Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:60]1([CH2:66][CH2:67][NH2:68])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][CH2:67][CH2:66][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NCCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CC[C@H](C(=O)NCCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 2-phenylethanamine (58.0 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to give the yellow title compound (198 mg). LC-MS (ES) m/z=459 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:26][C:24]1[N:25]=[C:21]([NH:20][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([C:8]3[N:6]4[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)=[CH:19][CH:18]=2)[S:22][CH:23]=1
Reactant: O=C(O)c1ccc(-c2cnc3ccc(Br)cn23)cc1
Reactant: Cc1csc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1csc(NC(=O)c2ccc(-c3cnc4ccc(Br)cn34)cc2)n1
Yield: 48.3 %

Procedure:
159 mg of 4-(6-bromoimidazo[1,2-a]pyridin-3-yl)benzoic acid (compound in Production Example 54), 58 mg of 2-amino-4-methyl-1,3-thiazole, 243 mg benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate and 83 μL triethylamine were reacted overnight in 4 mL dichloromethane. The reaction solution was purified by an NH silica gel column, to give 100 mg of the title compound (pale yellow crystals; recrystallization solvent, ethyl acetate-methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1cc(Cl)ccc1C(=O)O
Reaction time: 20 h
Yield: 54 %

Procedure:
A solution of 2-amino-4-chlorobenzoic acid (10 g, 0.06 mol) in anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) was cooled to 0° C. in a 300 mL 3-necked flask fitted with a magnetic stirring bar and a constant additional funnel. Bromoacetyl bromide was added dropwise over a 2 h period while maintaining the internal temperature between 0°-2° C. After the addition was completed, the ice-water bath was removed, and then the reaction mixture was stirred 20 h. The reaction mixture was cooled in an ice-bath, water (300 mL) was slowly added, and then the white crystalline product which formed was filtered. Recrystallization from EtOAc/hexane gave 9.2 g (54%) of the title compound as a white solid: mp 156.4°-158° C.; 1H NMR (DMSO-d6) δ13.99 (s, 1H, NH), 11.72 (s, 1H, COOH), 8.54 (d, 1H, J=2.0), 8.00 (d, 1H, J=8.8), 7.27 (dd, 1H, J=2.4, J=6.4), 4.28 (s, 2H); 13C NMR (DMSO-d6) δ168.60, 165.54, 141.12, 138.51, 133.88, 123.36, 119.23, 115.58, 30.54; MS (EI, m/z) 293 (M+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].Cl[C:7]1[C:20]2[C:19](=O)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[NH:12][C:11]=2[C:10]([N+]([O-])=O)=[CH:9][CH:8]=1>CO.C1COCC1>[CH3:23][O:22][C:16]1[C:17]2[N:4]([CH2:3][CH2:2][OH:1])[N:5]=[C:19]3[C:18]=2[C:13]([NH:12][C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:20]=23)=[CH:14][CH:15]=1
Reactant: COc1ccc2[nH]c3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Reactant: NNCCO
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c3c(nn(CCO)c13)-c1ccccc1N2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.6 g of 2-hydroxyethyl hydrazine in 5 ml of methanol and 20 ml of THF was added over 1.5 hours to a mixture of 6.09 g of 1-chloro-7-methoxy-4-nitro-9(10H)-acridinone in 75 ml of methanol and 55 ml of THF, and the resulting suspension was stirred 20 hours at room temperature. The precipitate was coliected and recrystallized from DMSC-methanol, providing 9=methoxypyrazolo[3,4,5-kl]acridine-2(6H)ethanol, mp 275°-276 C.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])[CH:9]=[CH:10][CH:11]=1)(=[O:5])[CH3:4]>O1CCOCC1.CCOCC>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])[CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)Nc1cccc(C(C)=O)c1
Reactant: BrBr
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)Nc1cccc(C(=O)CBr)c1
Reaction time: 2 h
Yield: 97.8 %

