Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].C(=O)=O.CC(C)=O.[N:9]1([CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>ClCCl>[N:9]1([CH2:15][CH2:16][CH2:17][S:18]([NH2:1])(=[O:20])=[O:19])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=S(=O)(Cl)CCCN1CCOCC1
Reactant: N
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: NS(=O)(=O)CCCN1CCOCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dichloromethane (40 ml) was saturated with ammonia gas with cooling (dry ice/acetone), and then 3-morpholin-4-yl-propane-1-sulphonyl chloride (279 mg, 1.23 mmoles) was added. The mixture was stirred at room temperature for 24 hours. The mixture was filtered, the filtrate evaporated and the residue was dried at 40° C. in vacuo to afford compound 58 (210 mg) as a gum. LC/MS System A; Rt=0.28 mins, m/z (ES+)=209 (M+H for C7H16N2O3S).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:43])[NH:14][CH2:15][C:16]([N:18]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:20][CH:19]2[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:17])[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[K+]>O.CO>[C:39]([O:38][C:36]([CH:19]1[CH2:20][CH:21]([C:29]([N:31]2[CH2:32][CH2:33][CH2:34][CH2:35]2)=[O:30])[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:43])[NH:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([OH:5])=[O:3])=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)N3CCCC3)C2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CC(C(=O)N2CCCC2)C(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 43.1 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 1.85 g of tert-butyl (2RS,4SR,5SR)-1-{2-[3-(3-(ethoxycarbonyl)phenyl)ureido]acetyl}-5-phenyl-4-(1-pyrrolidinylcarbonyl)pyrrolidine-2-carboxylate and 0.18 g of potassium hydroxide in a mixture of 20 cm3 of distilled water and 50 cm3 of methanol. After treatment, there is obtained 0.76 g of (2RS,4SR,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-4-(1-pyrrolidinylcarbonyl)-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid [Rf =0.17; eluent: methylene chloride/methanol (97.5/2.5)].
Reaction SMILES: C(O)C.[OH:4][C:5]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:6]=1[CH:7]=O.O.Cl.[NH2:16][C@H:17]([C:20]([OH:22])=[O:21])[CH2:18][SH:19].C([O-])(=O)C.[Na+]>O>[OH:4][C:5]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:6]=1[CH:7]1[NH:16][C@H:17]([C:20]([OH:22])=[O:21])[CH2:18][S:19]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=Cc1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CSC(c2ccc(O)cc2O)N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In a mixed solvent including ethanol (10 ml) and water (10 ml), a solution including 2,4-dihydroxybenzaldehyde (943 mg, 6.83 mmol), L-cysteine hydrochloride monohydrate (1.0 g, 5.69 mmol), and sodium acetate (495 mg, 6.03 mmol) was stirred at room temperature for 14 hours. The produced precipitate was filtered, and a filter cake was washed with water, and ethyl acetate to obtain the target product that is a solid white (1.316 g, 95.8%).
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=1)([O-:9])=[O:8].[Br:21]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:21][CH2:19][CH2:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1
Reactant: CCCC(O)c1ccc([N+](=O)[O-])cc1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CCCCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
Part A. Pyridine (0.66 mL, 8.21 mmol) was added slowly to an ice cooled solution of 4-nitrophenyl butanol (1.0 gm,5.13 mmol) and dibromotriphenylphosphorane (2.8 gm, 6.66 mmol) in 20 mL acetonitrile under a nitrogen atmosphere. The reaction solution was stirred for 1/2 hr and allowed to warm to ambient temperature and stir overnight. The reaction was concentrated invacuo to give a residue. The residue was filtered through a short plug of silica gel and then the product was purifed by flash chromatography on silica gel eluting methylene chloride:hexane (v:v, 50:50), to give 1-bromo-4-(4-nitrophenyl)butane as an oil 1.3 gm (98%) MS 275(M+NH4)+ 1 H NMR (CDCl3): 8.2(d, 2H), 7.4(d, 2H), 3.4(t, 2H), 2.8(t, 2H), 1.8-2.0(m, 4H).
Reaction SMILES: O[C:2]1[CH:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:7])[O:5][CH:6]=1.O.[NH2:15][NH2:16]>C(O)C>[OH:5][CH2:6][C:2]1[N:16]=[N:15][C:4](=[O:7])[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NN
Reactant: O=C1OC=C(O)C1c1ccccc1
Solvent: CCO
Solvent: O
Product: O=C1N=NC(CO)=C1c1ccccc1

