Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:18])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1.[CH:19]1[N:23]=[CH:22][N:21]([C:24](N2C=NC=C2)=[O:25])[CH:20]=1>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([NH:18][C:24]([N:21]2[CH:20]=[CH:19][N:23]=[CH:22]2)=[O:25])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(N)sc1-c1ccc(-n2cccn2)cc1
Solvent: ClCCl
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(-n2cccn2)cc1
Temperature: 25 °C

Procedure:
A suspension of 4-methyl-5-(4-pyrazol-1-yl-phenyl)-thiazol-2-ylamine (1.5 g, 5.85 mmol) in dry DCM is treated with CDI (1.1 g, 7.02 mmol) followed by TEA (1.2 ml, 8.77 mmol). The resulting orange suspension is heated to reflux for 3 hours and then allowed to cool to room temperature overnight. The suspension is filtered and washed with DCM to afford the title compound. [MH+ 315.35].
Reaction SMILES: [Na].[NH:2]([C:4]1[S:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[NH2:3].[C:13](#[N:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[NH2:22][C:13]1[CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:2]([C:4]2[S:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[N:3]=1
Reactant: NNc1nc2ccccc2s1
Reactant: N#CC=Cc1ccccc1
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2nc3ccccc3s2)C(c2ccccc2)C1

Procedure:
A 0.46 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 16.5 g. of 2-hydrazinobenzothiazole is added, followed by 12.9 g. of cinnamonitrile. The reaction mixture is refluxed for 16 hours, then is cooled. Some of the solvent is removed in vacuo and the mixture is filtered. The precipitate is washed with hexane to give 25.67 g. of crude product. A 3.0 g. amount of this material is recrystallized from acetone-hexane to give 2.35 g. of the product of the Example as buff colored prisms, m.p. 270°-271.5° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:21][CH3:22])([O:19][CH3:20])=[O:18])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:24]C(C)=O.CI.C(=O)([O-])[O-].[K+].[K+]>O>[Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:19][CH3:20])([O:21][CH3:22])=[O:18])[CH2:10][C:11]([O:13][CH3:24])=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)=O
Reactant: COP(=O)(CC(=O)C[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)C[C@@H](CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C

Procedure:
The concentrated solution (1.88 g) containing (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid, which was prepared by concentrating the ethyl acetate portion, was obtained in the same manner as Example 1. To the solution, 24 ml of acetone were added to prepare an acetone solution. 3.1 g of methyl iodide and 0.60 g of potassium carbonate were added to the solution with stirring, and then the mixture was further stirred for 5 hours at room temperature. After 24 ml of water was added to the solution, the solution was extracted with two portios of 30 ml of ethyl acetate. The ethyl acetate portions were combined and dried over anhydrous magnesium sulfate. Then, the solvent was removed by distillation in vacuo to give 1.2 g of methyl (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoate as an oil (optical purity: 98% ee; purity: 79%).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[C:10]([I:11])[C:5]2=[C:4]([Cl:12])[N:3]=1.[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1nc(Cl)c2c(I)cnc-2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
2,4-dichloro-5-iodo-1H-pyrrolo[2,3-d]pyrimidine (660 mg, 2.103 mmol) and tosyl-chloride (441 mg, 2.31 mmol) were combined in dry dichloromethane (20 ml). Diisopropylethylamine (0.734 mL, 4.21 mmol) was added and the reaction mixture was let stir at rt for 18 h. The reaction was then diluted with dichloromethane and the organic layer was washed with a saturated solution of sodium bicarbonate, water and a saturated solution of brine, then dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by chromatography on SiO2 to afford 2,4-dichloro-5-iodo-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (901 mg, 1.94 mmol) as a yellow solid. ESIMS (M+H)+=469.
Reaction SMILES: Cl[C:2]([C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[N:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:4].[C:26]([O-:29])(=[O:28])[CH3:27].[Na+]>C(O)(=O)C>[C:26]([O:29][C:2]([C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[N:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:4])(=[O:28])[CH3:27]
Reactant: COc1cc(OC)nc(C(Cl)(C(=O)NS(C)(=O)=O)c2ccccc2)n1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(OC)nc(C(OC(C)=O)(C(=O)NS(C)(=O)=O)c2ccccc2)n1
Yield: 98 %

