=1)(=[O:21])[CH3:37]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)c(C(=O)NC(C)C)c1
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(C)c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)c(C(=O)NC(C)C)c1
Temperature: 80 °C

Procedure:
The title compound of Example 2, Step C (0.7 g, 1.3 mmol) was dissolved in DMF (10 mL) and treated with tributyl-(1-ethoxyvinyl)tin (0.47 g, 1.3 mmol) and bis(triphenyl-phosphino)palladium dichloride (50 mg). The mixture was heated at 80° C. for 4 hours. The mixture was poured into water (50 mL) and extracted with ether (3×50 mL). The combined organic layers were washed with water (50 mL) and saturated brine (50 mL). The mixture was dried over magnesium sulfate and concentrated under reduced pressure. The residue was filtered through a silica gel cartridge using dichloromethane as eluent. The appropriate fractions were pooled and evaporated. The residue (400 mg) was dissolved in acetone (20 mL) and treated with 1N hydrochloric acid (5 mL). After 1 hour at 25° C. the reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel using ethyl acetate/hexanes (40:60) as eluent. Pooling appropriate fractions and evaporation of solvent provided the title compound, a compound of the invention, (150 mg) as a yellow solid, m.p.: 135–137° C. 1H NMR (CDCl3): δ 10.8 (NH), 8.42 (1H), 7.89 (1H), 7.87 (2H), 7.42 (1H), 7.31 (1H), 6.15 (1H), 4.21 (1H), 2.59 (3H), 2.27 (3H), 1.28 (6H).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[CH2:14][C:15]#N)=[CH:4][CH:3]=1.C(O)C.[OH-:22].[K+].[OH2:24]>>[CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[CH2:14][C:15]([OH:24])=[O:22])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Cc1ccc(Oc2ccc(C)cc2CC#N)cc1
Reactant: O
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(Oc2ccc(C)cc2CC(=O)O)cc1

Procedure:
A solution of 95 g. of crude 2-(4-methyl-phenoxy)-5-methyl-phenylacetonitrile in 500 ml. of ethanol is treated with a solution of 67 g. of potassium hydroxide in 120 ml. of water and heated to reflux for 5 hours. Then, the ethanol is evaporated in vacuo and the residue diluted with 500 ml. of water. The resulting mixture is extracted twice with ether. The ethereal extracts are extracted twice with sodium bicarbonate solution. The combined aqueous solutions are acidified and extracted three times with ether. The ethereal extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo, and there is obtained 2-(4-methyl-phenoxy)-5-methyl-phenylacetic acid which, after recrystallization from methanol/water, melts at 101°-104° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:25]=[CH:24][C:15]3[N:16]([CH:21]([CH3:23])[CH3:22])[C:17](=[O:20])[N:18]([CH3:19])[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:27]1C(C2C=CC3N(C(C)C)C(=O)NC=3C=2)=NC=C(C(F)(F)F)[CH:32]=1.C(Br)C#C>>[Cl:1][C:2]1[C:3]([C:12]2[CH:25]=[CH:24][C:15]3[N:16]([CH:21]([CH3:22])[CH3:23])[C:17](=[O:20])[N:18]([CH2:19][C:27]#[CH:32])[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CC(C)n1c(=O)[nH]c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Reactant: CC(C)n1c(=O)n(C)c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Agent: C#CCBr
Product: C#CCn1c(=O)n(C(C)C)c2ccc(-c3ncc(C(F)(F)F)cc3Cl)cc21
Yield: 47 %