Procedure:
4-Hydroxy-3-phenyl-2-furanone (3 g, 0.017 mol) was dissolved in ethanol (17 ml) with hydrazine hydrate (0.83 ml, 0.017 mol) and heated at reflux for 10 days (over this time the solvent evaporated). The residue was redissolved in ethanol (17 ml) and heated at reflux then allowed to cool and the solid that crystallised out was collected by filtration (2.2 g, mp=173° C.). Data for the title compound: 1H NMR (360 MHz, d6-DMSO) δ 4.45 (1H, s), 5.31 (1H, s), 7.14 (1H, t, J=7.3 Hz), 7.34 (2H, t, J=7.3 Hz), 7.55 (2H, d, J=7.3 Hz); MS (ES+) m/e 191 [MH]+.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[C:6]1[N:10]([C@H:11]2[O:17][C@@H:16]([CH3:18])[C@:14](C(=O)C)([OH:15])[C@:12]2(C(=O)C)[OH:13])[C:9]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:8]=2[N:7]=1.C(O)C>CN(C=O)C>[CH:1]([NH:4][C:6]1[N:10]([C@H:11]2[O:17][C@@H:16]([CH3:18])[C@H:14]([OH:15])[C@@H:12]2[OH:13])[C:9]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:8]=2[N:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(=O)[C@@]1(O)[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)O[C@@H](C)[C@@]1(O)C(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](C)[C@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Isopropylamine (5 mL ) and 2-bromo-5,6-dichloro-1-(5-deoxy-2,3-diacetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.40 g, 0.86 mmol) were combined with absolute ethanol (20 mL) and stirred at 80° C. for 24 h. The reaction mixture was concentrated and purified by multiple cyclings on a chromatotron fitted with a 2 mm silica gel rotor, with 1:30 methanol:dichloromethane and 1:1 ethyl acetate:hexanes and 1:4 acetone:dichloromethane to give a white solid (0.18 g, 0.70, mmol, 60%); m.p. 103-105° C.; [α]20D=(+) 38.8 (c=0.5 DMF); UV λmax (ε): pH 7.0:303 nm (10,400), 276 (2,500), 260 (10,000); MS (CI): m/z (rel. intensity) 360 (14.26, M−); 1H NMR (DMSO-d6) d 7.39 (s, 1H, Ar—H), 7.31 (s, 1H, Ar—H), 6.57 (d, 1H, NH, J=7.6 Hz), 5.68 (d, 1H, H-1′, J=6.6 Hz), 5.23 (d, 1H, OH, J=4.8 Hz), 5.21 (d, 1H, OH, J=7.1 Hz), 4.31 (q, 1H, H-4′, J=6.7 Hz), 4.04-3.98 (m, 1H, isopropyl-CH), 3.95-3.87 (m, 1H), 3.81-3.76 (m, 1H), 1.36 (d, 3H, H-5′, J=6.5 Hz), 1.20 (d, 6H, cyclopentyl-CH2, J=6.6 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][CH:6]=1.[OH-].[Na+].O>CO>[OH:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(N(C)CCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CCO)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.2 %