Procedure:
2-Chloro-2-(4,6-dimethoxypyrimidin-2-yl)-N-methanesulfonyl-2-phenylacetamide (0.5 g) and anhydrous sodium acetate (0.25 g) were refluxed in glacial acetic acid (10 ml) for 7 hours. The acetic acid was evaporated off under vacuum, and the residue was taken into ether. The ether solution was washed with water (3 times), dried over magnesium sulfate, and evaporated under vacuum to give 0.52 g of a brown glass. Trituration with diisopropyl ether gave an off-white solid, which was filtered off, washed with diisopropyl ether and dried to give 0.3 g of the desired product, mp 141°-143° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([O-:3])=[O:2]
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(OCCN2CCOCC2)c1
Yield: 70 %

Procedure:
A mixture of 3-nitrophenol (3.5 g, 25 mmol), N-(2-chloroethyl)morpholine hydrochloride (4.7 g, 25 mmol), and potassium carbonate (13.2 g, 125 mmol) in acetone (100 mL) was heated to reflux for 20 hours. The solvent was removed under vacuum. The residue was partitioned between water (150 mL) and ethyl acetate (150 mL) and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (3×100 mL) and extracted with dilute aqueous HCl (2×125 mL). These extracts were washed with CH2Cl2 (2×125 mL), made basic (NaOH) and extracted into ethyl acetate (3×75 mL). These organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 4.4 g, in 70% yield; 1H NMR (CDCl3) δ 2.59 (t, J=4.7 Hz, 4H), 2.84 (t, J=5.6 Hz, 2H), 3.75 (t, J=4.7 Hz, 4H), 4.19 (t, J=5.6 Hz, 2H), 7.22-7.25 (m, 1H), 7.43 (t, J=8.1 Hz, 1H), 7.76 (t, J=2.3 Hz, 1H), 7.82-7.85 (m, 1H).
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([N:19]([CH2:21][C:22]([OH:24])=O)[CH3:20])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:54]2[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=2)[N:33]2[CH2:36][C:35](=[CH:37][S:38]([CH2:41][C:42]3[CH:43]=[C:44]([N:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)[CH:45]=[CH:46][CH:47]=3)(=[O:40])=[O:39])[CH2:34]2)=[CH:28][CH:27]=1>ClCCl>[C:15]([O:14][C:12](=[O:13])[N:19]([CH2:21][C:22]([N:51]1[CH2:52][CH2:53][N:48]([C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([CH2:41][S:38]([CH:37]=[C:35]3[CH2:34][N:33]([CH:32]([C:29]4[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=4)[C:54]4[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=4)[CH2:36]3)(=[O:39])=[O:40])[CH:43]=2)[CH2:49][CH2:50]1)=[O:24])[CH3:20])([CH3:16])([CH3:17])[CH3:18]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CN(CC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1)C(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 100.2 %