Procedure:
24.1 gm of bromine were added slowly over a period of 30 minutes to a stirred suspension of 28.5 gm of ethyl N-(3-acetyl-phenyl)-carbamate in 13.3 gm of dry dioxane and 245 ml of dry ether. After stirring the reaction solution for 2 hours more, it was cooled, and the product which crystallized out was collected and washed with ether, yielding 38.5 gm of the title compound, m.p. 108°-110° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][N:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J27) (328 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K23) (287 mg, 1.0 mmol) according to the general procedure M. Obtained as an orange oil (250 mg, 46%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([Cl:13])[N:6]=[CH:5]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:7]1[N:6]=[CH:5][C:4]2[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([C:18]3[CH:17]=[C:16]([O:15][CH3:14])[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=3)[CH:3]=2)[N:8]=1
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: Clc1ncc2cc(Br)c(Cl)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)cc(-c2cc3cnc(Cl)nc3cc2Cl)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
A mixture of 6-bromo-2,7-dichloroquinazoline (3 g, 10.8 mmol), 3,5-dimethoxyphenylboronic acid (2.2 g, 11.9 mmol), cesium carbonate (1.06 g, 32.4 mmol) and Pd(PPh3)2Cl2 (702 mg, 1.08 mmol) in THF (50 mL) and water (10 mL) was degassed with nitrogen three times, and the reaction mixture was stirred at 85° C. for 3 hours. The reaction mixture was cooled to room temperature and directly concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=10:1˜4:1) to give the title compound (2.0 g, yield: 55%) as a yellowish solid. MS (ES+) requires: 334, 336, C16H12Cl2N2O2, found: 335, 337 [M+H]+.
Reaction SMILES: O=C1C2C=C(C=O)C=CC=2C(=O)C2C1=CC=CC=2.[C:19]1([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH2:32])C=CC=CC=1.C1(C)C=CC=CC=1>C(O)(=O)C>[N:32]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][CH:19]=1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: O=Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: c1ccc2[nH]cnc2c1
Yield: 139.9 %

Procedure:
9,10-Dioxo-9,10-dihydro-anthracene-2-carbaldehyde (1.63 g, 6.9 mmol) and N-phenyl-1,2-phenylenediamine (1.27 g, 6.90 mmol) were introduced into a mixture of 80 mL of toluene and 10 mL of acetic acid, and the mixture was refluxed for 12 hours. Solvent was removed and ethanol was poured therein to crystallize it, and then the precipitate was filtered to obtain a benzoimidazole compound ([2-(1-phenyl-1H-benzoimidazole-2-yl)-anthraquinone], 1.14 g, 41%).
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]([CH2:12]O)[CH2:10][N:9]([CH:14]([CH3:16])[CH3:15])[C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:26])=O.N1C=CC=CC=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:26][CH2:12][CH:11]1[CH2:10][N:9]([CH:14]([CH3:16])[CH3:15])[C:8](=[O:17])[C:7]1([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)N1CC(CO)C(c2ccccc2)(c2ccccc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CC(CCl)C(c2ccccc2)(c2ccccc2)C1=O

Procedure:
A solution of 43 g. (0.14 mole) of 3,3-diphenyl-4-hydroxymethyl-1-isopropyl-2-pyrrolidinone in 250 ml. of chloroform was treated with 33 g. (0.28 mole) of thionyl chloride over a one minute period followed by the dropwise addition of 22 g. (0.23 mole) of pyridine over a 30 minute period. The mixture was refluxed 18 hours and then poured onto ice. The cold mixture was made basic by the addition of sodium hydroxide. The chloroform layer was separated, dried over sodium sulfate and concentrated. The residue was crystallized using charcoal from a 25% ethyl acetate -- 75% isopropyl ether mixture. The crystalline solid was recrystallized from a 75% ethanol -- 25% water mixture and then from isopropyl ether. The dried 4-chloromethyl-3,3-diphenyl-1-isopropyl-2-pyrrolidinone weighed 23 g. and melted at 114°-116° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[CH:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]=C)(=[O:7])=[O:6].O=O.[O:26]=[O+][O-].CSC>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:22])([CH3:23])[CH:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:12]=[O:26])(=[O:6])=[O:7]
Reactant: C=CC(OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: O=[O+][O-]
Agent: O=O
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(COS(=O)(=O)CCCCl)C(C=O)OCc1ccccc1
Yield: 76 %

