Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14]([SH:15])=[N:13][N:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.[CH:16]([NH:18][NH:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)=[O:17].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[SH:15][C:14]1[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[NH:24][C:23]3[CH:22]=[CH:21][C:20]([NH:19][NH:18][CH:16]=[O:17])=[CH:26][CH:25]=3)[CH:5]=2)[N:11]=[N:12][N:13]=1
Reactant: Nc1ccc(NNC=O)cc1
Reactant: O=C(O)c1cccc(-n2nnnc2S)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=CNNc1ccc(NC(=O)c2cccc(-n3nnnc3S)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
In 50 ml of dimethylformamide were dissolved 11.1 g of 1-(3-carboxyphenyl)-5-mercaptotetrazole and 7.6 g of 4-(2-formylhydrazino)aniline, and a solution of 10.3 g of dicyclohexylcarbodiimide in 10 ml of dimethylformamide was added dropwise to the solution at 0° C. in a nitrogeneous atmosphere over about 30 minutes. After the addition, the mixture was stirred at room temperature for 3 hours. The precipitated dicyclohexylurea was separated by filtration, and the filtrate was added to 500 ml of ice-water while stirring. The thus precipitated crystals were filtered, washed with water and dispersed in 100 ml of hot methanol. The dispersion was allowed to cool to room temperature and filtered. The filtrate was washed with methanol to obtain 4.5 g of the desired compound. Melting point: 202° C. (with decomposition).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:28](OC)=[O:29])([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:10]=2[CH:9]=1.O>O1CCCC1>[Cl:7][C:8]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH2:28][OH:29])([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:10]=2[CH:9]=1
Reactant: COC(=O)C1(CCN(C)C)c2ccccc2N(C)c2ccc(Cl)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCC1(CO)c2ccccc2N(C)c2ccc(Cl)cc21
Yield: 89.1 %

Procedure:
14 cc of tetrahydrofuran were cooled to 0°C and 0.9 gm of lithium aluminum hydride and then a solution of 1.4 gm of 2-chloro-9-methoxycarbonyl-9-(β-dimethylaminoethyl)-10-methyl-acridane in 14 cc of tetrahydrofuran were added thereto while maintaining the temperature below +10°C. The reaction mixture was then heated at reflux for 21/2 hours and cooled to 0°, +5°C and 10 cc of tetrahydrofuran containing 20% water and then 50 cc of water were added thereto. The reaction mixture was extracted with methylene chloride and filtered. The organic phases were washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness to obtain 1.15 gm of 2-chloro-9-hydroxymethyl-9-(β-dimethylaminoethyl)-10-methyl-acridane which was used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:13]1([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:26]1([CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:20]2[CH2:21][CH2:22][N:23]([CH2:4][CH:5]([OH:12])[CH2:6][O:12][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]4[C:6]=3[CH:7]=[CH:8][CH:9]=[N:10]4)[CH2:24][CH2:25]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Oc1ccc(Cl)c2ncccc12
Product: OC(COc1ccc(Cl)c2ncccc12)CN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Following the same procedure as in Example 23-(c), reaction and treatment were carried out using 0.64 g of 8-chloro-5-hydroxyquinoline and 1.48 g of 4-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine synthesized in Example 23-(b), in order to obtain 0.68 g of 5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-8-chloroquinoline.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5](Cl)[C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:7]=2[N:8]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>CC(O)C.CO>[NH2:2][C:3]1[N:4]=[C:5]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:18]([Br:17])[CH:19]=2)[C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:7]=2[N:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: Nc1nc(Cl)c2c(n1)[nH]c1ccccc12
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: Nc1nc(Nc2cccc(Br)c2)c2c(n1)[nH]c1ccccc12
Reaction time: 18 h
Yield: 16 %

