Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:16])=[CH:18][CH:19]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1ccc(C(C)(C)C)cc1
Yield: 105.5 %

Procedure:
30.95 g (347 mmol) of 2-amino-2-methyl-1-propanol was weighed into a 500 mL Erlenmeyer flask fitted with a stir bar and septum. Added 200 mL CH2Cl2. Established and maintained nitrogen atmosphere. Stirred the solution in an ice/water bath. Added 34 mL (174 mmol) of 4-tert-butylbenzoyl chloride dropwise over 30 min. A white precipitate formed. Stirred at room temperature overnight. Removed the solids by filtration and washed with CH2Cl2. Removed the solvent from the filtrate on rotavap and dried at 60° C./4 torr to obtain 45.79 g of the title compound as a light yellow resin. MS (ESI) 248 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[O:18]1[C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=[N:19]1>>[O:18]1[C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:24])=[CH:21][CH:20]=[N:19]1
Reactant: O=C(Cl)c1ccno1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccno4)cc23)CC1
Yield: 57.3 %

Procedure:
Beginning with 13 mg (0.056 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 8.21 mg (0.062 mMol) isoxazole-5-carbonyl chloride, 10.4 mg (57%) of the title compound were recovered.
Reaction SMILES: CN(C)CCO[C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[O:27])[C:11]3[C:16]([N:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.[Cl:29]C1C=CC2C(=O)C3C(NC=2C=1)=CC=CC=3.C(Br)C1C=CC=CC=1.[H-].[Na+]>CN(C)C=O>[Cl:29][C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[O:27])[C:11]3[C:16]([N:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: O=c1c2ccccc2[nH]c2cc(Cl)ccc12
Reactant: CN(C)CCOc1ccc2c(=O)c3ccccc3n(Cc3ccccc3)c2c1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2n(Cc2ccccc2)c2cc(Cl)ccc12

Procedure:
3-(2-Dimethylaminoethoxy)-10-benzyl-9(10H)-acridinone [III; R' is C6H5CH2, R" is H, --O--Y--N=Z is 3-O-CH2CH2N(CH3)2 ], m.p. 134°-136° C. (light yellow powder). The intermediate 3-chloro-10-benzyl-9(10H)-acridinone, m.p. 186°-190° C. (yellow crystals) was prepared from 3-chloro-9(10H)-acridinone and benzyl bromide with sodium hydride in dimethylformamide.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH2:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17]>C(O)C>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: NCC(O)CO
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(NCC(O)CO)n1
Temperature: 0 °C
Yield: 43 %

Procedure:
4 g (0.0212 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 50 ml of ethanol and 3.9 g (0.0424 mol) of racemic 3-aminopropane-1,2-diol are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 2.19 g of yellow powder are obtained, ie a yield of 43%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:24]=[N:25][CH:26]=[N:27][CH:28]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)[CH2:16][CH2:15]3)[CH2:8]1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: Brc1cncnc1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2cncnc2)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 5-bromo-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][C:17]#[N:18])[CH2:11][CH2:10]1
Reactant: N#CCCl
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1CCN(c2cccc(Cl)c2Cl)CC1
Yield: 93.4 %

Procedure:
2,3-Dichlorophenyl piperazine (5.0 g, 0.0216 mol), chloroacetonitrile (1.37 mL, 0.0216 mol), and potassium carbonate (K2CO3) (14.95 g, 0.108 mol) are combined in acetonitrile and heated to reflux for 18 hours. The reaction mixture is concentrated in vacuo and the resulting residue is partitioned between water (H2O) and dichloromethane. The organic layer is dried (sodium sulfate) and concentrated to give 5.45 g of the title compound as a yellow solid; mp 89°-92° C.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:36][CH3:37])[C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH2:29]([NH:28][C:26](=[O:27])[N:25]([CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:38])=[O:3])[CH:7]=1)[CH2:36][CH3:37])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)NCc1ccccc1

Procedure:
[2′-(3-Benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester (46.57 g) in THF (470 mL) and ethanol (370 mL) was treated with 1N aqueous NaOH (2 mL) for 45 minutes at room temperature. The mixture was acidified with 1N aqueous HCl (270 mL) and extracted three times with dichloromethane, the organics were dried with magnesium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC to give [2′-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]2.[CH2:26]([NH:29][C:30]1[C:31]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:32][CH:33]=[CH:34][CH:35]=1)[CH2:27]C>C1COCC1.ClCCl>[CH3:27][CH2:26][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[N:36]1[CH2:41][CH2:40][N:39]([C:23]([C:18]2[NH:19][C:20]3[CH:21]=[CH:22][C:14]([Cl:13])=[CH:15][C:16]=3[CH:17]=2)=[O:25])[CH2:38][CH2:37]1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CCCNc1cccnc1N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNc1cccnc1N1CCN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reaction time: 1 h