Procedure:
To a solution (10 ml) of ethyl 4-[(2-hydroxyethyl)(methyl)amino]benzoate (500 mg, 2.24 mmol) in methanol was added 1M aqueous sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the mixture was washed with diethyl ether. 1M Hydrochloric acid (10 ml) was added, and the mixture was extracted with dichloromethane and concentrated under reduced pressure to give the title compound (119 mg, 27%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12](I)[C:11]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][N:10]3[C:9]2=[O:26])=[CH:4][CH:3]=1.[CH3:27]B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12]([CH3:27])[C:11]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][N:10]3[C:9]2=[O:26])=[CH:4][CH:3]=1
Reactant: CB(O)O
Reactant: O=c1n(-c2ccc(F)cc2)cc(I)c2nc(COc3ccccc3)cn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1cn(-c2ccc(F)cc2)c(=O)n2cc(COc3ccccc3)nc12
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 71.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (2.63 mg, 0.0023 mmol) was added to a stirred suspension of 6-(4-fluoro-phenyl)-8-iodo-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (35 mg, 0.076 mmol), methylboronic acid (22.7 mg, 0.38 mmol) and K2CO3 (31.5 mg, 0.23 mmol) in a mixture of 1,4-dioxane (4 mL) and DMF (1 mL) under nitrogen and in a sealed tube. The mixture was stirred at 150° C. for 45 minutes under microwave irradiation. The solvents were evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 6-(4-fluoro-phenyl)-8-methyl-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (19 mg, 72% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 2.36 (d, J=1.2 Hz, 3H), 5.22 (s, 2H), 6.92 (d, J=1.2 Hz, 1H), 6.97 (br. t, J=7.4, 7.4 Hz, 1H), 7.02 (br. d, J=8.1 Hz, 2H), 7.16-7.24 (m, 2H), 7.27-7.34 (m, 2H), 7.36-7.44 (m, 2H), 7.84 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14]CC)=[O:13])[CH:6]=[N:5]2.[OH-].[Na+].C(O)C>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[N:5]2
Reactant: CCOC(=O)c1cnc2cc(I)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1cnc2cc(I)ccc2n1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A solution of compound 9 (1.30 g, 3.96 mmol) in a 2.0 N sodium hydroxide/ethanol solution (1/1, v/v, 6 mL) was refluxed for 30 min. After cooling to room temperature, the reaction mixture was acidified (pH=4-5) with acetic acid and cooled to 0° C. The resulting precipitate was removed by filtration and dried in a vacuum oven to afford acid 23 (1.08 g, 3.29 mmol) as a white solid. Yield 91%; mp 242-244° C.; 1H NMR (200 MHz, DMSO-d6) δ 7.97 (d, 1H, J=8 Hz), 8.15 (d, 1H, J=8 Hz), 8.52 (s, 1H), 9.36 (s, 1H); ESI-MS m/z 298.6 [M−H]−.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C([BH3-])#N.[Na+]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH2:12][C:11](=[O:22])[N:10]([CH2:9][CH2:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:34][C:32]4[CH:31]=[CH:30][C:27]5[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=5[N:33]=4)[CH2:3][CH2:4]3)[C:15]=2[CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2c(c1)N(CC[C@H]1CC[C@H](N)CC1)C(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc2c(c1)N(CC[C@H]1CC[C@H](NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2

Procedure:
4-[2-(Trans-4-aminocyclohexyl)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 74) (310 mg, 1.73 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (1.73 mmol) and sodium cyanoborohydride were reacted as described under Example 21 to give 110 mg (24%) product.
Reaction SMILES: CO.C([O:5][C:6](=[O:47])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13](=[O:46])[N:14]2[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([N:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:28][C:29]2[CH:38]=[CH:37][C:32]3[O:33][CH2:34][CH2:35][O:36][C:31]=3[CH:30]=2)[CH2:23][CH2:22]1)C.[OH-].[Na+].Cl>O>[C:42]([O:41][C:39]([N:27]([CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)[CH:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][N:14]2[C:15]3[C:10](=[C:9]([O:8][CH2:7][C:6]([OH:47])=[O:5])[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:12][C:13]2=[O:46])[CH2:26][CH2:25]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CCOC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(OCC(=O)O)cccc32)CC1
Reaction time: 2.5 h

