Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][C:14]([CH3:16])=[O:15].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C1COCC1.CCCCCC>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](=[O:21])[CH2:13][C:14](=[O:15])[CH3:16]
Reactant: CC(C)=O
Reactant: O=C(Cl)c1ccccc1Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(=O)CC(=O)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 2.5 M hexane solution of BuLi (16.46 mL, 41.1 mmol) was added dropwise to a solution of diisopropylamine (6.11 mL, 42.9 mmol) in THF (150 mL) at −78° C. The mixture was stirred at 0° C. for 15 min and cooled to −78° C. Acetone (3.02 mL, 41.1 mmol) was added dropwise. After 2 h at −78° C., 2-chlorobenzoyl chloride (3.00 g, 17.14 mmol) in THF (10 mL) was added dropwise. The flask was rinsed with THF (2 mL) and added. After 1 h at −78° C., the mixture was quenched with brine (200 mL) and acidified to pH ˜1 with 1 N HCl. The organic solvents were evaporated in vacuo. The aqueous residue was extracted with EtOAc (3×100 mL). The combined extracts were dried (MgSO4) and concentrated to give crude 1-(2-chlorophenyl)butane-1,3-dione as a yellow liquid. The crude material was taken to next step without purification. MS (ES+) m/z: 197 (M+H).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]([CH2:31][C:32]([NH:34][CH2:35][C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[NH:41][CH:40]=[C:39]3[CH3:45])=[O:33])[C:5](=[O:30])[C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=2)[CH2:15][O:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[N:7][CH:8]=1.[OH-].[Na+]>CO>[NH3:4].[NH2:19][CH2:18][CH2:17][O:16][CH2:15][C:14]1[CH:13]=[C:12]([CH:29]=[CH:28][CH:27]=1)[CH2:11][CH2:10][NH:9][C:6]1[C:5](=[O:30])[N:4]([CH2:31][C:32]([NH:34][CH2:35][C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[NH:41][CH:40]=[C:39]3[CH3:45])=[O:33])[C:3]([CH3:2])=[CH:8][N:7]=1
Reactant: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NCCc4cccc(COCCNC(=O)OC(C)(C)C)c4)c3=O)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NCCc4cccc(COCCN)c4)c3=O)cc12
Product: N
Temperature: 25 °C
Yield: 110.5 %

Procedure:
Hydrochloric acid (10 ml, 6N, 60.0 mmol) was added to a solution of tert-butyl 2-{[3-(2-{[5-methyl-4-(2-{[(3-methyl-1H-indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}ethyl)benzyl]oxy}ethylcarbamate (preparation 108) (220 mg, 0.36 mmol) in methanol (10 ml), and the reaction stirred for an hour at room temperature. The mixture was basified using NaOH (1N) solution, and the mixture extracted with ethyl acetate (2×), and dichloromethane (1×). The combined organic extracts were dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:1) to afford the title compound as a white solid, (100 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N1C=CN=C1)([N:17]1C=CN=C1)=O.O1CCCC1.N>O>[NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:17])=[O:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N)c(C(N)=O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
A mixture of 23.7 g of 2-amino-4,5-dimethoxybenzoic acid, 19.5 g of 1,1'-carbonyldiimidazole and 600 ml of tetrahydrofuran Was stirred for 2 hours at room temperature and then saturated with anhydrous ammonia with ice bath cooling. After 24 hours, the reaction mixture was diluted with 50 ml of water, heated at reflux for 2 hours and then concentrated under reduced pressure to about 50 ml. This liquid was mixed with 100 ml of 0.1N sodium hydroxide and then extracted with three 200 ml portions of dichloromethane. The extracts were combined, dried and evaporated. The residue was crystallized from acetonitrile, giving 5.5 g of 2-amino-4,5-dimethoxybenzamide as light grey crystals, mp 135°-138° C.
