Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[Cl:21][C:22]1[CH:23]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1.N1C=CC=CC=1>O>[Cl:28][C:26]1[CH:25]=[C:24]([S:29]([NH:18][C:16]2[CH:17]=[C:12]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=4)[CH:13]=[CH:14][C:15]=2[O:19][CH3:20])(=[O:30])=[O:31])[CH:23]=[C:22]([Cl:21])[CH:27]=1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NS(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.274 g, 1.0 mmol) was mixed with 3,5-dichlorobenzenesulfonyl chloride (0.256 g, 1.0 mmol) and pyridine (3 mL) was added, and the reaction mixture was heated briefly to 50° C. and then allowed to stand overnight at room temperature. Water (7 mL) was added and the mixture allowed to stand 2 hours at room temperature. The mixture was partitioned between water (200 mL) and ethyl acetate (200 mL), and the organic layer was washed with 1N HCl (100 mL), water (100 mL), and brine (100 mL), dried (magnesium sulfate), filtered, and concentrated to a purple-tinted solid. The solid was triturated with hexanes/ethyl acetate, 1/1, v/v to give the product (0.355 g), mp 217-219° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[C:13]([CH2:21]O)=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O.CCCCCC>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[C:13]([CH2:21][Cl:25])=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)n1cc(CO)c2cc(Cl)ccc21
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)n1cc(CCl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-benzyloxycarbonyl-5-chloro-3-hydroxymethylindole (1.45 g) in dichloromethane (23 ml) was added thionylchloride (0.797 μl) at −78° C. After the mixture was stirred for 1.5 hours at room temperature, the reaction mixture was concentrated under the reduced pressure to give a residue. Hexane was added to the residue. 1-benzyloxycarbonyl-5-chloro-3-chloromethylindole (1.43 g) was obtained as a crystal.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].COCCCOCCCO.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CN(C)C1C=CC=CC=1>>[CH3:10][O:9][C:3]1[C:4]([CH3:8])=[N:5][CH:6]=[CH:7][C:2]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: COc1c(Cl)ccnc1C
Agent: COCCCOCCCO
Solvent: CN(C)c1ccccc1
Product: COc1c(N2CCNCC2)ccnc1C
Temperature: 140 °C
Reaction time: 72 h
Yield: 94.1 %

Procedure:
4-Chloro-3-methoxy-2-methyl-pyridine (0.47 g, 3 mmol) was mixed with dipropyleneglycolmonomethylether (3 ml), piperazine (1.1 g, 7.2 mmol) and N,N-dimethylaniline (0.36 g, 3 mmol) and stirred at 140° C. for 72 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (prepacked silica column, gradient ethyl acetate/methanol with the addition of 1% ammonia). The raw product was dissolved in 1M NaOH and extracted with a mixture of diethylether, dichloromethane and ethylacetate (1:1:1) several times. The combined organic phases were washed with water, dried over sodium sulfate, and the solvent was removed under reduced pressure to yield 585 mg of a yellow solid (2.8 g, 94%). MS (APCI): m/z=208.0 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: Clc1ncccn1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccc(Oc2ncccn2)c1
Yield: 70.9 %

Procedure:
EX-605A) A slurry of 3-hydroxybenzaldehyde (1.22 g, 10 mmol), 2-chloropyrimidine (1.14 g, 10 mmol) and K2CO3 (1.65 g, 12 mmol) in DMSO (20 mL) was heated to 100° C. for 1 h. The cooled mixture was poured into water and extracted with Et2O. The organic layer was washed with 2.5 N NaOH, 1 N HCl, saturated NaHCO3 and brine, dried (MgSO4) and evaporated to yield 1.42 g (71%) of the desired 3-(2-pyrimidinyl-oxy)benzaldehyde product as a white solid which was used without further purification. 1H NMR (C6D6) δ 7.12 (t, 1H), 7.54 (m, 1H), 7.66 (t, 1H), 7.78 (m, 1H), 7.83 (m, 1H), 8.64 (d, 2H), 10.05 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C>>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[O:7])=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: Nc1ccccc1
Agent: C
Product: Nc1ccc(C(=O)c2cccc(F)c2)cc1
Reaction time: 1 h