Procedure:
Following the general procedure for the preparation of aldehydes from alkenes of Description 11, (3R/S)-2,2-dimethyl-3-(phenylmethoxy)pent-4-enyl (3-chloropropyl]sulfonate (12a) (10.0 g, 27.7 mmol) dissolved in 150 mL of dichloromethane (DCM) was treated with a mixture of oxygen and ozone (O2/O3). Upon completion of the reaction, 4.0 mL (3.4 g, 55 mmol) of dimethyl sulfide (DMS) was added. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 7.6 g (76% yield) of the title compound (12b) as a colorless oil. The analytical data was consistent with the proposed structure and the data obtained for the enantiopure compound (11b).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:6][N:5]=[C:4]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([CH3:16])[C:3]=12.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:36]=1[CH2:37]Br>O>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:36]=1[CH2:37][N:5]1[CH:6]=[C:7]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C:2](=[O:1])[C:3]2[C:15]([CH3:16])=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:13][C:4]1=2
Reactant: Cc1c(-c2ccccc2)sc2ncc(C(=O)C(C)C)c(O)c12
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)sc2c1c(=O)c(C(=O)C(C)C)cn2Cc1c(F)cccc1F
Temperature: 45 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
4-Hydroxy-5-isobutyryl-3-methyl-2-phenylthieno[2,3-b]pyridine (35 g), potassium carbonate (18.6 g) and N,N-dimethylformamide (280 ml) were mixed and 2,6-difluorobenzyl bromide (27.9 g) was added and the reaction mixture was stirred at 40 to 50° C. for 2 hours. The reaction mixture was treated dropwise with water (560 ml), and the mixture was stirred for 1 hour and then cooled on ice, and then stirred further for 1 hour. The crude crystal was recovered by a filtration, washed with water (about 1000 ml), dried in air, suspended in a 1:1 solvent mixture (250 ml) of ethyl acetate and diisopropylether, and then the mixture was stirred at room temperature for 1 hour, and then stirred with cooling on ice for 1 hour. The crystal obtained by a filtration was washed with the same solvent mixture (180 ml), dried in vacuo at 40° C. for 5 hours to obtain the title compound (46.53 g, 94.6%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[N:5][N:6]=1.[C:16](OCC)(=[O:21])[CH2:17][C:18]([CH3:20])=O>O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][S:7][C:4]2[S:3][C:2]3=[N:1][C:18]([CH3:20])=[CH:17][C:16](=[O:21])[N:6]3[N:5]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1nnc(SCc2ccc(Cl)cc2)s1
Solvent: O
Product: Cc1cc(=O)n2nc(SCc3ccc(Cl)cc3)sc2n1
Reaction time: 0.75 h
Yield: 84 %

Procedure:
Twenty point two (20.2) g of the thus obtained 2-amino-5-(4-chlorobenzylthio)-1,3,4-thiadiazole and 12.2 g of ethyl acetoacetate were mixed with 24 g of polyphosphoric acid and the mixture was stirred at 130°~150° C. for 45 minutes. After cooling, water was added to the mixture, the mixture was extracted with chloroform, and the organic layer was washed with a sodium hydrogen carbonate aqueous solution and water respectively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was recrystallized from ethanol and thus 21.3 g of 2-(4-chlorobenzylthio)-7-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[N:17]=[C:18]=[O:19].FC1C=CC=C(N=C=O)C=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18]([NH:17][C:11]2[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=2[F:9])=[O:19])=[N:3][CH:4]=1
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: Nc1ccc(Br)cn1
Agent: O=C=Nc1cccc(F)c1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Br)cn2)c1