Procedure:
A mixture of 2-amino-4-chloroindolo[2,3-d]pyrimidine hydrochloride (123 mg, 0.6 mmol) and 3-bromoaniline (0.3 mL, 2.8 mmol) in 2-propanol (6 mL) is heated at reflux for 4 hr, filtered through a celite pad, and concentrated in vacuo. The residue is partitioned between ethyl acetate (25 mL) and water (25 mL). The aqueous phase is extracted with further ethyl acetate (2×20 mL), followed by washing the combined extracts with 1% aqueous sodium hydroxide (25 mL), water (2×40 mL), saturated brine (40 mL), and drying (Na2SO4). The solution is evaporated to dryness under reduced pressure to afford 105 mg crude product as a tan powder. The solid is dissolved in a minimum amount of methanol, filtered, and further purified by preparative plate chromatography (SiO2 ; 1:1, EtOAc: CH2Cl2 ; Rf =0.40 ). After extraction of the product from the silica gel with ethyl acetate, the volume of the warm solution is reduced to minimum, and it is filtered through celite, and the solvent is removed under reduced pressure. The oily solid thus obtained is dissolved in a minimum amount of 2-propanol and allowed to crystallize at 3 C. over an 18 h period. The crystals are collected by suction filtration, washed with a small amount of cold 2-propanol, and dried in vacuo to give 2-amino-4-(3-bromoanilino) indolo[2,3-d]pyrimidine (34 mg, 17%). 1 HNMR, (DMSO): δbrs), 8.57 (1H, s), 8.11 (1H, d, J =8.0 Hz), 8.01 (1H, s), 7.94 (1H, d, J=8.2 Hz), 7.34-7.12 (5H, m), 6.41 (2H, brs).
Reaction SMILES: Cl.CN.[CH2:4]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[CH3:22][N:23](C)CCCN=C=NCC>N1C=CC=CC=1>[CH2:4]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:23][CH3:22])=[O:17])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CN
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
1.77 g of methylamine hydrochloride was added to a pyridine (60 ml) solution of 3 g of 4-benzyloxybenzoic acid, and 5.04 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added to it, and stirred at room temperature. After the reaction, the solvent was evaporated away under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was crystallized from chloroform/hexane and taken out through filtration to obtain 2.272 g of the entitled compound.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([OH:3])=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(O)(=O)C>[CH2:17]([N:24]1[C:1](=[O:3])[CH2:4][C:5]2[C:6](=[CH:10][CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)[C:7]1=[O:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2cc([N+](=O)[O-])ccc2C(=O)N1Cc1ccccc1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of the diacid (9) (55 g, 0.244 mole) in acetic acid (550 mL) was added benzylamine (28.91 g, 0.27 mole). The reaction was heated to 115° C. for 18 hrs., cooled to 25° C., water was added (450 mL), the contents stirred for 2 hrs., and the product filtered off as a white solid. The product was washed with water (400 mL) and vacuum dried to give 59.51 g (82%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:20]=3[N:19]=[CH:18]2)=[CH:13][CH:12]=1.[C:29](N1C=CN=C1)([N:31]1C=CN=C1)=O.Cl.CN.CCN(C(C)C)C(C)C>C1COCC1>[CH3:29][NH:31][C:26]([C:24]1[CH:23]=[CH:22][C:21]2[N:17]([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:16][CH:15]=3)[CH:18]=[N:19][C:20]=2[CH:25]=1)=[O:27]
Reactant: O=C(O)c1ccc2c(c1)ncn2-c1ccc(OCCOc2ccccn2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)ncn2-c1ccc(OCCOc2ccccn2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1-{4-[2-(Pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxylic acid (100 mg, 0.266 mmol) and 1,1′-carbonyldiimidazole (86 mg, 0.53 mmol) were dissolved in dry THF (2 mL) under a N2 atmosphere. The reaction mixture was heated at 60° C. for 1 h and then cooled to rt. Methylamine hydrochloride (27 mg, 0.40 mmol) and N,N′-diisopropylethylamine (52 mg, 0.40 mmol, 70 μL) were added and the reaction was allowed to stir at rt. After 18 h, the reaction mixture was concentrated in vacuo, diluted with CH2Cl2 (2 mL), and washed with distilled water (1 mL). The aqueous phase was back extracted with CH2Cl2 (2 mL×5) and the combined organic extracts were concentrated in vacuo. The resulting yellow solid was purified using the Waters mass-directed HPLC purification system to give N-methyl-1-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxamide as a white powder. 1H NMR (d6-DMSO, 400 MHz): δ 8.57 (s, 1H), 8.49 (brq, J=4.4 Hz, 1H), 8.28 (d, J=1.2 Hz, 1H), 8.19 (ddd, J=5.2, 2.0, 0.8 Hz, 1H), 7.85 (dd, J=8.6, 1.4 Hz, 1H), 7.74 (ddd, J=8.8, 6.8, 2.0 Hz, 1H), 7.61 (ddd, J=5.2, 3.2, 3.2 Hz, 2H), 7.55 (d, J=9.2 Hz, 1H), 7.23 (ddd, J=5.8, 3.6, 3.6 Hz, 2H), 7.01 (ddd, J=7.2, 5.2, 1.2 Hz, 1H), 6.88 (ddd, J=8.4, 0.8, 0.8 Hz, 1H), 4.63 (m, 2H), 4.43 (m, 2H), 2.82 (d, J=4.8 Hz, 3H). MS(ES+): m/z 389 [MH+].
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[N:9][S:10][CH:11]=1)(=O)=O.[F:19][C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH:23]=[C:24]([F:27])[C:25]=1O>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[C:7]([CH2:6][O:5][C:25]3[C:24]([F:27])=[CH:23][C:22]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:21][C:20]=3[F:19])=[CH:11][S:10][N:9]=2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OCc1csnc1-c1ccc(Br)cc1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: O=C(O)CCc1cc(F)c(OCc2csnc2-c2ccc(Br)cc2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(4-bromophenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.71 (d, J=6.8 Hz, 2H), 6.76 (d, J=7.2 Hz, 2H), 5.15 (s, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:23]=1[C:24](O)=O>>[F:18][C:17]([F:19])([F:20])[C:4]1[C:3]([C:1]#[N:2])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:12][C:13]1[N:16]=[C:24]([C:23]2[C:22]([F:21])=[CH:30][C:29]([F:31])=[CH:28][C:27]=2[F:32])[O:15][N:14]=1
Reactant: O=C(O)c1c(F)cc(F)cc1F
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3c(F)cc(F)cc3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 2,4,6-trifluorobenzoic acid: MS (ES) m/z 423 (M+1).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[N:9]1([C:14]([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1>O1CCOCC1>[O:6]=[C:5]([N:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:14](=[O:15])[N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:22][CH2:21]1)[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: O=C1CCCC(=O)O1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Solvent: C1COCCO1
Product: O=C(O)CCCC(=O)N1CCN(CC(=O)N2CCCC2)CC1
Reaction time: 4 h
Yield: 81.3 %