Procedure:
To stirred 90° C. polyphosphoric acid (150 g) was added 10.72 g (7.65 mmol) of 3-fluorobenzoic acid and 6.98 g (7.5 mmol) of aniline and the bath temperature raised to 180°-190° C. and held there for 1 hour. A solution was obtained at about 130° C. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 60 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 50 mL of 3N HCl added, the mixture poured into 750 mL of water and filtered through a pad of Celite. The filtrate was basified with 15% sodium hydroxide and the resulting solid extracted with methylene chloride. The dried (MgSO4) solution was filtered and the solvent removed to yield a brown solid. Recrystallization from ethanol-hexane (1:3) returned a greenish yellow solid that was chromatographed on silica gel (methylene chloride) to yield 4.83 g (30%) of yellow 4-amino-3'-fluorobenzophone, mp 98°-100° C. 1H NMR (300 MHz, CDCl3): 4.21 (s, 2H, NH2) 6.66-6.70 (m, 2H, aromatic) 7.23-7.26 (m, 1H, aromatic) 7.39-7.51 (m, 3H, aromatic) 7.69-7.72 (m, 2H, aromatic). MS (CI, CH4): 216 (M+1).
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[CH:19][C:18]([I:22])=[CH:17][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH2:14][CH2:15][OH:16])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C=O)C>[F:1][C:2]1[C:20]([F:21])=[CH:19][C:18]([I:22])=[CH:17][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH2:14][CH2:15][O:16][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(=CNCCO)C(=O)c1cc(I)cc(F)c1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=CNCCO[Si](C)(C)C(C)(C)C)C(=O)c1cc(I)cc(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
Ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-(2-hydroxyethylamino)acrylate (2.0 g, 4.7 mmol) obtained in Step 2 was dissolved in DMF (10 ml), imidazole (705 mg, 10.4 mmol) and tert-butyldimethylsilyl chloride (1.49 g, 9.9 mmol) were added, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4) to give the object product (2.3 g, yield 91%) as a white solid.
Reaction SMILES: C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.[CH3:17][C:18]1[CH:44]=[CH:43][C:21]([NH:22][C:23]2[CH:31]=[C:30]([C:32]([OH:34])=O)[C:29]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)=[CH:28][C:24]=2[C:25](O)=[O:26])=[CH:20][CH:19]=1.CO>O>[CH3:17][C:18]1[CH:44]=[CH:43][C:21]2[NH:22][C:23]3[C:24]([C:25](=[O:26])[C:20]=2[CH:19]=1)=[CH:28][C:29]1[NH:35][C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:37]=2[C:32](=[O:34])[C:30]=1[CH:31]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Solvent: O
Solvent: CO
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 123 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To 300 g of polyphosphoric acid (112% phosphoric acid) heated at 88° C. was added 6.8 g of anthraquinone followed by 68.2 g of 2,5-di(4-methylanilino)terephthalic acid added over a period of 35 minutes, the temperature being maintained below 120° C. by adjustment of the addition rate. The mixture was heated at 123° C. for two hours. After the melt was cooled to 93° C., it was slowly poured into 494 g of methanol, the temperature being maintained below 64° C. by external cooling and adjustment of melt addition rate. The slurry was heated at reflux for one hour, cooled to below 60° C., diluted with water, filtered, and washed until acid free. The resultant presscake was reslurried in water. After adjustment of the pH to greater than 7, 5.5 g of 50% sodium hydroxide was added and the resultant slurry was heated at 90° C. for one hour. The slurry was cooled, filtered, and washed with water until alkali free, then reslurried in water. After adjustment of the pH to 9.5, the slurry was heated at 143° C. for two hours in a closed system (e.g., a pressure reactor), and cooled to 40° C. After the slurry was acidified to pH 3.3, an emulsion of 2.2 g of an anionic suffactant, 30 g of a petroleum distillate, and 80 g of water was added, and the slurry was stirred for three hours. The solid component was collected by filtration and washed with water. The wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 60 g of 2,9-dimethylquinacridone as a magenta pigment.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[N:10]1[C:14](=[O:15])[NH:13][C:12]([CH:16]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[C:33]([CH2:39][NH:40]C(OC(C)(C)C)=O)[CH:32]=2)[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH2:26][CH2:27][OH:28])[C:18]=2[F:29])=[N:11]1)=[O:4].CO.[OH-].[Na+]>C(O)(=O)C>[F:29][C:18]1[C:19]([O:25][CH2:26][CH2:27][OH:28])=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=1[CH:16]([NH:30][C:31]1[CH:32]=[C:33]2[C:34](=[CH:35][CH:36]=1)[C:37](=[NH:38])[NH:40][CH2:39]2)[C:12]1[NH:13][C:14](=[O:15])[N:10]([C:6]2[N:7]=[CH:8][S:9][C:5]=2[C:3]([OH:2])=[O:4])[N:11]=1
Reactant: COC(=O)c1scnc1-n1nc(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2cc(OC)cc(OCCO)c2F)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc3c(c2)CNC3=N)c2nn(-c3ncsc3C(=O)O)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.9 %