Procedure:
1.02 g of supported EDCI (5 mM), 47.3 mg of N-Boc-sarcosine and then 10 cm3 of dichloromethane are successively added, at a temperature close to 20° C., to 108.5 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 20 hours at a temperature close to 20° C., the reaction mixture is filtered on sintered glass. The resin is rinsed with three times 5 cm3 of dichloromethane. The combined filtrates are washed with 20 cm3 of water, dried over magnesium sulfate, filtered on sintered glass and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 143 mg of (2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N-methylcarbamic acid tert-butyl ester are thus obtained in the form of a cream-colored lacquer [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm). A mixture of rotamers is observed at room temperature; 1.31 and 1.41 (2s, 9H in total), 2.78 and 2.81 (2s, 3H in total), 2.93 (2s, 3H), from 3.10 to 3.25 (unresolved complex, 4H), from 3.45 to 3.65 (mt, 4H), 3.80 (mt, 2H), 4.06 and 4.09 (2s, 2H in total), 4.19 (mt, 2H), 4.78 (s, 1H), 6.83 (broad d, J=8 Hz, 1H), 6.93 (broad s, 1H), 7.00 (dd, J=8 and 2.5 Hz, 1H), 7.27 (t, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H)].
Reaction SMILES: [CH3:1][NH:2][CH3:3].CCN(CC)CC.[CH3:11][C:12]([CH3:43])([CH3:42])[C:13](=[O:41])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([C:37](Cl)=[O:38])[CH:31]=[CH:30]3)([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:40].Cl>O>[CH3:1][N:2]([CH3:3])[C:37]([C:32]1[CH:31]=[CH:30][C:29]2[C:34](=[CH:35][CH:36]=[C:27]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13](=[O:41])[C:12]([CH3:43])([CH3:42])[CH3:11])=[C:17]([CH3:40])[CH:18]=3)([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:28]=2)[CH:33]=1)=[O:38]
Reactant: CNC
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)Cl)ccc2c1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)N(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
Treat a solution of dimethylamine (2.0 M in THF) (0.12 mL, 0.25 mmol) and Et3N (0.034 mL, 0.25 mmol) in CH2CL2 (3 mL) with 6-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}naphthalene-2-carbonyl chloride (0.057 g, 0.123 mmol) in CH2CL2 (1 mL). Stir the mixture at RT for 16 h; dilute with CH2CL2 and water. Acidify the resulting mixture to pH 1 using 5N HCl. Separate the organic layer from the aqueous layer. Wash the organic layer with brine, dry over Na2SO4, and filter. Concentrate the filtrate to give the title compound as a yellow solid (0.033 g, 57%). MS (ES) m/e 474 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8]1[N:15]=[CH:16][NH:17][C:18](=[O:19])[C:7]=1[CH2:6]2.[OH-].[Na+].[CH3:22]OS(OC)(=O)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8]1[NH:15][CH2:16][N:17]([CH3:22])[C:18](=[O:19])[C:7]=1[CH2:6]2
Reactant: COc1cc2c(cc1OC)Nc1nc[nH]c(=O)c1C2
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1OC)NC1=C(C2)C(=O)N(C)CN1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
To a heated (90° C.), stirred solution of 7,8-dimethoxy4-oxo-3,4,5,10-tetrahydropyrimido[4,5-b]quinoline (0.25 g, 0.96 mmol) and sodium hydroxide (0.05 g, 1.25 mmol) in water (3 mL) was added dimethylsulfate (0.23 mL, 2.4 mmol). After 0.5 hour, the reaction mixture was diluted with water (20 mL), the solids filtered, washed with acetonitrile and dried in vacuo to afford 0.13 g of the title compound; m.p. 225-230° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[C:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CC(C)(C)OC(=O)N1CCC(=O)C1