Procedure:
To a mixed solution of 5 mL methanol and 0.5 mL water containing 126 mg of ethyl(1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)acetate, 0.2 mL of 5 mol/L aqueous sodium hydroxide solution was added and allowed to stand at room temperature for 2.5 hours. To the reaction mixture, water was added, and the solvent was removed under reduced pressure. After the residue thus obtained was acidified by adding 1 mol/L hydrochloric acid, it was extracted with chloroform. The extracts were washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 90 mg of (1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)acetic acid as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16](=O)[NH:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=O)[CH2:14][N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:40]>>[CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[N:40]=2)[CH2:14][N:13]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)NC(C(=O)N1CN(c2ccccc2)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CN(c2ccccc2)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
(1-{5-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3-phenyl-imidazolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (90 mg) was dissolved in m-xylenes (3 mL) and heated at 135° C. Solid ammonium acetate (100 mg, 1.29 mmol) was added and the reaction was stirred at 135° C. After 120 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc/hexanes) to yield the product {1-[4-(4-Bromo-phenyl)-1′-phenyl-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (40.2 mg, 0.0764 mmol): LCMS-ESI+: calc'd for C25H28BrN5O3: 526.4 (M+). Found: 526.4/528.3 (M+H+).
Reaction SMILES: CO.[CH2:3]([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21])[CH2:4][CH2:5][CH3:6].Cl[C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1.C[O-].[Na+]>O>[Cl:14][C:12]1[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:9]([N+:20]([O-:22])=[O:21])=[C:8]([O:7][CH2:3][CH2:4][CH2:5][CH3:6])[C:13]=1[S:30][C:27]1[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCCCOc1cc([N+](=O)[O-])c(OCCCC)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCOc1cc([N+](=O)[O-])c(OCCCC)c(Sc2ccccc2)c1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 110 parts of methanol was added 51 parts of 2,5-dibutoxy-4-chloronitrobenzene. The mixture was heated to 50° C. A methanol (50 parts) solution of 25 parts of p-chlorobenzenethiol and 9.8 parts of sodium methylate was added dropwise thereto over a period of about one hour to carry out a reaction. After completion of the dropwise addition, the reaction was further continued under reflux for 5 hours. After completion of the reaction, 85 parts of water were added to the reaction mixture to precipitate a crystal. The resulting crystal was recovered by filtration and recrystallized from methanol to obtain 59 parts of 4-chlorophenylthio-2,5-dibutoxynitrobenzene having a m.p. of 74° to 75° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([F:10])[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:20]1([CH2:26][S:27](Cl)(=[O:29])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:27]([CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:29])=[O:28])=[C:4]([F:10])[CH:3]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Cc1ccccc1)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
To a solution of (4-bromo-2-fluoro-phenyl)methanamine (3 g, 14.7 mmol) in dichloromethane (50 mL) was added N,N-diisopropylethylamine (3.3 mL, 19.1 mmol), followed by phenylmethanesulfonyl chloride (3.3 g, 17.6 mmol) and the reaction was stirred at ambient temperature for 3 hours. The reaction was diluted with dichloromethane and washed with water and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (20-100% EtOAc in heptane) to give N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-methanesulfonamide (4.22 g, 80% yield). LCMS (m/z) ES+ 358 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C@H:10]2[CH2:14][C@@H:13]([CH2:15][OH:16])[CH:12]=[CH:11]2)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].Cl.[CH2:18](OC(OCC)OCC)C>>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]2[C:2]=1[N:1]=[CH:18][N:9]2[C@H:10]1[CH2:14][C@@H:13]([CH2:15][OH:16])[CH:12]=[CH:11]1
Reactant: Nc1c(Cl)ncnc1N[C@@H]1C=C[C@H](CO)C1
Reactant: CCOC(OCC)OCC
Agent: Cl
Product: OC[C@H]1C=C[C@@H](n2cnc3c(Cl)ncnc32)C1

Procedure:
(1R,cis)-4-[(5-Amino-6-chloro-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol (from part d of this example, 9.63 g, 40.0 mmol), triethylorthoformate (150 mL), and concentrated hydrochloric acid (14 mL) were stirred for 3 hours. Volatiles were evaporated and the residual solid was partitioned between chloroform (300 mL) and saturated aqueous sodium carbonate (100 mL). The aqueous layer was extracted with chloroform (2×100 mL). The combined chloroform layers were dried (sodium sulfate). Volatiles were evaporated under reduced pressure and the residual yellow glass was chromatographed on silica gel. Elution with ethyl acetate gave title compound as white needles from ethyl acetate (7.45 g, 74%), m.p. 121–124° C.; 1H-NMR (DMSO-d6) δ 8.81 (s, 1H), 8.64 (s, 1H), 6.24 and 6.21 (two m, 2H), 5.75 (m, 1H), 4.75 (t, J=5.4 Hz, 1H), 3.34 (m, 2H), 2.95 (m, 1H), 2.75 (m, 1H), 1.75 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10](=[CH:11][C:12]3[NH:13][C:14]([CH3:27])=[C:15]([CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:16]=3[CH3:17])[C:9](=[O:28])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:29]([C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])#[CH:30].Cl>>[CH3:17][C:16]1[C:15]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[C:14]([CH3:27])[NH:13][C:12]=1[CH:11]=[C:10]1[C:3]2[C:2]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([C:29]#[CH:30])[CH:32]=3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9]1=[O:28]
Reactant: C#Cc1cccc(N)c1
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Cl)c32)c(C)c1CCCN1CCOCC1
Agent: Cl
Product: C#Cc1cccc(Nc2ncnc3c2C(=Cc2[nH]c(C)c(CCCN4CCOCC4)c2C)C(=O)N3)c1
Yield: 7 %