Procedure:
1,1'-carbonyldiimidazole (0.42 g) is added to a 20°-25° solution of 5-chloroindole-2-carboxylic acid (I, 0.5 g) in THF (5 ml). After 1 hour of stirring at 20°-25°, the above reaction is added dropwise over 10 minutes via cannula to a -10° (ice/acetone bath) solution of [3-(ethylamino)-2-pyridinyl]piperazine (II, 0.58 g) in THF (5 ml). After 30 minutes of stirring at -10°, the reaction is warmed to 20°-25° and stirring is continued for 5 hours. The reaction is diluted with dichloromethane (50 ml), washed with saturated aqueous sodium bicarbonate (40 ml), water (40 ml) and saline (40 ml). The organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by flash column chromatography (50 g silica gel), eluting with ethyl acetate/hexane (1/1). The appropriate fractions are pooled and concentrated to give the title compound, mp 208°-209°; IR (mineral oil) 3200, 2920-3000, 1632, and 1425 cm-1 ; NMR (300 MHz, CDCl3) 9.77, 7.72, 7.60, 7.36, 7.22, 6.97, 6.86, 6.75, 4.23, 4.09, 3.23-3.15, and 1.33 δ; MS (m/e) 383, 178, 176, 162, 150, 148, 137, 134, and 120.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:15][C:16]([O:18]CC2C=CC=CC=2)=[O:17])[C:5]1=[O:26])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:15][C:16]([OH:18])=[O:17])[C:5]1=[O:26]
Reactant: [N-]=[N+]=NC1CCc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: NC1CCc2ccccc2N(CC(=O)O)C1=O

Procedure:
A solution of 3-azido-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (14.0 g, 0.04 mol) in ethanol (300 ml) was hydrogenated for 25 hours on a Parr shaker at 45 psi at room temperature using 5% Pd-C (2.0 g) as catalyst. The catalyst was filtered off and the solvent removed under reduced pressure. The residue was dissolved in water (500 ml) and the solution extracted with dichloromethane (2×400 ml). The aqueous solution was filtered, and evaporated under reduced pressure. Ethanol (50 ml) was added and the solution evaporated under reduced pressure. More ethanol (50 ml) was added, and the evaporation repeated. The residue was recrystallized from ethanol/ethyl acetate to give 3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 147°-50°.
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9]O)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.C(Cl)(Cl)Cl.P(Br)(Br)[Br:19]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9][Br:19])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Temperature: -5 °C
Yield: 42.5 %

Procedure:
A 500-mL three-necked round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was purged with nitrogen and charged with 124b (37.0 g, 148 mmol) and chloroform (160 mL). The reaction was cooled to −5° C. using an ice/acetone bath and phosphorous tribromide (40.0 g, 148 mmol) was added portionwise. The cooling bath was removed and the reaction stirred at reflux for 2 h. After this time, the reaction was cooled to −5° C. and saturated aqueous sodium bicarbonate (250 mL) was added until a pH of 8.5 was reached. The mixture was extracted with ethyl acetate (3×150 mL) and the combined organic layers were washed with saturated aqueous sodium carbonate (2×50 mL), brine (75 mL), dried over sodium sulfate and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to afford a yellow residue that was dissolved with gentle heating in methylene chloride (60 mL). Hexanes (approximately 20 mL) was added and the solution became cloudy. The mixture was heated until a solid precipitate formed, methylene chloride (9 mL) was added and the solution became clear. The solution was left to cool to room temperature and after 4 h the resulting crystals were collected by vacuum filtration. The filter cake was washed with an ice-cold 1:2 mixture of methylene chloride:hexanes (2×20 mL) to afford 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (19.7 g). The combined filtrates were evaporated and the procedure was performed again to afford an additional 9.70 g of 1-(2-bromoethyl)-5-(bromo-methyl)-3-nitro-1H-pyrazole. The solids were combined and dried under high vacuum for 18 h to afford a 57% yield (26.0 g) of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 124c as white crystals: mp 95-97° C.; 1H NMR (300 MHz, CDCl3) δ 6.93 (s, 1H), 4.63 (t, 2H, J=6.0 Hz), 4.54 (s, 2H), 3.86 (t, 2H, J=6.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[N:24][CH:25]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:29]1[CH2:30][CH:31]=[C:26]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][N:24]=2)[CH2:27][CH2:28]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: Fc1ccc(C2=CCNCC2)nc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H](N1CC=C(c2ccc(F)cn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 47.8 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.76 g, 3.0 mmol) and 5-fluoro-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (1.63 g, 9.3 mmol) were dissolved in acetonitrile (20 ml), and lithium perchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.63 g of the intended substance (yield 47.8%).
Reaction SMILES: C[N+]1([O-])CCOCC1.[CH3:9][C:10]1([CH3:39])[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([O:34][Si](C)(C)C)=[CH:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:16]=2)[O:11]1>O.CC(C)=O.[Os](=O)(=O)(=O)=O>[CH3:9][C:10]1([CH3:39])[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20](=[O:34])[CH2:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:16]=2)[O:11]1
Reactant: COc1cc(C=C(O[Si](C)(C)C)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(CC(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Reaction time: 3 h
Yield: 10.3 %