Procedure:
In a similar manner to the preparation of 5-(3-chloro-5-trifluoromethylpyridin-2yl)-3-methyl-1-(1-methylethyl)benzimidazol-2-one described above, 2.5 g of 5-(3-chloro-5-trifluoromethylpyridin-2yl)-1-(1-methylethyl)benzimidazol-2-one and 0.9 g of propargyl bromide gave, after chromatography on silica gel, 1.3 g (47%) of colorless crystals. Yield: 47%; m.p.: 109-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1>ClC1C=CC=CC=1>[ClH:1].[N:13]1([C:2]2[CH:11]=[C:10]([CH3:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: Cc1cc(Cl)nc2ccccc12
Reactant: c1nc[nH]n1
Solvent: Clc1ccccc1
Product: Cc1cc(-n2cncn2)nc2ccccc12
Product: Cl
Temperature: 100 °C
Reaction time: 7 h
Yield: 69.6 %

Procedure:
A mixture of 1.78 g of 2-chloro-4-methyl-quinoline, 0.76 g of 1,2,4-triazole and 10 ml of chloro benzene is stirred at 100° C. for 7 hours. The reaction mixture is cooled, the precipitated product is filtered, dissolved in 5 ml of ethanol and precipitated by adding 10 ml of ethyl ether. The precipitated product is filtered. Thus 1.72 g of the desired compound are obtained, yield 70%. Mp.: 193°-194° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]2=[O:20]>>[CH2:1]([C:13]1([OH:20])[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([Cl:9])[CH:11]=2)[NH:15][C:14]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: O=C1Nc2ccc(Cl)cc2C1(O)Cc1ccccc1
Yield: 37.3 %

Procedure:
With 5.00 g of benzyl bromide and 1.50 g of 5-chloroisatin as starting material, 844 mg of the title compound (white solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([C:6](Cl)=[O:7])[C:3](Cl)=[O:4].[OH:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1.C(OCC)(=[O:27])C.O>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][C:2]([C:6]([OH:27])=[O:7])([CH3:9])[C:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:23][CH:24]=1)=[O:4]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CCOC(C)=O
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C(=O)O)C(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2 g (12 mmol) of dimethylmalonyl chloride in 19 ml of methylene chloride, a solution of 2 g (10 mmol) of 4-hydroxybenzophenone in 10 ml of pyridine was added over 15 min at -5° C. The mixture was stirred at 0° C. for 0.5 h, allowed to warm to 25° C. over 1 h, then stripped of the solvent, and finally stirred with 1:1 ethyl acetate-water for 1.5 h at 25° C. The organic phase was washed with cold 2% hydrochloric acid, then with water, and finally extracted with 5% sodium bicarbonate solution. The aqueous extract was acidified to pH 3 and filtered to collect crude product, which was purified by recrystallization from EtOH-water to yield the title compound. 0.325 g (10%); M.P.~147°-150° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH2:8][CH2:9][C:2]1=2.S(=O)(=O)(O)O.[NH2:15][C:16]([NH2:18])=[O:17]>>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:15][C:16]([NH2:18])=[O:17])[CH2:7][CH2:8][CH2:9][C:2]1=2
Reactant: NC(N)=O
Reactant: C1=Cc2ccsc2CC1
Agent: O=S(=O)(O)O
Product: NC(=O)NC1CCCc2sccc21

Procedure:
A sample of 6,7-dihydrobenzo[b]thiophene is stirred in the cold in 96% sulfuric acid containing 4-6 mole equivalents of urea. After 1 hour the mixture is poured on ice and the organic phase is removed. Evaporation of the organic phase to dryness in vacuo affords 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:37]2[C:38]([C:43]3[CH:48]=CC=CC=3F)=[N:39][O:40][C:41]=2C)=NC=1.NC1CCOCC1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:39][CH:38]2[CH2:43][CH2:48][O:40][CH2:41][CH2:37]2)=[O:25])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(C)c3)noc2C)nc1
Agent: NC1CCOCC1
Product: Cc1cccc(-c2noc(C)c2COc2ccc(C(=O)NC3CCOCC3)cn2)c1
Yield: 79 %