Reaction SMILES: [CH2:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.Cl[O:13][N:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1.C(N(CC)CC)C>CCOCC>[F:23][C:22]([F:24])([F:25])[C:18]1[CH:17]=[C:16]([C:15]2[CH2:1][C:2]3([C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4](=[O:5])[O:3]3)[O:13][N:14]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: C=C1OC(=O)c2ccccc21
Reactant: FC(F)(F)c1cccc(C=NOCl)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C1OC2(CC(c3cccc(C(F)(F)F)c3)=NO2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
To a solution of 109.5 g (0.75 mole) of 3-methylenephthalide and 285 g (1.27 mole) of m-trifluoromethylbenzaldehyde chlorooxime in 3.5 liters of ether was added 128.3 g (1.27 mole) of triethylamine in 250 ml. of ether at 0° C. during 3 hours. The solution was then stirred at room temperature overnight. An infrared spectrum indicated that the reaction was complete. The solid was filtered off. The ethereal solution was washed once with 10% HCl, twice with sodium chloride saturated water, dried over CaSO4 and concentrated under vacuum. Only 19.5 g of impure product was obtained. The solid material which was filtrated from the original reaction solution was stirred with 4 liters of tetrahydrofuran for 4 hours and filtered through a Buchner funnel. The tetrahydrofuran solution obtained was washed once with 10% HCl solution and twice with water saturated with sodium chloride. After being dried and concentrated, the tetrahydrofuran solution gave 140.6 g of pure product, m.p. 170° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[N:3]=1.BrC1C=CC(S([N:19]2[CH2:24][CH2:23][N:22]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)(=O)=O)=CC=1.C(N(CC)CC)C.CCOCC>C1COCC1>[CH3:8][C:4]1[N:3]=[C:2]([N:30]2[CH2:31][CH2:32][CH:27]([C:25]([N:22]3[CH2:23][CH2:24][NH:19][CH2:20][CH2:21]3)=[O:26])[CH2:28][CH2:29]2)[CH:7]=[CH:6][N:5]=1
Reactant: O=C(C1CCNCC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: Cc1nccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nccc(N2CCC(C(=O)N3CCNCC3)CC2)n1
Yield: 52.7 %

Procedure:
4-Chloro-2-methylpyrimidine (135 mg) was added to a solution of 1-(4-bromophenylsulphonyl)-4-(piperidin-4-ylcarbonyl )piperazine (415 mg) in THF (15 ml) containing triethylamine (0.2 ml). The mixture was heated at reflux for 16 hours. After cooling, the THF was evaporated. The residue was treated with H2O (20 ml) and the aqueous extracted with EtOAc (3×20 ml). The combined organic phases were washed with saturated brine (1×20 ml) dried and evaporated to give an oil which was purified by chromatography on silica gel. Elution with CH2Cl2 /MeOH/0.88NH3 (96:3:1) gave an oil. Trituration with Et2O (10 ml) gave, as a colourless solid, 1-(4-bromophenylsulphonyl) 4-(4-(1-(2-methylpyrimidyl)piperidin-4-ylcarbonyl)piperazine (152 mg), mp 200-202° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][NH:7][C:6]2=O.O=P(Cl)(Cl)[Cl:21]>C1(C)C=CC=CC=1>[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1cc2nc[nH]c(=O)c2cc1OC
Solvent: Cc1ccccc1
Product: COCCOc1cc2ncnc(Cl)c2cc1OC
Temperature: 125 °C
Yield: 96 %

Procedure:
According to the procedure described in Example 6A Step 5, a mixture of 6-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one (7.83 g, 31.3 mmol) and POCl3 (20 mL) in toluene (50 mL) was heated at 125° C. for 5 hours, to afford 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline as a solid (8.098 g, 96%). 1H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 7.49 (s, 1H), 7.41 (s, 1H), 4.36 (t, 2H), 4.01 (s, 3H), 3.76 (t, 2H), 3.34 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:20][CH:21]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCN(C)CC2)nc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCN(C)CC2)nc1
Yield: 31.5 %

Procedure:
Following general procedure D, [1-(6-bromo-4-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)quinolin-3-yl)ethanone (50 mg, 0.113 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (34 mg, 0.124 mmol) to afford the desired product (18 mg, 31%) as a yellow-orange solid: 1H NMR (500 MHz, CD3OD) δ 9.08 (s, 1H), 8.07 (d, J=3 Hz, 1H), 7.91 (s, 2H), 7.82 (s, 1H), 7.49 (dd, J=12, 2.0 Hz, 1H), 7.00-6.92 (m, 3H), 3.66 (t, J=10 Hz, 4H), 2.77 (s, 3H), 2.62 (t, J=10 Hz, 4H), 2.39 (s, 3H); ESI MS m/z 506, [C27H25ClFN5O2+H]+; HPLC 98.9% (AUC), tR=14.39 min.