Procedure:
1.52 g of glutaric anhydride and then 2.62 g of pyrrolidinocarbonylmethylpiperazine are added to 10 cm3 of dry didoxane. After stirring for 4 hours, the precipitate formed is diluted with 10 cm3 of dioxane and then stirred for 1 hour. The insoluble matter is filtered on No. 4 sintered glass, rinsed several times with diethyl ether and then dried (90 Pa) at 20° C. to give 3.36 g of 5-oxo-5-[4-(2-oxo-2-pyrrolidin-1-yl ethyl)piperazin-1-yl]pentanoic acid in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][NH:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](Cl)=[O:32]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][N:13]([C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)=[O:32])[C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3
Reactant: O=C(Cl)c1ccccn1
Reactant: Clc1cnc2nc1Nc1cccc(c1)NCc1cccc(c1)N2
Agent: Cl
Product: O=C(c1ccccn1)N1Cc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc1c2
Yield: 29 %

Procedure:
The desired compound was prepared as a white powder according to the procedure of Example C22, step F, using 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene and pyridine-2-carbonyl chloride hydrochloride as the starting materials in 29% yield. LCMS for C23H18ClN6O (M+H)+: m/z=429.0.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].[OH-].[Na+]>C(Cl)Cl>[CH2:1]([NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=1[O:15][CH3:14])[CH:2]=[CH2:3]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCNCc1ccc(OC)cc1OC
Yield: 40 %