Procedure:
The desired product was prepared by substituting 2-amino-5-bromopyridine and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 324.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][C:26](=[O:32])[NH:27]2>>[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[C:25](=[CH:20][C:3]1[NH:4][C:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=1[CH3:1])[C:26](=[O:32])[NH:27]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: O=C1Cc2c(Br)cccc2N1
Product: Cc1c(C=C2C(=O)Nc3cccc(Br)c32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 93.6 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-bromo-1,3-dihydro-indol-2-one (prepared according to US20030225127) as starting materials to give 2-(4-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (74 mg, 93.6%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[C:31](#N)[CH3:32]>C(O)C>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[C:26]([O:28][CH2:31][CH2:32][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1)(=[O:27])[CH3:25]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC#N
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)OCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), K2CO3 (3.5 g, 25 mmol) 2-bromoethyl acetate (4 g, 26.5 mmol) in acetonitrile (50 ml) was heated at reflux for 4 hours. After cooling to room temperature, the inorganic salts were filtered and washed with DCM (dichloromethane 50 ml). The organic solvent was removed on a rotary evaporator to give an oil. The oily product was purified on a flash chromatography column (60 g of SiO2; eluted with MeOH 2%-4% in DCM). The pure product thus obtained weighed 4.43 g. This oil was dissolved in ethanol and treated with a solution of fumaric acid (1.2 g) in ethanol. The sale crystallized out at room temperature to yield 3.44 g (57%) m.p.=154°-155° C. ANALYSIS: Calculated for C10H19FN2O3.C4H4O4: 56.86%C 5.49%H 6.63%N Found: 56.75%C 5.41%H 6.54%N
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]2[CH2:7][CH2:8][O:9][C:10]3[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:11]=3[C:12]=2[N:13]=1)=[N+:2]=[N-:3].[CH3:19][CH:20]([CH3:23])[C:21]#[CH:22]>>[Br:18][C:16]1[CH:15]=[CH:14][C:11]2[C:12]3[N:13]=[C:4]([N:1]4[C:21]([CH:20]([CH3:23])[CH3:19])=[CH:22][N:3]=[N:2]4)[S:5][C:6]=3[CH2:7][CH2:8][O:9][C:10]=2[CH:17]=1
Reactant: [N-]=[N+]=Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: C#CC(C)C
Product: CC(C)c1cnnn1-c1nc2c(s1)CCOc1cc(Br)ccc1-2

Procedure:
Following the procedure for 414, Step 3, 2-azido-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3-methyl-1-butyne to afford the title compound as a beige solid. LCMS (Method A): RT=4.88 min, [M+H]+=391 and 393. 1H NMR (CDCl3): 8.12 (1H, d, J=8.5 Hz), 7.59 (1H, s), 7.30-7.25 (2H, m), 4.41 (2H, t, J=5.0 Hz), 3.98-3.90 (1H, m), 3.36 (2H, t, J=5.0 Hz), 1.44 (3H, s), 1.42 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:20]COC)[C:18]=1I)[CH2:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[CH3:2].Br[C:25]1[CH:26]=[CH:27][C:28]([CH3:38])=[C:29]([NH:31]C(=O)C(F)(F)F)[CH:30]=1.BrC1C=CC(C)=C(C=1)N>>[NH2:31][C:29]1[CH:30]=[C:25]([C:18]2[C:17]([OH:20])=[CH:16][C:6]([CH2:7][C:8]3[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=3)=[CH:5][C:4]=2[O:3][CH2:1][CH3:2])[CH:26]=[CH:27][C:28]=1[CH3:38]
Reactant: Cc1ccc(Br)cc1NC(=O)C(F)(F)F
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCOC)c1I
Agent: Cc1ccc(Br)cc1N
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1ccc(C)c(N)c1
Yield: 30 %