Reaction SMILES: FC(F)(F)C(O)=O.[BH4-].[Na+].[Cl:10][C:11]1[C:24]([C:25](=O)[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[CH:23][C:14]2[CH2:15][CH:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:17][C:13]=2[C:12]=1[Cl:34]>C(Cl)Cl>[Cl:10][C:11]1[C:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=2)=[CH:23][C:14]2[CH2:15][CH:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:17][C:13]=2[C:12]=1[Cl:34]
Reactant: CCOC(=O)C1Cc2cc(C(=O)c3ccc(O)cc3)c(Cl)c(Cl)c2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1Cc2cc(Cc3ccc(O)cc3)c(Cl)c(Cl)c2O1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To trifluoroacetic acid (120 ml.) under a nitrogen atmosphere were added sodium borohydride pellets (5.39 g.) over a period of 30 minutes at 5° C. A solution of ethyl 6,7-dichloro-2,3-dihydro-5-(p-hydroxybenzoyl)-benzofuran-2-carboxylate (7.35 g.) in methylene chloride (50 ml.) was then added dropwise over 30 minutes, and the mixture stirred at room temperature for 22 hours.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[Cl:16][C:17]([Cl:21])([Cl:20])[CH2:18]O.C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1>ClCCl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:18][C:17]([Cl:21])([Cl:20])[Cl:16])=[O:14]
Reactant: OCC(Cl)(Cl)Cl
Reactant: O=C(O)CCCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCCCCCCCCO)OCC(Cl)(Cl)Cl
Yield: 113.5 %

Procedure:
This compound was prepared from 12-hydroxydodecanoic acid (2.0 g; 9.2 mmol), 2,2,2-trichloroethanol (6.0 g; 40 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 4.1 g; 20 mmol), and pyridine (5.0 mL) in dry dichloromethane (50 mL) using the procedure of Example 12a. 3.63 g (66%) product was obtained (colorless oil).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[CH:25]=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl([O-])=[O:28].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.C(#N)C.O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25]([OH:28])=[O:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)OC(=O)n1c(C=O)cc2cc(OCc3ccccc3)cnc21
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)n1c(C(=O)O)cc2cc(OCc3ccccc3)cnc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
To the solution of 0.41 g (1.2 mmol) 5-benzyloxy-2-formyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester in 10 ml tert-butanol, 7 ml 2-methyl-2-butene and 20 ml acetonitrile, a mixture consistent of 1.2 g (10.6 mmol; 80%) sodium chlorite and 0.97 g (8.1 mmol) sodium dihydrogen phosphate in 10 ml water was added dropwise. The resulting two-phase mixture was stirred 1.5 h at room temperature. Then the organic components were evaporated at a rotary evaporator and the remaining aqueous phase was extracted three times with dichloromethane. The combined organic layers were washed with 10% aqueous sodium thiosulfate solution and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel with ethyl acetate:n-heptane (1:1 v/v) as eluant to give 0.35 g (74%) of the compound as a yellow foam.