Procedure:
A solution of osmium tetroxide (25% wt., 0.574 mL) and NMO (13.24 mg, 0.113 mmol) dissolved in water (0.27 mL) and acetone (0.48 mL) were cooled to −5° C. [1-(2,2-dimethyl-chroman-6-yl)-2-(3,4,5-trimethoxy-phenyl)-vinyloxy]-trimethyl-silane (50 mg, 0.113 mmol) dissolved in acetone (0.2 mL) was added dropwise to the cooled stirring solution. After completion of addition the reaction continued to stir at 0° C. After 3 h, the reaction was quenched with sodium hydrosulfite and florisil. The reaction mixture was filtered and the filtrate was concentrated. The crude material was purified using silica gel chromatography (4:1 pentane: ethyl acetate to 1:1 pentane ethyl acetate) to afford the desired compound (4.3 mg, 8%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:22][CH3:23])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:24][C:25]1[N:26]=[CH:27][N:28]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=2[O:37][CH3:38])[CH:29]=1>C(O)(=O)C.C1COCC1>[Cl:24][C:25]1[N:26]=[CH:27][N:28]([C:30]2[CH:36]=[CH:35][C:33]([NH:34][C:2]3[N:3]=[C:4]([NH:22][CH3:23])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:32][C:31]=2[O:37][CH3:38])[CH:29]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Yield: 26.9 %

Procedure:
2-Chloro-N-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (220 mg, 0.640 mmol) was added to a solution of 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (215 mg, 0.960 mmol) in acetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heated at 80° C. overnight. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (92 mg, 0.172 mmol, 26.8% yield). LC-MS (M+H)+=531.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.93 (1H, s), 7.66 (1H, br s), 7.50 (1H, s), 7.10-7.23 (4H, m), 7.02 (2H, d, J=15.3 Hz), 6.83 (1H, d, J=8.2 Hz), 4.70-4.83 (1H, m), 4.13-4.28 (1H, m), 3.12 (3H, d, J=4.9 Hz), 2.74 (1H, br. s.), 2.65 (2H, d, J=8.2 Hz), 1.97-2.08 (1H, m), 1.25 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1>CN(C=O)C.O>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([O:1][C:2]2[CH:14]=[C:13]3[C:5]([C:6]4[CH:7]=[CH:8][C:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][C:11]=4[NH:12]3)=[CH:4][CH:3]=2)=[CH:31][CH:32]=1)([O-:38])=[O:37]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(Oc3ccc([N+](=O)[O-])cc3)ccc12
Temperature: 140 °C
Yield: 44.8 %

Procedure:
To a round bottom flask containing Compound 9 (80 mg, 0.268 mmol) in DMF (2 mL) was added potassium carbonate (74.1 mg, 0.536 mmol) and 4-fluoro-nitrobenzene (41.6 mg, 0.295 mmol). The reaction mixture was heated for 20 min at 140° C. After cooling down to rt, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The organic layers were dried, concentrated. The residue was purified on a silica gel column (EtOAc:Hexanes=3:7) to afford Compound 10 as a yellow solid (50 mg, 0.12 mmol, 44% yield). 1H NMR (400 MHz, CDCl3) δ: 8.22 (d, J=9.2 Hz, 2H), 8.10 (br, 1H), 8.00-7.90 (m, 3H), 7.12 (s, 1H), 7.06-6.90 (m, 4H), 6.70 (br, 1H), 1.56 (s, 9H); LRMS for C23H21N3O5+H+, calc'd: 420.2. found: 420.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:5]([NH2:7])=[NH:6])([CH3:4])[CH3:3].Cl.[O-]CC.[Na+].C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[C:2]([C:5]1[N:7]=[C:16]([OH:15])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][N:6]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)C(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C(C)(C)C)nc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.7 %