Procedure:
Starting from 5-(3-ethoxy-4-iodo-5-methoxymethoxy-benzyl)-pyrimidine-2,4-diamine (2.11 g; 4,9 mmol) and N-(5-bromo-2-methyl-phenyl)-2,2,2-trifluoro-acetamide (prepared from 5-bromo-2-methyl-aniline analogously to example 41) (2.3 g; 8.17 mmol), 0.963 g (30%) 3′-amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-4′-methyl-biphenyl-2-ol is obtained as a beige powder after Suzuki coupling (in situ generation of R2—B(OH)2) and splitting off of the protective group under acid conditions.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14]C(NC3C=CC(OC4C=CN=C(NCCCCN(C)C)N=4)=CC=3C)=O)=[CH:10][C:9]=2[C:40]([F:43])([F:42])[F:41])[CH:5]=[CH:6][CH:7]=1.[Br:44]C1C=C(B(O)O)C=CC=1>CCCCCC.CCOC(C)=O>[Br:44][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[C:40]([F:43])([F:42])[F:41])[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(Oc2ccnc(NCCCCN(C)C)n2)ccc1NC(=O)Nc1ccc(-c2cccc(Cl)c2)c(C(F)(F)F)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2cccc(Br)c2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Ex. 3 (Step 3.1) for 1-(3′-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butylamino)-pyrimidin-4-yloxy]-2-methyl-phenyl}-urea but using 3-bromophenylboronic acid (Aldrich). The title compound: MS: 315.9 [M-1]−; HPLC DtRet=4.9; Rf=0.16 (Hexane/EtOAc, 4:1).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1.C1COCC1.[H-].[Na+].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>O>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][N:7]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:2](=[O:1])[CH:3]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:21]=1)=[O:9])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1Cc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccc(OCc3ccccc3)cc2)C1=O
Reaction time: 8 h

Procedure:
To a solution of t-boc-(4-benzyloxybenzyl) piperazinone 3a (2.66 g, 6.72 ×10-3 mole) and dry THF (20 ml) under argon at room temperature is added portionwise NaH (0.30 g, 7.4 ×10-3 mole, 59% oil dispersion). After stirring 1/2hour at room temperature a solution of methyl α-bromoacetate (0.62 ml, 7.4 ×10-3 mole) is added via syringe. After stirring overnight the reaction mixture is poured into water which is subsequently extracted with Et2O (3 times). The combined ethereal extracts are washed with saturated aqueous NaCl before being dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate affords a viscous oil which after column chromatography (silica gel, 10% EtOAc/CHCl3)gives a clear, colorless oil. After standing in the refrigerator this oil crystallizes. The resulting solid is triturated with hexane and collected by filtration affording 4a as colorless matted needles: 2.3 g (74%), m.p. 84°-87° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:31])[NH:14][C:15]1[CH:16]=[C:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=2)[C:18]([Cl:21])=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:38][CH2:37]1)(=[O:35])=[O:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:31])[NH:14][C:15]1[CH:16]=[C:17]([C:22]2[CH:23]=[CH:24][C:25]([C:28](=[O:29])[NH:49][C:46]3[CH:47]=[CH:48][C:43]([CH2:42][N:39]4[CH2:38][CH2:37][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:41][CH2:40]4)=[CH:44][CH:45]=3)=[CH:26][CH:27]=2)[C:18]([Cl:21])=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)O)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(S(C)(=O)=O)CC4)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (R)-2-(4′-Carboxy-6-chloro-biphenyl-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg), 4-(4-methanesulfonyl-piperazin-1-ylmethyl)-phenylamine (86 mg) and HBTU (121 mg) in dry DMF (4 ml) containing N-methylmorpholine (69 μl) was stirred at room temp for 18 h.