Procedure:
0.32 ml of allylbromide (3.66 mM) and 0.7 ml of diisopropyl ethylamine (3.99 mM) were added to the reaction solution containing 500 mg of 2,4-dimethoxybenzylamine (3.33 mM) dissolved in methylene chloride with stirring and the solution was left alone at room temperature. After the reaction mixture was neutralized with 10% NaOH solution, the mixture was extracted with chloroform, washed with saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 276 mg of allyl-(2,4-dimethoxybenzyl)amine (1b) (yield: 40%).
Reaction SMILES: [CH:1]1([C@H:4]([NH:7][C:8]2[C:13]([NH2:14])=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[CH3:23])[N:11]=[CH:10][N:9]=2)[CH2:5][CH3:6])[CH2:3][CH2:2]1.[C:24](OCC)(=[O:28])[C:25]([CH3:27])=O>C(O)C>[CH:1]1([C@H:4]([N:7]2[C:8]3[N:9]=[CH:10][N:11]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[C:13]=3[N:14]=[C:25]([CH3:27])[C:24]2=[O:28])[CH2:5][CH3:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)=O
Reactant: CC[C@@H](Nc1ncnc(-c2ccc(OC)cc2C)c1N)C1CC1
Solvent: CCO
Product: CC[C@H](C1CC1)n1c(=O)c(C)nc2c(-c3ccc(OC)cc3C)ncnc21
Reaction time: 18 h

Procedure:
(R)-N4-(1-Cyclopropyl-propyl)-6-(4-methoxy-2-methyl-phenyl)-pyrimidine-4,5-diamine (0.21 g, 0.67 mmol) was diluted in ethanol (7 ml) and ethyl pyruvate was added (0.75 ml, 6.7 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 2.0 mg of (R)-8-(1-Cyclopropyl-propyl)-4-(4-methoxy-2-methyl-phenyl)-6-methyl-8H-pteridin-7-one (Example 612a). 1H NMR (300 MHz, CDCl3) δ ppm 8.86 (s, 1 H), 7.33 (d, J=9.15 Hz, 1 H), 6.80 (d, J=2.20 Hz, 1 H), 6.78 (d, J=2.20 Hz, 1 H), 4.56 (m, 1 H), 3.80 (s, 3 H), 2.45 (s, 3 H), 2.30 (m, 1 H), 2.20 (s, 3 H), 2.12 (m, 1 H), 0.81 (t, J=7.51 Hz, 3 H), 0.76 (m, 1 H), 0.68 (m, 1 H), 0.42 (m, 1 H), 0.29 (m, 1 H), 0.12 (m, 1 H). MS (EI) 377.3 [(M+H)+, 100].
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][C:29]=1B(O)O>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:33]2[CH:32]=[C:31]([O:34][CH:35]([CH3:36])[CH3:37])[CH:30]=[CH:29][C:28]=2[F:27])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)Oc1ccc(F)c(B(O)O)c1
Product: CC(C)Oc1ccc(F)c(-c2ccc(C(=O)C(NC(=O)OC(C)(C)C)c3ccc(Cl)c(Cl)c3)cc2)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-iodo-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 2-fluoro-5-isopropoxyphenylboronic acid in analogy to Example 2b): MS (ISP): 532.1 and 534.1 (M+H)+, 432.2 and 434.1 ((M-Boc)+H)+.
Reaction SMILES: [NH:1]([C:36]([O:38][CH2:39][CH:40]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[C@H:2]([C:18]([NH:20][C@H:21]([C:29]([O:31]C(C)(C)C)=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>FC(F)(F)C(O)=O>[NH:1]([C:36]([O:38][CH2:39][CH:40]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[C@H:2]([C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 1 h