Procedure:
To a mixture of 4-(3-{[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylamino]-[2-fluoro-5-methoxy-3-(2-hydroxyethoxy)phenyl]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiazole-5-carboxylic acid methyl ester (31 mg) and methanol (2.0 mL) there was added a 5N sodium hydroxide aqueous solution (28 μL), and the mixture was stirred overnight at room temperature. After neutralizing the mixture with acetic acid, the solvent in the mixture was distilled off under reduced pressure. Dichloromethane (2.0 mL) was added to the residue, and then a 4N hydrogen chloride-ethyl acetate solution (500 μL) was added to the mixture prior to stirring at room temperature for 15 minutes. Toluene (10 mL) was added to the mixture, and the solvent in the mixture was distilled off. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile/water mixed solvent, 0.1% acetic acid) to obtain the target compound (10 mg).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.[N:37]1[CH:42]=[CH:41][C:40]([CH:43]=O)=[CH:39][CH:38]=1>C1OCCC1>[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7](/[C:15](/[CH3:16])=[CH:43]/[C:40]3[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccncc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C/C(=C\c1ccncc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
378 g of [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphonium bromide were suspended in 4 l of butylene oxide. After the addition of 51 ml of 4-pyridinecarbaldehyde the mixture was boiled at reflux for 1.5 hours. After cooling the majority of the solvent was evaporated in a water-jet vacuum, the residue was poured into 1.5 l of a methanol/water mixture (ratio 6:4) and extracted repeatedly with hexane. The organic phase was washed three times with water and, after drying over sodium sulphate, evaporated. After flash chromatography (eluting agent hexane/ether=2:1) and recrystallization from hexane there were obtained 216 g of 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]pyridine in colorless crystals, melting point 84°-85°.
Reaction SMILES: [CH3:1][C:2]([C:4]1([CH3:19])[CH2:9][O:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[O:6][CH2:5]1)=[O:3].[BH4-].[Na+]>CO.O>[CH3:1][CH:2]([C:4]1([CH3:19])[CH2:9][O:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[O:6][CH2:5]1)[OH:3]
Reactant: CC(=O)C1(C)COC(c2cccc([N+](=O)[O-])c2)OC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)C1(C)COC(c2cccc([N+](=O)[O-])c2)OC1