Procedure:
As described for example 84f, 6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (200 mg, 0.6 mmol) was converted, instead of [6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (190 mg, 79%) which was obtained as a white solid. MS: m/e=408.4 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]3[C:26]([CH3:27])=[CH:25][N:24]([S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:30])=[O:29])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:14][CH2:13]1)=[O:11])(C)(C)C.Cl.O>O1CCOCC1.C(OCC)C>[NH2:7][CH2:8][CH:9]([C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)[C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[C:19]3[C:26]([CH3:27])=[CH:25][N:24]([S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:30])=[O:29])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:16][CH2:17]1)=[O:11]
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCN(C(=O)C(CNC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCN(C(=O)C(CN)c4ccc(Cl)cc4)CC3)c12
Reaction time: 4 h
Yield: 77.6 %

Procedure:
The [3-[4-(7-benzenesulfonyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-chlorophenyl)-3-oxo-propyl]-carbamic acid tert-butyl ester (295 mg, 0.464 mmol) was dissolved in 2.3 mL of 1,4-dioxane and treated with 4M HCl in 1,4-dioxane (2.3 mL, 9.29 mmol). The mixture was allowed to stir for 4 hours to completion affording a yellow precipitate. The suspension was diluted with diethyl ether and poured into water. More diethyl ether was added, and the layers were shaken. The ether wash was discarded, and the aqueous was treated with saturated NaHCO3 solution until basic to pH paper (about 10) to afford a white precipitate. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the near-pure 3-amino-1-[4-(7-benzenesulfonyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-chlorophenyl)-propan-1-one as a colorless oil (194 mg, 77%). 1H NMR (free-base, CDCl3, 400 MHz) δ 8.44 (s, 1H), 8.16 (d, J=8.4 Hz, 2H), 7.59 (t, J=7.2 Hz, 1H), 7.49 (appt, J=7.6 Hz, 2H), 7.31 (m, 3H), 7.19 (d, J=8.0 Hz, 2H), 3.92 (m, 1H), 3.85 (dd, J=8.4, 5.2 Hz, 1H), 3.61 (m, 1H), 3.56-3.50 (m, 4H), 3.43 (m, 2H), 3.32 (m, 2H), 2.90 (m, 2H), 2.29 (s, 3H). LCMS (APCI+) m/z 539 [M+H]+; Rt=2.40 min.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].[CH2:16]=[C:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18](O)=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH:14][C:18](=[O:19])[C:17](=[CH2:16])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:10]
Reactant: CCOC(=O)CN
Reactant: C=C(Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(Cc1ccccc1)C(=O)NCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (3.10 mL, 0.022 mol, 1.2 eq) was added to a suspension of glycine ethyl ester hydrochloride (2.84 g, 0.020 mol, 1.1 eq) in anhydrous dichloromethane (100 mL) (see FIG. 6). The mixture was stirred for 15 min at room temperature and then cooled to 0° C. (ice bath). Compound 17 (3 g, 0.018 mol, 1 eq) and dicyclohexylcarbodiimide (4.19 g, 0.020 mol, 1.1 eq) were added successively to the reaction mixture which was stirred at room temperature for 17 h. The precipitate (dicyclohexylurea and triethylamine hydrochloride) was collected by filtration. The filtrate was washed successively with a saturated aqueous solution of sodium bicarbonate (100 mL), 1N aqueous solution of HCl (100 mL), brine (100 mL) and was then dried over sodium sulfate. Evaporation of the solvent afforded an oil which was purified by column chromatography (eluent:hexane/EtOAc=8:2). The desired product 18 was obtained as a solid (3.79 g, 83%). Rf=0.14 (hexane/EtOAc=7:3). m.p. 51° C. 1H NMR δ (CDCl3) 1.25 (t, 3H), 3.65 (s, 2H), 4.05 (d, 2H), 4.20 (q, 2H), 5.30 (s, 1H), 5.85 (s, 1H), 6.30 (s, 1H), 7.15–7.35 (m, 5H). [M+H]+ 248.0, tR=3.03 min; purity: 99.5%.