Procedure:
Prepared from (R)-(+)-1-Boc-3-pyrrolidinol using the Dess-Martin oxidation (Dess, D. B.; Martin, J. C.; J. Am. Chem. Soc., 1991, 113, 7277)(85%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][CH:3]=1.[CH:9]1([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:15]2[CH2:16][CH2:17][CH:12]([CH:9]3[CH2:11][CH2:10]3)[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: C1CC(C2CC2)CCN1
Reactant: Fc1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc(N2CCC(C3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A round bottomed flask was charged with 1-bromo-4-fluorobenzene (1.93 g, 11.0 mmol), 4-cyclopropylpiperidine (1.65 g, 13.2 mmol) and DIEA (7.67 g, 44.0 mmol). The flask was purged with nitrogen. Anhydrous 1-methyl-2-pyrrolidinone (25 mL) was added, and the resulting mixture was degassed via nitrogen sparge. The mixture was then placed in a pre-heated oil bath (180° C.), and was held at this temperature for 2 days, whereupon it was allowed to cool to ambient temperature, then was poured into water. The aqueous phase was extracted with ethyl acetate and the organic phase was washed with brine. The organic phase was then dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by chromatography on silica gel (0 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 281.8 [M+H]+; 1H NMR (500 MHz, CD2Cl2) δ 7.30 (d, J=8.8 Hz, 2 H),6.79 (d, J=8.8 Hz, 2 H),3.62 (d, J=12.2 Hz, 2 H),2.62 (t, J=12.1 Hz, 2 H),1.83 (d, J=12.8 Hz, 2 H),1.56-1.42 (m, 2 H),0.69-0.53 (m, 2 H),0.41 (d, J=7.5 Hz, 2 H),0.11 (d, J=4.5 Hz, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][OH:16])[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1)#[N:2].C([Li])CCC.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][O:16][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[C:11]([NH2:13])=[O:12])=[CH:17][CH:18]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(OCCN(CCO)C(N)=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCCN(CCOc2ccc(C#N)cc2)C(N)=O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of intermediate 1-[2-(4-cyanophenoxy)ethyl]-1-(2-hydroxy-ethyl)urea (4.7 g, 0.0188 mol; see step (i) above) in dry THF (150 mL) was added n-butyllithium (18.89 mL, 1.1 M) at −78° C. The reaction mixture was stirred at −78° C. for 1 h, after which a solution of freshly crystallised p-toluenesulfonyl chloride (4.3 g, 0.023 mol) in THF (50 mL) was added dropwise. The reaction mixture was then stirred at −78° C. for a further 30 min, before being warmed to −30° C., and stirred for 2 h more. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, concentrated and the residue was recrystallised in ethyl acetate/hexane to yield the title compound as an off-white solid. Yield: 3.5 g.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][N:24]2[C@@H:27]2[CH2:31][C@H:30]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[C@@H:29]([OH:37])[C@H:28]2[OH:38])=[C:20]([NH:39][CH2:40][CH:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:19]=1>CN1C(=O)CCC1>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:18]2[N:26]=[C:25]3[C:21]([N:22]=[CH:23][N:24]3[C@@H:27]3[CH2:31][C@H:30]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[C@@H:29]([OH:37])[C@H:28]3[OH:38])=[C:20]([NH:39][CH2:40][CH:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[N:19]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CCNC1)OCc1ccccc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: CN1CCCC1=O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OCc5ccccc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A solution of (R)-pyrrolidin-3-yl-carbamic acid benzyl ester hydrochloride (0.88 g, 3.45 mmol) in DCM is free-based using sodium hydrogen carbonate solution to yield (R)-pyrrolidin-3-yl-carbamic acid benzyl ester (0.487 g, 2.22 mmol). This amine is added to N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Example 4) (0.5 g, 0.96 mmol) and TEA (0.224 g, 2.22 mmol) and then dissolved in NMP (7 ml). The reaction mixture is heated using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 190° C. for 1 hour. The resulting mixture is purified by chromatography on silica eluting with 5% MeOH in DCM to yield the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CC(C)c1ccc(Cl)c(CC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc(Cl)c(CC(=O)O)c1
Yield: 99.4 %

Procedure:
Dissolve tert-butyl 2-(2-chloro-5-isopropyl-phenyl)acetate (483 mg, 1.80 mmol) in dichloromethane (5.1 mL). Add trifluoroacetic acid (1.09 mL, 14.4 mmol) slowly and stir the reaction mixture 3 hours at ambient temperature. Concentrate under reduced pressure to give the title compound (380 mg, 1.79 mmol). MS (m/z): 229.8 (M+18). The following compound is prepared essentially by the method of Preparation 49.
Reaction SMILES: C([Al:5]([CH2:10][CH:11]([CH3:13])[CH3:12])CC(C)C)C(C)C.[C:14]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]=1[OH:29])([CH3:17])([CH3:16])[CH3:15]>CCCCC>[C:25]([C:20]1[CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:19]=1[O:29][Al:5]([O:29][C:19]1[C:20]([C:25]([CH3:26])([CH3:27])[CH3:28])=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=1[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH:11]([CH3:12])[CH3:13])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCCCC
Product: Cc1cc(C(C)(C)C)c(O[Al](CC(C)C)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1