Procedure:
The title compound (7% yield) was prepared from 4-chloro-5-[3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrol-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one and 3-ethynylaniline according to the procedure described for Example 12 without the conversion to HCl salt. MS 483.3 [M++1].
Reaction SMILES: [N:1]#[C:2]Br.[NH:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]([NH:15][NH2:16])=[O:14])=[CH:5]1.C(=O)([O-])O.[Na+]>O.CN(C=O)C>[NH:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[O:14][C:2]([NH2:1])=[N:16][N:15]=2)=[CH:5]1
Reactant: N#CBr
Reactant: NNC(=O)c1c[nH]c2ncccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nnc(-c2c[nH]c3ncccc23)o1
Yield: 78.8 %

Procedure:
360.8 mg of cyanogen bromide is added dropwise with stirring to a mixture of 500 mg of 1-(1H-pyrrolo[2,3-b]pyridine-3-carbohydrazide, 1.192 g of sodium hydrogencarbonate in 50 ml of water and 5 ml of DMF. The reaction mixture starts to foam, and a fine precipitate forms. This is filtered off with suction after 2 hours and dried, giving 450 mg of 5-(1H-pyrrolo[2,3-b]-pyridin-3-yl)-1,3,4-oxadiazol-2-ylamine (yield: 78.8%); MS-FAB (M+H+)=202.2; Rf (polar method): 1.00 min;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:10][CH:11]1[NH:13][CH2:12]1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][CH2:10][CH:11]([NH2:13])[CH3:12]
Reactant: Cc1cc(C)cc(O)c1
Reactant: CC1CN1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)cc(OCC(C)N)c1
Reaction time: 3 h
Yield: 32.5 %

Procedure:
The reaction according to the method described in a known literature [J. Am. Chem. Soc., 73 2584 (1951)] was carried out by the use of the same starting materials as those used in Example 17. That is, 24.4 g (0.20 mol) of 3,5-dimethylphenol was dissolved in 100 ml of chloroform, and the resultant mixture was refluxed under atmospheric pressure. A solution prepared by dissolving 3.8 g (0.067 mol) of propyleneimine in 20 ml of chloroform was added dropwise over 30 minutes, and the refluxing was further continued for 3 hours. The reaction product was subjected to extraction with 50 ml of 5% hydrochloric acid three times, and then the water layer of the product was neutralized with sodium hydroxide. The water layer was subjected to extraction with 50 ml of ether three times. The ether layer was washed with water and dried. Then, ether was distilled off, and the residue was distilled under reduced pressure to give 3.9 g of 1-(3,5-dimethylphenoxy)- 2-propylamine. Its yield was as low as 33%.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH3:10]I>>[CH3:10][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: CI
Product: CN1C(=O)NC(C)(C)C1=O

Procedure:
Using 5,5-dimethylimidazolidine-2,4-dione (1.00 g) and methyl iodide (0.53 mL) and by the reaction and treatment in the same manner as in Preparation Example 214, the title compound (1.03 g) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:19])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([Cl:18])[N:6]=2.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][C:29]([CH3:34])([CH3:33])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:2][C:3]2[N:4]([CH3:19])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([Cl:18])[N:6]=3)[C:29]([CH3:34])([CH3:33])[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Cn1c(CBr)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(CN2CCN(C(=O)OC(C)(C)C)CC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.9 %

Procedure:
A mixture of 8-bromomethyl-2-chloro-9-methyl-6-morpholin-4-yl-9H-purine (400 mg, 1.16 mmol), 3,3-dimethylpiperazine-1-carboxylic acid tert-butyl ester (250 mg, 1.17 mmol) and K2CO3 (176 mg, 1.28 mmol) in DMF (20 mL) was allowed to stir at r.t. for 16 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound (150 mg, 27%). 1H NMR (CDCl3, 400 MHz): δ 4.26 (4 H, brd s), 3.82-3.80 (9 H, m), 3.33 (2 H, brd s), 3.22 (2 H, brd s), 2.42-2.35 (2 H, m), 1.45 (9 H, s), 1.15 (6 H, s).