Procedure:
2.95 g of Fmoc-Lys(Z)-Phe-OtBu are dissolved in 30 ml of 90% strength aqueous trifluoroacetic acid. The solution is left to stand at room temperature for one hour, and is concentrated in vacuo. The residue is triturated with diethyl ether and filtered off with suction.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[S:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](=O)([O-])[O-].[Na+].[Na+].IC>C(O)C>[C:14]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:11][CH:10]([S:12][CH3:20])[NH:9][C:8]2=[O:13])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=S)NC1(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CSC1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Yield: 60 %

Procedure:
7.0 g of 5,5-diphenyl-2-thiohydantoin is dissolved in 50 ml of ethanol and 10 ml of 3N sodium carbonate added followed by 3 ml of iodomethane. The mixture is refluxed for 18 hours, then cooled and the solvent evaporated. The residual solid is recrystallized from ethanol to give 4.6 g (60%) of the title compound.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([O:19]C)=[O:18])[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.CO.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([OH:19])=[O:18])[CH:10]=[CH:9]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc2ccn(Cc3ccc(-c4ccccc4)cc3)c12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc2ccn(Cc3ccc(-c4ccccc4)cc3)c12
Temperature: 60 °C
Reaction time: 16 h
Yield: 41.3 %

Procedure:
To methyl 1-(biphenyl-4-ylmethyl)-1H-indole-7-carboxylate (2.5 g) were added methanol (20 mL), THF (20 mL), and a 1 M aqueous sodium hydroxide solution (10 mL), followed by stirring at 60° C. for 16 hours. To the reaction mixture was added a 10% aqueous citric acid solution (20 mL), followed by extraction with ethyl acetate, and the organic layer was washed with brine. After dehydration over anhydrous sodium sulfate, filtering and concentrating under reduced pressure, the obtained residue was added with diisopropylether, solidified, and collected by filtration. This solid was purified by silica gel column chromatography (chloroform/methanol=99/1-97/3) to obtain 1-(biphenyl-4-ylmethyl)-1H-indole-7-carboxylic acid (0.99 g).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:34]([O:38][C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[C:49]1[CH:54]=[CH:53][C:52]([CH2:55]O)=[CH:51][CH:50]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35].S([O-])(=O)(=O)C>CN(C)C=O>[CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:55][C:52]2[CH:51]=[CH:50][C:49]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[CH2:42][NH:41][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])=[CH:54][CH:53]=2)[C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
To a solution of 514 mg (1.22 mmol) of 3-[2(R)-benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide in 5 mL of dry dimethylformamide under nitrogen was added 53 mg (1.34 mmol) of 60% sodium hydride/oil dispersion. After stirring for 15 minutes, a solution of 499 mg (1.28 mmol) of 2'-[(t-Butoxycarbonylamino)methyl]-1,1-biphenyl-4-methanol, methanesulfonate ester (Example 11, Step I) in 2 mL of dry dimethylformamide was added by cannula. The flask which originally contained the mesylate was rinsed with 1 mL of dimethylformamide which was added to the reaction mixture. After stirring at room temperature for 2 hours, the reaction mixture was diluted with 200 mL of ethyl acetate, washed with water (2×40 mL) and 40 mL of saturated aqueous sodium chloride. The organic layer was removed, dried over sodium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash chromatography on silica gel eluting with chloroform/10% concentrated ammonium hydroxide in methanol (94:6) to afford 872 mg (100%) of the product as a white foam. FAB-MS: calculated for C44H54N4O5 718; found 719 (M+H,40%). 1H NMR (200 MHz, CD3OD): 1.11 (s,3H), 1.12 (s,3H), 1.18 (d,6 Hz,3H), 1.39 (s,9H), 1.80-2.05 (m,1H), 2.15-2.38 (m,3H), 2.45-2.70 (m,4H), 3.70 (m,1H), 4.05 (s,2H), 4.42 (dd;5.11 Hz,1H), 4.47 (d,11 Hz, 1H, 4.60 (d,11 Hz, 1H), 4.93 (d,15 Hz, 1H), 4.47 (d,11 Hz, 1H, 4.60 (d,11 Hz, 1H), 4.93 (d,15 Hz, 1H), 7.05-7.40 (m,17H).