Procedure:
To a solution of 5-methyl-2-(m-nitrophenyl)1,3-dioxan-5-yl methyl ketone (9.0 g) in methanol (100 ml) was added a solution of sodium borohydride (4.5 g) in water (20 ml). The mixture was heated under reflux for 1 hour, methanol was removed in vacuo and the residue was extracted with ether (3 × 100 ml). The extracts were dried (Na2SO4) and concentrated and the residue was crystallised from diethyl ether as pale yellow crystals m.p. 97°, cis isomer.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[OH:23][C:24]1([C:31]2[S:35][CH:34]=[N:33][CH:32]=2)[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>>[OH:23][C:24]1([C:31]2[S:35][CH:34]=[N:33][CH:32]=2)[CH2:25][CH2:26][CH:27]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:28][CH2:29]1
Reactant: O=C1CCC(O)(c2cncs2)CC1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Product: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(O)(c3cncs3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-hydroxy-4-thiazol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10].C(N(CC)CC)C.CCCCCCCCCCCC>[Pd]>[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C=CC(=O)OC
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCCCCCCCCCCC
Product: COC(=O)C=Cc1ccccc1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
Starbon®-Pd(10% wt) was prepared according to example 39 and was tested in the Heck reaction of iodobenzene and methyl acrylate (see Reaction Scheme 7). Iodobenzene (8 mmol, 0.85 mL), methyl acrylate (8 mmol, 0.70 mL), triethylamine (5 mmol) and the Starbon-Pd catalyst (0.050 g) were mixed together in a microwave tube and placed in a Microwave reactor under stirring at 70° C. for 5 min. The microwave power employed in the reaction was 300 W. Dodecane (1 mmol) was employed as internal standard and results were analysed by GC. The Starbon-Pd material afforded complete (>99 mol %) conversion of the starting material with a selectivity higher than 80 mol % to the cross-coupled product, methyl cinnamate in 5 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:21][CH2:22][C:17]([CH2:32]OS(C5C=CC(C)=CC=5)(=O)=O)([CH2:18][CH2:19]4)[CH2:16][N:15]3[C:44](=[O:47])[C:45]=2[OH:46])=[O:11])=[CH:4][C:3]=1[CH3:48].[C-:49]#[N:50].[K+]>CC(N(C)C)=O>[C:49]([CH2:32][C:17]12[CH2:22][CH2:21][C:20]([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])([C:14]3[N:15]([C:44](=[O:47])[C:45]([OH:46])=[C:12]([C:10]([NH:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:48])[CH:4]=4)=[O:11])[N:13]=3)[CH2:16]1)[CH2:19][CH2:18]2)#[N:50]
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(N(C)C(=O)C(=O)N(C)C)(CC2)c2nc(C(=O)NCc4ccc(F)c(C)c4)c(O)c(=O)n2C3)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CC2(CC#N)CCC3(N(C)C(=O)C(=O)N(C)C)CC2)ccc1F
Temperature: 160 °C
Yield: 19.3 %

Procedure:
A mixture of N-[2-[[[(4-fluoro-3-methylphenyl)methyl]amino]carbonyl]-6,7,8,9-tetrahydro-3-hydroxy-7-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-4-oxo-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl]-N,N′,N′-trimethyl-ethanediamide, Intermediate 28, (50 mg, 0.073 mmol) and KCN (47.6 mg, 0.731 mmol) in DMA (1.5 mL) was heated at 160° C. in a sealed tube for 3 h. The mixture was then cooled and the product purified by preparative HPLC to afford the title compound (8 mg, 0.014 mmol, 19.30% yield) as off-white solid. 1HNMR (500 MHz, CDCl3) δ: 11.97 (1H, br. s.), 9.61 (1H, br. s.), 7.18-7.26 (2H, m), 6.94 (1H, t, J=9.00 Hz), 4.56-4.68 (2H, m), 4.41-4.50 (1H, m), 3.61 (1H, d, J=15.87 Hz), 3.41-3.52 (1H, m), 3.05 (3H, s), 3.03 (3H, s), 3.01 (3H, s), 2.50 (2H, d, J=2.75 Hz), 2.27 (3H, d, J=1.83 Hz), 2.15-2.21 (3H, m), 1.96-2.05 (2H, m), 1.72-1.81 (1H, m), 1.57-1.69 (1H, m). LCMS (M+H)=539.4.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH3:13])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Br[CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:15]=3)[CH3:13])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: CN(c1ccc(O)cc1)c1ncnc2cc(Cl)ccc12
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2ncnc3cc(Cl)ccc23)cc1

Procedure:
4-[N-(7-Chloro-4-quinazolinyl)-N-methylamino]phenol was reacted with ethyl 2-bromopropionate, following essentially the same procedure as that described in Example 3 part(b), to give ethyl 2-{4-[N-(7-chloro-4-quinazolinyl)-N-methylamino]phenoxy}propionate as a yellow solid mp 92° C. The assigned structure was confirmed by proton magnetic resonance spectroscopy and mass spectrometry.
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54]([O:56][C:57]1[CH:58]=[C:59]2[C:63](=[CH:64][CH:65]=1)[NH:62][CH:61]=[C:60]2[CH2:66][CH2:67][NH:68][C:69]1[N:77]=[C:76]([C:78]2[C:79]3[CH:86]=[CH:85][CH:84]=[CH:83][C:80]=3[S:81][CH:82]=2)[N:75]=[C:74]2[C:70]=1[N:71]=[CH:72][N:73]2[CH:87]([CH3:89])[CH3:88])=[O:55]>CN(C=O)C>[O:14]=[C:13]1[NH:12][C@H:11]2[CH2:10][S:9][C@@H:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:2]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54]([O:56][C:57]3[CH:58]=[C:59]4[C:63](=[CH:64][CH:65]=3)[NH:62][CH:61]=[C:60]4[CH2:66][CH2:67][NH:68][C:69]3[N:77]=[C:76]([C:78]4[C:79]5[CH:86]=[CH:85][CH:84]=[CH:83][C:80]=5[S:81][CH:82]=4)[N:75]=[C:74]4[C:70]=3[N:71]=[CH:72][N:73]4[CH:87]([CH3:89])[CH3:88])=[O:55])=[O:3])[C@H:16]2[NH:15]1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(OC(=O)CCCCCN)cc34)nc(-c3csc4ccccc34)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(OC(=O)CCCCCNC(=O)CCCC[C@@H]5SC[C@@H]6NC(=O)N[C@@H]65)cc34)nc(-c3csc4ccccc34)nc21
Reaction time: 0.17 h