Procedure:
In ethanol (40 mL) was placed t-butylcarbamidine hydrochloride (3.71 g, 27.2 mmol). This was treated with 21% sodium ethoxide in ethanol (8.80 g, 27.2 mmol) and stirred at RT for 15 min. To this was added the diethyl ethoxymethylenemalonate (5.87 g, 27.2 mmol) and the reaction mixture was stirred overnight at RT. The reaction mixture was refluxed for 1 hour and then cooled to RT. The solution was evaporated, the residue dissolved in water (100 mL) and the pH adjusted to 3-4 (wet litmus) with acetic acid. The mixture formed a precipitate. The solid collected by filtration, washed with water (50 mL) and dried in vacuo to obtain ethyl 2-tert-butyl-4-hydroxypyrimidine-5-carboxylate (2.18 g, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.6 (brs, 1H), 8.44 (s, 1H), 4.20 (q, J=7.2 Hz, 2H), 1.25 (s, 9H), 1.23 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 225.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH2:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[CH3:21]>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:25]3[CH2:26][CH2:27][N:22]([CH2:20][CH3:21])[CH2:23][CH2:24]3)[CH3:13])=[CH:8][C:6]=2[N:7]=1
Reactant: CCN1CCC(=O)CC1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CCN1CCC(N(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 50 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)methylamine was reacted with 1-ethyl-4-piperidone using standard reductive amination conditions. The resulting crude solid was triturated with a small amount of diethyl ether and methanol to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-ethyl-piperidin-4-yl)-methyl-amine as a solid (50% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethylether and methanol to give 347 as a solid (75% yield). NMR (CDCl3, 400 MHz), 1.10 (3H, t, J=7.2), 1.56-1.73 (2H, m), 1.84-1.95 (4H, m), 2.38 (3H, s), 2.42 (2H, q, J=7.0), 2.51-2.58 (1H, m), 3.06 (2H, d, J=11.8), 3.88-3.91 (4H, m), 3.93 (2H, s), 4.03-4.06 (4H, m), 5.21 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=469
Reaction SMILES: [S:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:18]([C:26](O)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:29]([NH:17][C@H:18]([C:26]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][S:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3])=[O:27])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)NCCCCN)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: Cc1ccc(S(=O)(=O)NCCCCNC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Yield: 85.3 %

Procedure:
In substantially the same manner as in Example 5, N-tosyl-1,4-diaminobutane (1.27 g) was condensed with Boc-L-Phe-OH (1.47 g) to give N-(Boc-L-phenylalanyl)-N'-tosyl-1,4-diaminobutane (2.19 g) (yield 85%). After Boc group elimination with TFA, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate (774 mg) as obtained in Reference Example 8 to yield the title compound (compound 32; 1.55 g) [yield 67%].
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[OH:28][C:29]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CN(C1C=CN=CC=1)C.O1CCOCC1>[I:16][C:11]1[CH:10]=[C:9]([NH:8][C:6]([C:5]2[CH:17]=[CH:18][C:2]([N:32]3[CH2:33][CH2:34][C:29]([OH:28])([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:30][CH2:31]3)=[N:3][CH:4]=2)=[O:7])[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Reactant: OC1(c2ccccc2)CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)c2ccc(N3CCC(O)(c4ccccc4)CC3)nc2)cc1I
Yield: 65 %

Procedure:
A solution of 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide (100 mg, 0.26 mmol), a catalytic amount of DMAP, diisopropylethyl amine (0.14 mL, 8.1 mmol), 4-hydroxy-4-phenyl piperidine (140 mg, 8.1 mmol) in 5 mL in dioxane was heated at 95° C. in a sealed tube for about 48 h. The reaction mixture was then cooled and partitioned between EtOAc and aq. saturated Na2CO3. The organic layer was then collected, dried over Na2SO4 filtered and concentrated. The residue was chromatographed with a silica gel column and 20-100% EtOAc in hexanes to afford the product (90 mg. Yield: 65%). HRMS m/z calcd for C24H24N3O2I [M+H]+: 514.0986. Found: 514.0987.