Procedure:
Using a 250 ml balloon flask disposed in an argon atmosphere and provided with a magnetic stirrer rod, a solution of 0.493 g of triisobutylaluminium in 20 ml of pentane is introduced, and then a solution of 1.095 g of 2,6-di-t-butyl-4-methylphenol in 30 ml of pentane is introduced dropwise with agitation and at ambient temperature. After about 30 hours of reaction the pentane is evaporated under vacuum and analysis of the white solid remaining indicates that it is formed essentially by bis-(2,6-di-t-butyl-4-methylphenoxy)-isobutylaluminium. That compound is put back into solution in 5 ml of heptane.
Reaction SMILES: [C:1]1([CH3:39])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH:12]([NH:30][C:31](OC(C)(C)C)=[O:32])[C:11]2=[O:38])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:40][C:41]1[CH:51]=[CH:50][C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:43][CH:42]=1>>[C:1]1([CH3:39])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:13][CH:12]([NH:30][C:31]([NH:40][C:41]3[CH:42]=[CH:43][C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:50][CH:51]=3)=[O:32])[C:11]2=[O:38])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1ccccc1
Product: CCOC(=O)c1ccc(NC(=O)NC2CN(C(=O)c3ccccc3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)cc1

Procedure:
Step 2 of Example 10 was repeated except that 1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzoyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine was used instead of 1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine. Subsequently, Step 3 of Example 10 was repeated except that ethyl 4-aminobenzoate was used instead of ethyl 3-aminobenzoate, to thereby obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([Cl:22])[CH:3]=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].O>[Cl:22][C:4]1[CH:3]=[C:2](/[CH:25]=[CH:24]/[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:7]=[CH:6][C:5]=1[C:8](=[C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1
Reactant: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2Cl)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(Cl)c1
Temperature: 140 °C
Yield: 59.8 %

Procedure:
A mixture of 72 (459 mg, 1.22 mmol), tert-butyl acrylate (0.369 mL, 2.55 mmol), Pd(OAc)2 (15.0 mg, 0.067 mmol), P(o-tolyl)3 (40.0 mg, 0.131 mmol), and Et3N (0.520 mL, 3.73 mmol) were heated under microwave irradiation at 140° C. for 30 min. Water (30 mL) was added and the mixture was extracted with Et2O (3×20 mL). The combined ethereal extracts were washed with water (30 mL), brine (30 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 310 mg (60%) of 73. 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 1.58 (m, 6H), 1.99 (m, 2H), 2.28 (m, 2H), 4.71 (s, 1H), 6.31 (d, J=16.0 Hz, 1H), 6.73 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.6 Hz, 2H), 7.17 (d, J=7.9 Hz, 1H), 7.31 (dd, J=7.9 Hz, 1.5 Hz, 1H), 7.47 (m, 2H).
Reaction SMILES: C([Li])CCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1.[C:31](=[O:33])=[O:32]>O1CCCC1>[Br:22][C:23]1[C:24]([C:31]([OH:33])=[O:32])=[C:25]([F:30])[C:26]([F:29])=[CH:27][CH:28]=1
Reactant: Fc1ccc(Br)cc1F
Reactant: O=C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1c(Br)ccc(F)c1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A solution of 1.6M butyllithium in hexane (60 mL, 96 mmol) was diluted with tetrahydrofuran (180 mL) under an argon atmosphere, and cooled to −78° C. To the solution, were added dropwise 2,2,6,6-tetramethylpiperidine (16.2 g, 116 mmol) and subsequently 4-bromo-1,2-difluorobenzene (15.4 g, 80 mmol), and the mixture was stirred at the same temperature for 2 hours. The solution was carefully poured onto crushed dry ice, and the mixture was allowed to warm to room temperature. The solution was concentrated under reduced pressure, and the residue was poured into water. After the solution was washed with diethylether, the aqueous layer was made acidic by the addition of 6N hydrochloric acid, and organic matter was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (10.8 g, 57% yield).