Procedure:
To a solution of (+)-biotin (35 mg, 0.14 mmol) and Et3N (36 mg, 0.35 mmol) in DMF (1 ml) was added HATU (90 mg, 0.24 mmol). The mixture was stirred for 10 min, and then was added to a solution of (3-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)-1H-indol-5-yl 6-aminohexanoate (b) (68 mg, 0.12 mmol) in DMF (1 ml). The reaction mixture was stirred for 16 hr at rt and then was concentrated. The residue was purified by reverse-phase HPLC (C18 column, eluting with MeOH—H2O 0.05% TFA) to afford the title compound as an off-white solid. Example 210 showed an EC50 value in the % CD34+ assay of 2.1 μM.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4].[CH3:20][C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>>[CH3:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:29])[NH:1][CH2:2][C:3]([N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][C:7](=[O:13])[N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:4])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NCC(=O)N(CC(=O)N1CCCC1)c1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCCC2)c2ccccc2)c1
Yield: 52.1 %

Procedure:
Working in a manner similar to that described in Example 1, but starting with 2-amino-N-phenyl-N-[2-oxo-2-(1-pyrrolidinyl)ethyl]acetamide (0.7 g) and 3-methylphenyl isocyanate (0.36 g), and after recrystallization in acetonitrile, 2-[3-(3-methylphenyl)ureido]-N-phenyl-N-[2-oxo-2-(1-pyrrolidinyl) ethyl)acetamide (0.55 g), m.p. 206° C., is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10].CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24].[NH4+].[Cl-]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])(=[O:25])=[O:24]
Reactant: C=CCOC(=O)NCCCCCCO
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)NCCCCCCOS(C)(=O)=O
Temperature: 0 °C

Procedure:
A solution of N-(6-hydroxyhexyl)prop-2-enyloxycarboxamide (2.55 g, 12.7 mmol; Charreyre, M. T.; Boullanger, P.; Pichot, C.; Delair, T.; Mandrand, B.; Llauro, M. F. Mak. Chem. 1993, 194(1), 117-35.) in dry CH2Cl2 (30.0 mL) was treated with Et3N (4.06 mL, 29.1 mmol) then cooled to 0° C. To this solution was transferred MsCl (15.2 mmol; 20.0 mL of a 0.76 M solution in CH2Cl2) using a cannula; full conversion coincided with completion of the transfer. The resulting solution was warmed to 22° C., then treated with 2 M NH4Cl (50 mL) and transferred to a separatory funnel. The layers separated and the aqueous layer washed with CH2Cl2 (3×50 mL). The combined washes were washed with 20% aqueous NaCl then dried over MgSO4, filtered and concentrated in vacuo to a pale yellow oil (3.2 g) that was used without further purification in the subsequent alkylation step. 1H NMR (CDCl3, 300 MHz): δ 5.90 (1H, ddt, J=17.2, 10.4, 5.6 Hz), 5.29 (1H, dq, J=17.2, 1.6 Hz), 5.19 (1H, dq, J=10.4, 1.3 Hz), 4.71 (1H, brs), 4.54 (2H, brd, J=5.5 Hz), 4.20 (2H, t, J=6.5 Hz), 3.17 (2H, brs), 2.98 (3H, s), 1.79-1.69 (2H, m), 1.55-1.29 (6H, m).