Reaction SMILES: C(=[N:8]/[C:9]([CH3:21])([CH3:20])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])\C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[NH2:8][C:9]([CH3:21])([CH3:20])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: CN(CC(C)(C)/N=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(CC(C)(C)N)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of (E)-tert-butyl (2-(benzylideneamino)-2-methylpropyl)(methyl)carbamate (G9, 3.17 g) in tetrahydrofuran (25 mL), 5% aqueous citric acid (25 mL) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, and the aqueous layer was extracted with methylene chloride. The organic layer and the extract were combined, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 0% hexane in ethyl acetate) to obtain tert-butyl (2-amino-2-methylpropyl)(methyl)carbamate (G10, 506 mg).
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([C:7]([NH:9][NH:10][C:11](=[O:30])[C@H:12]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[C:18]=2[CH3:29])[C@H:13]([OH:15])[CH3:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:33][C:34]([Si:37](Cl)([CH3:39])[CH3:38])([CH3:36])[CH3:35].N1C=CN=C1>CN(C=O)C>[Si:37]([O:15][C@H:13]([CH3:14])[C@@H:12]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[C:18]=1[CH3:29])[C:11]([NH:10][NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:32][CH:31]=1)=[O:30])([C:34]([CH3:36])([CH3:35])[CH3:33])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@@H](C)O)ccc(C#N)c1C(F)(F)F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
The crude material 4-cyano-N′-((2R,3R)-2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)-3-hydroxybutanoyl)benzohydrazide (800 mg, 1.75 mmol) was added to DMF (40 mL), followed by addition of TBDMS-Cl (1.06 g, 7.00 mmol) and imidazole (954 mg, 14.01 mmol) at 0° C. The solution was allowed to stir at 0° C. for 30 min and then at room temperature for overnight. The reaction was quenched with the addition of 200 mL brine and extract with EtOAc. The resulting crude material was chromatographed to get the desired product (640 mg) 1H NMR (400 MHz, acetone-d6, δ in ppm): 9.62 (br s), 7.93 (d, J=9 Hz, 2H), 7.79 (d, J=9 Hz, 2H), 7.55 (d, J=9 Hz, 1H), 6.98 (d, J=9 Hz, 1H), 5.38 (d, J=9 Hz, 1H), 4.41 (m, 1H), 4.18 (m, 1H), 2.25 (m, 3H), 1.31 (d, J=6 Hz, 3H), 0.77 (s, 9H), 0.03 (s, 6H), 0.00 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>>[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[O:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:32][N:31]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2nc(N3CCOCC3)c3oc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidine (Example 153) was reacted with 2-methoxypyrimidine-5-boronic acid via General Procedure E to give, after purification by reverse HPLC, 4 mg of 237. MS (Q1) 490 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8](B(O)O)[CH:9]=1)[CH3:2].[C:14](=O)([O-])[O-].[Na+].[Na+].Br[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]2[CH2:31][CH2:30][C@@:29]3([CH2:35][CH2:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:32]3=[O:44])[N:28]=2)[CH:22]=1>C(COC)OC.O.C(Cl)Cl.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3[CH2:31][CH2:30][C@:29]4([CH2:14][CH2:35][CH2:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:32]4=[O:44])[N:28]=3)[CH:22]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: C[Si](C)(C)CCOCN1CC[C@@]2(CCC(c3cc(Br)ccn3)=N2)C1=O
Reactant: O=C([O-])[O-]
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CCOc1ccc(F)c(-c2ccnc(C3=N[C@@]4(CCCN(COCC[Si](C)(C)C)C4=O)CC3)c2)c1
Yield: 82.2 %

Procedure:
5-Ethoxy-2-fluorophenylboronic acid (129.98 mg, 0.7100 mmol) and sodium carbonate (213.96 mg, 2.02 mmol) were added to a solution of (5S)-2-(4-bromo-2-pyridyl)-7-(2-trimethylsilylethoxymethyl)-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 47) (295 mg, 0.6700 mmol) in monoglyme (6 mL) and water (1.8 mL) under N2 at ambient temp. The mixture was degassed by bubbling N2 through it for 10 mins. Bis(triphenylphosphine)palladium (II) dichloride (23.62 mg, 0.0300 mmol) was then added and the stirred mixture was refluxed under N2 for 2.25 h. The reaction was cooled, diluted with DCM (40 ml) and the solution washed with water (40 ml), dried (MgSO4) and evaporated to a dark brown oil, which was dried at RT under vacuum for 2 hours. This was purified by SiO2 column chromatography: the oil was dissolved in DCM (3 ml) and the solution was applied to a 10 g cartridge which was then eluted on a Biotage SP4 system with a gradient of EtOAc/iso-hexane (20-100%). Relevant fractions were pooled and evaporated to a light brown oil, dried at RT under vacuum for 16 hours to afford (S)-2-[4-(5-ethoxy-2-fluoro-phenyl)-pyridin-2-yl]-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-diaza-spiro[4.5]dec-1-en-6-one (D48) 274 mg;
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Cl:19][CH2:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH3:30])=[C:26]([CH3:31])[N:25]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24]1=[O:39]>>[ClH:19].[CH2:32]([N:25]1[C:26]([CH3:31])=[C:27]([CH3:30])[C:28](=[O:29])[N:23]([CH2:22][CH2:21][CH2:20][N:14]2[CH2:15][CH2:16][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3][C:2]([F:1])([F:17])[F:18])[CH2:12][CH2:13]2)[C:24]1=[O:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Reactant: Cc1c(C)n(Cc2ccccc2)c(=O)n(CCCCl)c1=O
Product: Cc1c(C)n(Cc2ccccc2)c(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O
Product: Cl

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 3-(3-chloropropyl)-1-benzyl-5,6-dimethyl-2,4(1H,3H)-pyrimidinedione gave 1-benzyl-3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5,6-dimethyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 221°14 222° C.; Anal.: Calcd. for C28H33F3N4O3.(HCl)1.1 : C, 58.37; H, 6.06; N, 9.72%; Found: C, 58.38; H, 5.96; N, 9.58%;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCCC1

Procedure:
Using analogous procedures to those described in Note [33] immediately above, 1-(tert-butoxycarbonyl)-L-proline was reacted with pyrrolidine to give (2S)-1-(tert-butoxycarbonyl)-2-(pyrrolidin-1-ylcarbonyl)pyrrolidine which was deprotected and reacted with 2-bromoethanol. There was thus obtained the required starting material; NMR Spectrum: (CDCl3) 1.7-2.05 (m, 8H), 2.1-2.3 (m, 1H), 2.42.5 (m, 1H), 2.55-2.7 (m, 1H), 2.8-2.9 (m, 1H), 3.2-3.3 (m, 2H), 3.4-3.7 (m, 5H), 4.1 (br s, 1H); Mass Spectrum: M+H+ 213.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:29][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: NC1CCCCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCCC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (10 g, 29.6 mmol), cyclohexyl amine (3.4 ml, 30.0 mmol), diisopropylethylamine (11 ml, 65.0 mmol) in propan-2-ol (150 ml) was heated at 80° C. for 14 h. The mixture was then cooled to 25° C. and stirred for 6 h. The resulting yellow solid was collected by vacuum filtration, washed with propan-2-ol (1×30 ml), and was air-dried to afford (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-cyclohexyl-amine (10.45 g, 90%). LCMS (Method G, ESI): RT=1.33 min, m+H=401.2; 1H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.91 (s, 1H), 8.13 (d, J=7.6 Hz, 2H), 7.82 (d, J=4.1 Hz, 1H), 7.77 (t, J=7.4 Hz, 1H), 7.66 (t, J=7.8 Hz, 2H), 6.99 (d, J=4.2 Hz, 1H), 4.12-4.01 (m, 1H), 2.02-1.93 (m, 2H), 1.76-1.54 (m, 3H), 1.55-1.38 (m, 4H), 1.33-1.20 (m, 1H).